Citation: 

Fava VM, Schurr E. 21 September 2016, posting date. The complexity of the host genetic contribution to the human response to Mycobacterium lepraeIn Scollard DM, Gillis TP (ed), International textbook of leprosy. www.internationaltextbookofleprosy.org.

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No funding has been declared.
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No competing interests have been stated.

Introduction

Prior to the advent of microbiology, infectious diseases had no known etiology and therefore were often qualified as hereditary. With the advances in medicine, the key role of microbes in the etiology of infectious diseases was recognized. However, with the description of latent infections it became clear that in addition to pathogens, unknown host factors are required to establish disease. We know now that a substantial proportion of factors that make a host vulnerable to infectious disease are germline encoded. While much remains to be discovered, in leprosy the role of host genetic factors in disease susceptibility has made remarkable advances over the last 15 years. Genetic epidemiology methods ranging from twin studies to genome wide association studies (GWAS) have helped to unravel the host genetic contribution to leprosy susceptibility. Variants of genes involved in both innate and adaptive immune responses have been identified as key mediators in different stages of leprosy pathogenesis. Here, we present a summary of genetic mediators for leprosy and leprosy-related disease manifestations that have been implicated in susceptibility in multiple studies.

Leprosy: An Infectious Disease, a Hereditary Disease, or Both?

Leprosy is a dermato-neurological infectious disease caused by the intracellular parasite Mycobacterium leprae [1]. However, this characterization was not always the consensus among scientists. In the mid-nineteenth century, it was believed that leprosy was in truth a hereditary disease that could only be transmitted among family members. The Norwegian physician Daniel Cornelius Danielssen proposed the heredity concept of leprosy in 1857 in the book entitled Om spedalskhed (On leprosy). Danielssen implied that leprosy was a congenital dysplasia not caused by a pathogen [2]. It was Danielssen’s son-in-law Gerhard Armauer Hansen who identified M. leprae as the cause of leprosy in 1873 [1]. Leprosy is indeed an infectious disease; however, Danielssen also was correct regarding the role of heredity in leprosy. Heredity is an allusion to a genetic component impacting disease outcome. Human genetics was still in its infancy in Danielssen’s era, and the limited knowledge about the genetic control of complex traits severely hampered studies of heredity in leprosy [3]. It was only in the 1960s that epidemiological studies accumulated convincing data in support of a genetic component in leprosy susceptibility.

The heredity in leprosy supported by genetic epidemiology data

Prior to the advent of DNA-based genetics, epidemiological studies based on observational data and prediction models inferred that there was a genetic component in susceptibility to leprosy. For example, twin studies showed a strong contribution of host genetics to leprosy per se susceptibility and clinical leprosy subtype [4], [5]. In two independent twin studies, concordance of leprosy in monozygotic twins was 82.6% and 59.7%, while concordance in dizygotic twins was 16.7% and 20.0%, respectively [4], [5]. Among the leprosy-affected pairs of monozygotic twins, concordance for leprosy subtype was larger than 85% in both studies [4], [5]. Since monozygotic twins share the same germline, while dizygotic twins share only a proportion of their genetic material, these results provided strong support for an important role of host genetics in leprosy. Similarly, analysis of the segregation pattern of leprosy in multiplex families of distinct ethnic background including Caribbean, Brazilian, Vietnamese, and Thai inferred that a genetic component in leprosy susceptibility existed. This approach, termed complex segregation analysis (CSA), estimates the contribution of environmental, familial, and genetic factors that best explain the disease segregation pattern. If a genetic component is inferred, the model of inheritance, the penetrance, and the frequency of the genetic component can also be estimated. Most of the CSA consistently detected evidence of a major gene impacting on leprosy susceptibility with a background of additional genes with milder effects, although there was no consensus for the mode of major gene inheritance [6], [7], [8], [9], [10], [11], [12], [13]. Twin studies and CSA provided the rationale for molecular investigations in search of the genetic component in leprosy.

Genetic Control of Host Responses to M. leprae at Different Stages of Leprosy Pathogenesis

Leprosy is a complex disease with multiple factors influencing the outcome of exposure to M. leprae. Undoubtedly, intensity and length of exposure to M. leprae are central for leprosy pathogenesis, albeit little is known about this key step due to our inability to cultivate M. leprae in vitro. Following exposure, a combination of environmental and host genetic factors discriminates those who will become infected without clinical signs from those who will progress to clinical disease and commits a subset of patients to adverse immune reactions. In a scenario where environmental factors intervene at all phases of the human/M. leprae interaction, the impact of host genetics can be dissected in different stages (Figure 1).

Innate resistance

The majority of people exposed to M. leprae are innately resistant to clinical leprosy. This conclusion was derived from epidemiological studies in which more than 90% of household contacts of multibacillary leprosy cases did not progress to clinical disease (Figure 1) [14], [15], [16]. However, in contrast to tuberculosis (TB), where latent infection is deduced from a positive Tuberculin Skin Test (TST) or by Interferon Gamma Release Assay (IGRA), in leprosy no biological assay for latent infection is available. Therefore, among those who are resistant to clinical disease it is not possible to identify those who are susceptible to infection, and it is not known if humans do become latently infected with M. leprae. However, it is likely that innate resistance to infection may account for much of the genetic contribution to leprosy. Possible mechanisms of innate resistance to infection in leprosy are unknown but may represent resistance to host cell infection or rapid clearance of phagocytosed bacilli before the establishment of latent infection (Figure 1). Alternatively, it is possible that a large number of exposed humans are latently infected with M. leprae but only few ever progress to clinical disease. There are several notable examples of the inability to invade host cells in other infectious diseases. In HIV, a deletion in the CCR5 gene causes a knockout and obstructs the route of viral invasion [17]. In malaria, cell-specific knockouts for the Duffy blood group receptors (FyFy) mediate innate resistance to Plasmodium vivax infection [18], [19]. The possibility that infection resistance is mediated by early bacterial clearance or the presence of adverse conditions that lead to a decreased ability of parasite survival is supported by TB and HIV infection (Figure 1). In HIV, for example, individual carriers of a combination of KIRDL1/HLA-B*57 present superior and earlier viral clearance [20]. In malaria, patients heterozygous for the sickle-cell mutation present premature erytosis of plasmodium infected cells and the accelerated apoptosis delays parasitemia, favoring bacterial clearance [21].

FIG8_1_1.png

FIG 1 The stages of leprosy pathogenesis and the corresponding phenotypes employed for genetic studies.

Genetic factor may contribute to different stages of leprosy pathogenesis ranging from innate infection resistance to variants modulating host pathological immune responses. Given sufficient exposure to M. leprae, an individual may progress from exposure to infection or present an early resistance phenotype. Innate resistance may be defined by a genetic profile that may impair the ability of bacterial invasion or favor a more efficient bacterial clearance. Persons who are destined to develop clinical leprosy will advance to a pre-clinical stage common to all forms of leprosy that is termed leprosy per se. The genetic factors that contribute to leprosy per se may be different from those that impact the clinical immunological response to M. leprae. Patients with clinical forms of leprosy display a variety of immune responses ranging from a strong cellular immune response (tuberculoid) to a strong humoral immune response (lepromatous). Yet, the majority of leprosy patients display a balance of cellular and humoral responses and are classified as borderline leprosy cases. The specifics of the host immune response are controlled by host genetic variants that modulate the cytokine profile in responses to M. leprae. Certain leprosy patients may experience excessive inflammatory responses known as leprosy reactions. There are two major types of leprosy reaction: Type-1 reaction and Type-2 reaction. Both are characterized by a delayed activation or exacerbation of cellular immune responses which are at least in part controlled by host genetic factors.

Clinical disease and leprosy subtypes

Leprosy per se, which is leprosy irrespective of the clinical subtype, is a widely used phenotype (Figure 1). It is not known what stage of leprosy pathogenesis is captured by the per se phenotype. Given that all clinical subtypes are governed by the per se definition, the most parsimonious explanation is that leprosy per se reflects an early stage of non-symptomatic pathogenesis. If this explanation is correct, leprosy per se genes and mechanisms would determine the transition from a latent infection to clinical disease (Figure 1). This interpretation is supported by reports of high rates of self-healing leprosy in the absence of antibiotic intervention (Figure 1) [22], [23]. Self-healing is most pronounced if clinical symptoms are mild and has been reported to occur in up to 70% of non-lepromatous cases, demonstrating the continuum of leprosy pathogenesis [22], [23], [24]. Hence, per-se genes likely impact on different stages of latent infection and, as the infection progresses and manifests itself as clinical disease, different sets of genes impact on leprosy subtype. Patients with self-healing—before or after the emergence of clinical symptoms—could be a reservoir for ongoing transmission of leprosy. However, independently of late bacterial clearance or not, patients suffering from leprosy per se share a common genetic component that is fundamental for the clinical manifestation of disease (Figure 1).

Leprosy presents a good opportunity to evaluate the host genetic contribution to clinical symptoms of an infectious disease, since M. leprae is essentially monoclonal (Figure 1) [25]. Hence, susceptibility is mainly influenced by environmental factors and by host genetics. Following the first signs of clinical infection, each leprosy patient will develop a particular adaptive immune response. Some patients have the capability to develop granuloma and contain the infection. These patients are characterized as tuberculoid and present a cytokine profile of an effective cellular immune response (Figure 1). On the opposite side of the spectrum are patients with lepromatous leprosy, who are permissive for extensive bacillary replication. These patients develop a humoral immune response that is not effective for bacterial containment (Figure 1). The majority of leprosy cases will present a balance between cellular and humoral immune responses and are commonly referred to as borderline leprosy patients (Figure 1). The host genetic control of different leprosy subtypes is a largely understudied area of leprosy pathogenesis [26].

Adverse immune responses

An interesting aspect of leprosy pathogenesis is that protective immune reactions can be clearly separated from those that cause host tissue damage. In leprosy, up to 50% of patients develop excessive inflammatory responses know as leprosy reactions (LR) [27]. LR afflict leprosy patients during the course of the disease or even after microbiological cure and are a major cause of tissue damage and disabilities [28], [29]. There are two major types of LR: the type-1 reactions (T1R) and the type-2 reactions (T2R). T1R are more frequent and mostly affect individuals classified in the borderline spectrum of leprosy [28]. T2R affect only patients of the lepromatous and borderline subtype who display strong humoral immune responses. LR are characterized by a shift towards a cell-mediated immune response with a strong and rapid boost in TNF and IFN-γ production [30]. LR present a unique opportunity to study the modulatory factors in the host immune response to pathogens. A dysregulated pro-inflammatory response to a pathogen is an immune characteristic in Crohn’s disease (CD) and a main cause of tissue damage in dengue [31], [32], [33], [34].

Genetic Approaches Applied to the Study of Human Susceptibility to Leprosy

Different approaches have been applied to identify the host genetic factors uncovered by epidemiological studies and CSA. From a candidate gene approach to hypothesis-free genome wide testing, multiple factors have been connected with clinical disease or subtypes. The research efforts since the beginning of the century have resulted in a better picture of the host contribution to disease outcome (Figure 2). Nevertheless, we are still far from explaining the strong genetic component reported by twin studies.

Candidate gene approaches

The candidate gene approach was the first strategy used to describe the molecular identity of the genetic component in leprosy. It is a powerful strategy if the biological process contributing to disease pathogenesis is well known. Focusing on genes most likely to be relevant to a disease reduces the risk of false positive findings due to multiple comparisons. There are several examples in leprosy in which candidate gene associations have been successfully replicated in independent populations.

Studies of the ABO system

The first reports of a specific gene associated with leprosy pathogenesis focused on the ABO blood type, with many studies performed since the 1920s [35], [36]. The ABO gene is located on chromosome region 9q34.2, where amino acid changes in exons 6 and 7 differentiate the AB blood groups while the O blood group represents a frame shift mutation. Individual studies of the ABO system in leprosy have reported no correlation of blood types and disease susceptibility [37], [38], [39]. In 1967, compiled information of 27 independent population from 14 countries indicated no correlation of ABO and Rh with leprosy per se or its clinical forms [35]. Subsequent work employing an alternative statistical approach and increased sample size detected a loose association between leprosy per se and ABO blood groups [36]. Individuals with the A blood type were more susceptible to leprosy per se in a dominant model than the B or O blood types. Moreover, the O blood type was more frequent among lepromatous cases [36], [40], [41], [42]. The effect of the ABO system in leprosy is likely very subtle, since almost half a million samples were needed to capture the weak association signal with the disease. Therefore, the ABO gene explains very little of the genetic susceptibility to leprosy.

FIG8_1_2_H.png

The Toll-like receptor family

The Toll-like receptors (TLRs) are an important class of pattern recognition receptors (PRP) involved in the host defense against a broad spectrum of pathogens [43]. In leprosy, cell surface expressed heterodimers of TLR1, TLR2, and TLR6 mediate cell activation by recognizing M. leprae antigen [44], [45]. Two amino acid substitutions in TLR1, I602S (rs5743618) and N248S (rs4833095), were associated with leprosy phenotypes [46], [47], [48]. The 602S allele of TLR1 was associated with protection for leprosy per se in Indian and Turkish populations, but this association was not validated in Brazilian and Chinese populations [46], [47], [49]. Moreover, the 602S allele was associated with protection from T1R in Nepalese [48]. TLR1 carrying the 602S allele inhibits surface trafficking of the TLR1/TLR2 dimer, resulting in hypo-responsiveness to Mycobacteria [50], [51]. The 248S allele of TLR1 was associated with susceptibility to leprosy per se in independent samples from Brazil and a sample from Bangladesh [47], [52]. The S248 allele alters the electrostatic surface potential of TLR1, influencing protein interaction affinity [47]. Both I602S and S248N polymorphisms have been associated with susceptibility to intracellular pathogens, suggesting an important role for these two variants that is not exclusive to leprosy [53], [54].

Variants in TLR2 and TLR4 have been associated with leprosy phenotypes. A synonymous amino acid substitution N299N (rs3804099) and a microsatellite in the TLR2 gene region were associated with T1R in Ethiopians [55]. In leprosy lesions, TLR2 was shown to mediate in vivo apoptosis of Schwann cells contributing to nerve injury, which is a hallmark of T1R [56]. TLR4 is mostly known as a lipopolysaccharides (LPS) receptor but it can also bind other microbial molecules. Two TLR4 missense polymorphisms, D299G (rs4986790) and T399I (rs4986791), were associated with leprosy per se [57], [58]. The 299G and 399I alleles of TLR4 were risk factors for leprosy per se in Ethiopians and Indians [57], [58].

Interleukins

Interleukins are secreted by leukocytes and play an important role in cell-cell communication and in the modulation of host defense against infection [59]. In leprosy, interleukins are essential for an effective cellular immune response and to develop infectious granuloma to contain M. leprae dissemination [60]. A key modulatory cytokine in the cellular immune response is IL12. The IL12 cytokine is formed by two subunits, 12p35 and 12p40, that are encoded by the IL12A and IL12B genes, respectively. IL12 exerts its function through the interaction with its receptor, which consists of two subunits encoded by the IL12RB1 and IL12RB2 genes. The IL12B gene is expressed by macrophages to induce the differentiation of Th1 cells [61]. Variants near the IL12B gene have been associated with leprosy phenotypes in multiple populations. A variant in the IL12B 3’ UTR was associated with a risk for leprosy per se and TB in India and with leprosy subtypes in Mexico [62], [63]. Common variants located in the vicinity of the IL12B gene were also associated with leprosy per se and multibacillary leprosy in Indian and Chinese patients [64], [65], [66]. Variants in the promoter region of the IL12RB2 gene were associated with a leprosy subtype in a Japanese population but not in a Brazilian study [67], [68]. No association was reported for the IL12RB1 gene in leprosy [69]. The 12p40 subunit is part of IL23 and therefore interacts with the IL23 receptor. Copy number variants in the IL23R gene region have been shown to be associated with a leprosy clinical subtype [65].

IL10 is the most studied interleukin in leprosy [70]. IL10 inhibits the production of pro-inflammatory cytokines by effector cells such as macrophages and Th1 cells. IL10 activates the humoral immune response and induces antibody production in leprosy patients. The SNP rs1800890 located at -819 bases upstream to the IL10 transcription starting site (TSS) was associated with leprosy per se in multiple populations [71]. The most common association with leprosy per se and clinical subtypes was the haplotype containing the three TSS polymorphisms at positions -1082 (1800896), -819 (rs1800871), and -592 (rs1800872) in Brazilian, Colombian, and Indian populations [71], [72], [73], [74], [75]. A recent meta-analysis of ten studies of the IL10 gene in leprosy phenotypes confirmed the association of the TSS promoter variants with leprosy per se [70]. Interestingly, a meta-analysis of TB cases also reported the haplotype of the -819 and -592 SNPs associated with susceptibility to TB in the same direction as observed in leprosy per se. However, the association was limited to individuals with an Asian ethnic background [76], [77]. An IL10 promoter haplotype—which included SNPs associated with leprosy—impacted on IL10 expression, providing a possible mechanism for the modulation of IL10 function by genetic risk factors [78].

Other associations of interleukin genes have been reported for leprosy phenotypes. A study in an Indian population detected an association of the IL17F missense H161R polymorphism (rs763780) with leprosy per se [79]. However, a subsequent study in a Mexican population failed to validate the IL17F association [80]. A Brazilian study focused on LR showed the independent association of two IL6 polymorphisms with T2R [81]. The IL6 variants -174 (rs1800795) and +6804 (rs2069840) associated with T2R influenced IL6 gene expression and were correlated with circulation levels of IL6, respectively [81], [82]. Variants near the IL18 receptors have been associated with leprosy per se in Chinese patients [66]. The IL18RAP and IL18R1 genes are clustered with the IL1RL1 gene on chromosomal region 2q12.1. The associated signal observed in the Chinese population extended across these three genes and did not differentiate which gene(s) in the locus was (were) the cause of association with leprosy per se.

The lectin pathway

The mannose binding lectin (MBL) is involved in pathogen recognition and clearance by the innate immune response [83]. A haplotype overlapping the MBL2 gene (encoding MBL) was associated with susceptibility to leprosy per se and clinical subtypes in Brazilian and Chinese populations [84], [85]. Moreover, association of the missense G54D polymorphism (rs1800450) in MBL2 exon 1 was validated for a leprosy clinical subtype in a population sample from Nepal but not in an independent Brazilian sample [86], [87]. MBL activates the complement pathway by co-opting MBL-associated serine proteases (MASPs) [88]. Two genes, MASP1 and MASP2, encode MASP proteins. Five polymorphisms near the MASP2 gene were associated with susceptibility to leprosy per se in a Brazilian sample [89]. The complex formed by MBL with MASP1 and MASP2 can cleave complement proteins C2 and C4 and induce pathogen opsonisation [88]. Alleles of the C4B gene were associated with lepromatous leprosy and susceptibility to T2R [90]. The ficulin-2 protein encoded by the FCN2 gene is a complement activating lectin that forms a complex with MASPs [91]. Variants near the promoter region of the FCN2 gene have been associated with leprosy per se and clinical subtypes in Brazilian and Chinese populations [85], [92]. Finally, variants near the CFH gene, encoding the complement regulating factor H, were associated with leprosy in a Chinese population [85]. Taken together, these results demonstrate the participation of the lectin pathway in leprosy per se and clinical subtype susceptibility.

Additional candidate genes

The active form of vitamin D modulates innate and adaptive immune responses [93]. The VDR gene encodes the vitamin D receptor and is expressed by macrophages in response to TLR1/2 stimulation [94]. Two functional VDR polymorphisms were associated with leprosy phenotypes. A VDR synonymous SNP I352I (rs731236 alias Taq1) located in a splicing site was associated with leprosy subtypes and granuloma formation [95], [96]. A missense M1T polymorphism (rs2228570 alias Fok1) at the first amino acid of a VDR isoform showed a trend for association with T1R [86]. Interestingly, VDR expression has been associated with progression to leprosy reaction [97]. A forward genetic screen in zebrafish identified the lta4h gene as a hyper susceptibility factor [98]. Two non-coding SNPs (rs1978331 and rs2660898) at the human LTA4H gene were associated with multibacillary leprosy in a population from Nepal [98]. Due to the role of beta-defensin 1 in epithelial innate immunity, a study evaluated the association of the DEFB1 gene in leprosy. The DEFB1 5’ UTR variant rs1800972 was associated with leprosy per se and a clinical subtype in a Mexican population [99]. M. leprae was shown to invade myelinating Schwann cells by recognizing and binding laminin alpha 2, which in humans is encoded by the LAMA2 gene [100]. A missense V2587A variant (rs2229848) of LAMA2 was associated with a leprosy subtype in a Brazilian population [101]. Type II interferon (IFN-γ) is a critical cytokine of the innate and adaptive immune response against intracellular pathogens [102]. A promoter polymorphism at position +874 (rs2430561) of the IFNG gene was associated with leprosy per se in independent Brazilian populations [103], [104]. A lower expression of BCL10 was reported in lesions of leprosy patients when compared to healthy controls [105], [106]. The SNP (rs2735591) near the BCL10 gene was associated with leprosy per se in three independent population samples from China [106]. A common outcome in leprosy is nerve injury, which frequently leads to permanent disabilities [27]. The NINJURIN1 protein encoded by the NINJ1 gene has been implicated in the cellular repair mechanism in Schwann cells after nerve injury [107]. A NINJ1 missense A110D polymorphism (rs2275848) has been associated with protection from disabilities in two independent Brazilian samples [108], [109].

A newly recognized class of endogenous controllers of gene expression are named microRNAs (miRNAs). Alterations in miRNAs structure may influence their ability to exert their function properly. In leprosy, the polymorphism rs2910164 in the seed region of Pre-miR-146a encoded by the MIR146A gene has been associated with susceptibility to leprosy per se in independent populations from Brazil [110]. Functionally, it was shown that M. leprae induced MIR146A expression in THP-1 cells. Moreover, nerve biopsies of leprosy cases exhibited a higher expression of MIR146A compared to nerve biopsies from pathologies not related to leprosy [110]. However, there was no evidence of a direct impact of the leprosy per se risk variant on MIR146A activity. An independent study implicated microRNA-21 in a clinical subtype of leprosy via the vitamin D antimicrobial pathway [111].

Summary of candidate genes studies

Resistance or susceptibility to M. leprae invasion relies on different stages of host immunity. The first line of defense against external pathogens is provided by sentinel cells, such as macrophages and dendritic cells, of the innate immune response. These cells express PRP that belong to the toll-like receptor family and components of lectin pathways. Candidate gene approaches have helped to identify key genes in this early phase of host-pathogen interaction. Associations of TLR1, MBL2, and FCN2 with leprosy have been confirmed in independent populations, suggesting that alterations in these genes are critical to facilitate M. leprae invasion. In response to pathogen recognition, host sentinel cells kick-up the production of interleukins. Indeed, candidate gene approaches showed that the IL23R, IL12B, and IL17F genes are associated with leprosy susceptibility. These genes are important regulators that direct the adaptive immune response towards Th1 and Th17 cells. Patients with an efficient cellular immune response are more likely to contain M. leprae dissemination.

Genome wide linkage approaches to gene discovery in leprosy

Genome wide linkage studies (GWLS) are hypothesis-free analytical approaches that investigate the non-random transmission of a genomic region among affected individuals in a family-based approach. A series of GWLS have identified host genomic regions as likely locations of leprosy susceptibility genes. However, among the chromosomal regions identified by GWLS, only a few have led to the identification of leprosy susceptibility genes via the fine-mapping of the linked regions.

Region 2q35

The murine Slc11a1 (alias Nramp1) gene located on chromosome 1 in mice controls susceptibility to a variety of intracellular pathogens [112], [113], [114], [115]. The human SLC11A1 gene has been implicated in leprosy risk by multiple studies. An extended haplotype overlapping the SLC11A1 gene was linked with leprosy per se in Vietnamese patients [116]. A SNP located in intron 4 (rs3731865) was associated with paucibacillary leprosy in Indonesia [117]. Heterozygosity for a 3’ untranslated insertion/deletion of the SLC11A1 gene was a risk factor for multibacillary leprosy in Mali [118]. The SLC11A1 exon 3 UTR variant -274C/T (rs2276631) was reported as associated with both T1R and T2R with opposite risk effects in Brazilians [119]. Interestingly, two GWLS in Vietnamese samples linked chromosomal region 2q35, which in humans harbors the SLC11A1 gene, with the capacity to mount an in vivo granulomatous response to lepromin (a so-called Mitsuda reaction) [120], [121]. Subsequent studies identified an SLC11A1 promoter variant in association with the extent of the Mitsuda reaction in Brazilians [122].

Region 10p13

The first GWLS in leprosy described the chromosomal region 10p13 in linkage with paucibacillary leprosy in an Indian sample of multiplex families [123]. A subsequent GWLS in Vietnamese families confirmed the initial report [124]. The linked chromosomal segment harbored the MRC1 gene. This gene encodes a mannose receptor present in macrophages and immature dendritic cells, where it is involved in phagocytosis of bacteria. Hence, the MRC1 gene was tested as a positional candidate leprosy gene. A SNP G396S (rs1926736) in exon 7 of the MRC1 gene was found to be associated with leprosy per se and multibacillary leprosy in Vietnamese and Brazilian, but not Chinese, patients [125], [126]. Two non-coding variants of MRC1 located in intron 5 and intron 7 were associated with paucibacillary leprosy in Chinese but not Vietnamese patients [126], [127]. The differences between the risk markers across studies suggest that more than one variant of MRC1 may play a role in leprosy pathogenesis. Subsequently, high density association mapping of the 10p13 region evaluated 39 genes for association with leprosy per se and clinical manifestation of the disease [127]. In these experiments, the Cubin (CUBN) and Nebulette (NEBL) genes were found to be associated with multibacillary leprosy in two independent Vietnamese populations [127]. Hence, contrary to expectations, the majority of associations of genetic polymorphisms in the 10p13 region were either with leprosy per se or multibacillary leprosy, but not with paucibacillary leprosy. The reason(s) for this unexpected observation is (are) not known.

Region 6q25-q26

A second linkage hit for leprosy was located on chromosome region 6q25-q26 [124]. High resolution association mapping of 43 genes located in the 6q25-q26 locus pointed to the co-regulatory region of the PARK2 and PACRG genes as the main association signal with leprosy per se [128]. The association of PARK2/PACRG variants was confirmed in independent samples from Vietnam, India, and Brazil [64], [128], [129], [130], [131]. Specifically, the PARK2 promoter variant rs9356058 was shown to be a global risk factor in leprosy per se [130]. A second independent signal of association in the PARK2/PACRG locus was represented by the SNP rs10400079 but was only observed in early onset cases of leprosy [130]. Interestingly, the same polymorphisms associated with susceptibility to leprosy per se were also risk factors for infection with Salmonella typhi and S. paratyphi A in Indonesia [132]. PARK2 is a key regulatory element in the production of IL6 and CCL2 by human macrophages, and stimulation of whole blood with M. leprae sonicate triggers the transcriptional activation of both immune mediators [133]. Interestingly, in the latter assay, transcript levels of both IL6 and CCL2 were significantly correlated with the presence or absence of PARK2 leprosy susceptibility alleles [130], [133]. PARK2 encodes the E3-ligase Parkin, which is the cause of a small number of cases with early onset Parkinson’s disease [134], [135]. Parkin ubiquitinates phagosomes containing an intracellular macrophage pathogen, which destines the tagged vesicles and their microbial content for destruction by autophagy [136], [137], [138]. While these findings identify PARK2 as an effector gene of innate immunity, the mechanistic details of how genetic leprosy risk variants modulate the Parkin function and its microbicidal activity are unknown.

Region 6p21

Independent studies have reported a linkage peak for leprosy per se on chromosome region 6p21.3 in the human leukocyte antigen (HLA) complex [124], [139], [140]. High-resolution linkage disequilibrium mapping of the 6p21.3 locus led to the identification of the LTA gene in HLA class III and the HLA-C gene in HLA class I as independent signals of association with leprosy per se [141], [142]. Lymphotoxin alpha (LTA) is an important mediator for lymphocytes recruitment in response to infection [143], [144]. The LTA +80 SNP (rs2239704) was identified as a risk factor for leprosy per se in India, Vietnam, and Brazil, with a stronger risk effect before the age of 25 [141]. The leprosy per se risk allele “A” of LTA +80 disrupts an ABF1 binding site, resulting in lower LTA expression [145]. Fine mapping of the HLA class I locus identified an SNP variant tagging the HLA-C*15:05 allele in association with leprosy per se in two population samples, one from Vietnam and one from India [142]. The variants associated with leprosy correlated with higher HLA-C expression [142].

Candidate gene approaches have long reported genes in the HLA region associated with leprosy [146]. In the HLA class III region, the promoter polymorphisms located at -238 (rs361525), -308 (rs1800629), and -1031 (rs1799964) of the TNF gene were associated with leprosy per se and/or a clinical subtype in different ethnic groups [11], [139], [147], [148], [149], [150], [151]. The TNF gene encodes a potent inflammatory mediator that is essential for granuloma formation in response to Mycobacteria [152]. Moreover, variants tagging the BAT1, NFKB1L1, LTA, TNF, and BTNL2 genes were associated with leprosy per se in unrelated samples from India [153]. In the HLA class I region, the truncated allele *5A5.1 of the MICA gene was associated with leprosy per se in India [154]. The HLA-B*13:01 allele was identified as a risk factor for Dapsone hypersensitivity syndrome, a condition that affects 1% to 1.5% of leprosy cases with an estimated 10% chance of mortality [155]. In addition, a combination of killer cell immunoglobulin receptor (KIR) and its respective HLA class I ligands was associated with leprosy per se in a population from Brazil [156], [157]. In the HLA class II region, different alleles of the HLA-DRB1 gene were identified as risk factors for leprosy per se and clinical subtypes [46], [158], [159], [160], [161], [162], [163], [164]. The HLA class II molecules are expressed on antigen-presenting cells (APC) such as dendritic cells and macrophages, and they play an important role in the communication between APC and CD4+ T-cells during the early phase of the inflammatory response [165]. Taken together, the HLA locus is the genomic region with the highest concentration of leprosy risk factors.

Additional chromosomal regions

Additional chromosomal regions have been shown to be linked to leprosy phenotypes by independent GWLS. The chromosome regions 20p13 and 20p12 were linked to leprosy per se in Brazilian and Indian families, respectively [140], [166]. Chromosome region 17q11-q21 was linked to leprosy per se in Brazilian patients, while the region 17q21-q25 was linked to Mitsuda reactivity in Vietnamese families [121], [167]. The ERRB2 gene located on chromosome region 17q12 has been selected as a positional candidate gene for leprosy per se in the 17q11-q21 locus. The ERBB2 gene encodes a surface receptor in the Schwann cell that is used by M. leprae for cellular invasion [168]. ERRB2 alleles were associated with susceptibility to leprosy per se in some, but not all, Brazilian samples [169], [170]. A GWLS reported a linkage hit for leprosy per se on chromosome regions 2p14, 8q24, 4q22, and 16q24 in Chinese families [171]. The leprosy susceptibility genes underlying these linkage hits are not known.

Summary of linkage studies

Linkage studies have been successfully used in the analysis of host susceptibility to leprosy. Linkage peaks led to the subsequent identification of two of the most replicated associations with leprosy. A linkage peak on chromosome region 6q25 led to the identification of the PARK2 gene as the first gene identified by positional cloning in a common infectious disease. The linkage peak on the 6p21.3 chromosomal region led to the identification of variants near the HLA-C, LTA, and HLA-DR / HLA-DQ genes as leprosy risk factors. Interestingly, these findings were later confirmed by GWAS. While linkage analysis was superseded by GWAS, with the advent of next generation sequencing, linkage analysis is now increasingly used to identify rare variants causally associated with disease susceptibility.

The genome wide association approach

GWAS in infectious diseases have not been as successful as in other phenotypes [172]. Compared to other common infectious diseases, leprosy has the advantage that the genetic variability of the M. leprae is extremely low and essentially worldwide cases of leprosy are infected by a monoclonal bacterium [25], [173]. To what extent the monoclonality of M. leprae underlies the success in mapping host genetics factors in leprosy is not known. The first GWAS performed in leprosy reported six genomic loci near the HLA-DR-DQ, RIPK2, TNFSF15, LRRK2, CCDC122/LACC1, and NOD2 genes associated with leprosy per se in a Chinese population [174]. The associations of HLA-DR alleles with leprosy had been well documented previously; however, the other GWAS loci pointed to new susceptibility genes. Studies in population samples from Vietnam, India, West-Africa, and Brazil validated the association of variants near the RIPK2, CCDC122/LACC1, and NOD2 genes with leprosy per se, supporting the robustness of the GWAS results in leprosy [175], [176], [177], [178]. The LRRK2 gene was tagged by a suggestive hit in the initial GWAS and was not consistently associated with leprosy per se or a clinical subtype in independent populations [175], [176], [179], [180]. Conversely, the association of the TNFSF15 locus with leprosy per se was not replicated in follow-up studies [175], [176], [177]. Unexpectedly, variants near the TNFSF15 region were associated with T1R but not leprosy per se in a Vietnamese sample [181]. Moreover, the TNFSF15 variants belonged to a larger group of highly correlated SNP that extended from the TNSF15 locus to the neighboring TNFSF8 gene. The role of TNFSF8 in T1R was further strengthened by the observation that all of the T1R SNPs, including those located within TNFSF15, were expression quantitative trait loci (eQTL) for TNFSF8 [181]. The detection of eQTL signifies that the genotypic constellation at a given set of SNPs is correlated with the expression levels of a given gene. The variants overlapping TNFSF8 were validated for the association with T1R in independent Brazilian samples [181]. A similar situation was observed for the LRRK2 gene. In a Vietnamese sample, a missense M2397T polymorphism (rs3761863) previously reported as a leprosy per se risk factor was significantly associated with T1R but not leprosy per se [182]. Most of the leprosy susceptibility genes identified by the GWAS also were associated with inflammatory bowel disease (IBD), suggesting an overlap in the pathogenesis between the two diseases [183]. However, the demonstration that a subset of these genes predisposes to T1R rather than leprosy per se suggested that the overlap between IBD and leprosy not only may be found in the response to mycobacteria but also may be an innate predisposition of some hosts to undergo excessive inflammatory responses that lead to tissue damage.

The number of subjects enrolled in the first leprosy GWAS was expanded twice [49], [184]. The first expansion resulted in the discovery of two additional leprosy per se loci near the IL23R and RAB32 genes, respectively [49]. The variants in the IL23R region were validated in a Vietnamese population [185]. An association of the RAB32 variants and leprosy per se was also observed in a Vietnamese population. However, the most significant SNPs in the Vietnamese sample were not the same as those observed in the Chinese GWAS, suggesting that the true causal variant remains to be established [49], [185]. Six additional GWAS loci were associated with leprosy per se in the second subject expansion of the Chinese GWAS population [184]. However, these findings are yet to be validated. Interestingly, one of the new GWAS loci near the COX4I1 gene falls within a previous linkage peak for leprosy per se on chromosome region 16q24.1 [171].

Conclusion

Studies of the host genetic component in leprosy have discovered new genes and candidate pathways that contribute to disease pathogenesis. Many of the findings were confirmed by studies in ethnically distinct populations, thereby demonstrating the fundamental importance for leprosy susceptibility of the pathways tagged by host genetic studies. Despite the progress made in deciphering the contribution of host genetic variants to leprosy pathogenesis, a comprehensive picture has not yet emerged. Notably, the lack of diagnostics for latent infection and our continued ignorance of the mode of dissemination of M. leprae prevent a study of the genetic controllers of these important stages of leprosy pathogenesis. Following the impressive success in identifying genetic modulators of leprosy susceptibility, additional contributions will depend on the study of more refined phenotypes such as early onset cases or subgroups of the generalized leprosy per se phenotype. For example, recent studies have indicated that the genetic contribution to leprosy susceptibility differs between children/adolescents and adults. Moreover, the contribution of epigenetic processes and the role of rare genetic variants impacting on the primary protein structure and biological function in leprosy are largely unknown. An important feature derived from recent data was the genetic overlap of leprosy with IBD and Parkinson’s disease. Perhaps by restricting our investigations to the commonalities between these apparently unrelated phenotypes, we will be able to identify novel pathways and regulators of host immune responses in leprosy.

Footnotes

  1. a, b Hansen GA. 1873. Causes of Leprosy. Norsk Magazin for Laegevidenskaben 4:76–79.
  2. ^ Getz B. 1958. Leprosy research in Norway, 1850–1900. Med Hist 2:65–67.
  3. ^ Dahm R. 2008. Discovering DNA: Friedrich Miescher and the early years of nucleic acid research. Hum Genet 122:565–581.
  4. a, b, c Mohamed Ali P, Ramanujan K. 1966. Leprosy in twins. Int J Lepr 34:405–407.
  5. a, b, c Chakravartti MR, vogel F. 1973. A twin study on leprosy. Stuttgart: Georg Thieme:1–123.
  6. ^ Abel L, Demenais F. 1988. Detection of major genes for susceptibility to leprosy and its subtypes in a Caribbean island: Desirade island. Am J Hum Genet 42:256–266.
  7. ^ Abel L, Vu DL, Oberti J, Nguyen VT, Van VC, Guilloud-Bataille M, Schurr E, Lagrange PH. 1995. Complex segregation analysis of leprosy in southern Vietnam. Genet Epidemiol 12:63–82.
  8. ^ Lazaro FP, Werneck RI, Mackert CC, Cobat A, Prevedello FC, Pimentel RP, Macedo GM, Eleuterio MA, Vilar G, Abel L, Xavier MB, Alcais A, Mira MT. 2010. A major gene controls leprosy susceptibility in a hyperendemic isolated population from north of Brazil. J Infect Dis 201:1598–1605.
  9. ^ Feitosa MF, Borecki I, Krieger H, Beiguelman B, Rao DC. 1995. The genetic epidemiology of leprosy in a Brazilian population. Am J Hum Genet 56:1179–1185.
  10. ^ Shields ED, Russell DA, Pericak-Vance MA. 1987. Genetic epidemiology of the susceptibility to leprosy. J Clin Invest 79:1139–1143.
  11. a, b Shaw MA, Donaldson IJ, Collins A, Peacock CS, Lins-Lainson Z, Shaw JJ, Ramos F, Silveira F, Blackwell JM. 2001. Association and linkage of leprosy phenotypes with HLA class II and tumour necrosis factor genes. Genes Immun 2:196–204.
  12. ^ Smith DG. 1979. The genetic hypothesis for susceptibility to lepromatous leprosy. Hum Genet 50:163–177.
  13. ^ Wagener DK, Schauf V, Nelson KE, Scollard D, Brown A, Smith T. 1988. Segregation analysis of leprosy in families of northern Thailand. Genet Epidemiol 5:95–105.
  14. ^ de Matos HJ, Duppre N, Alvim MF, MachadoVieira LM, Sarno EN, Struchiner CJ. 1999. [Leprosy epidemiology in a cohort of household contacts in Rio de Janeiro (1987–1991)]. Cad Saude Publica 15:533–542.
  15. ^ Fine PE, Sterne JA, Ponnighaus JM, Bliss L, Saui J, Chihana A, Munthali M, Warndorff DK. 1997. Household and dwelling contact as risk factors for leprosy in northern Malawi. Am J Epidemiol 146:91–102.
  16. ^ Sales AM, Ponce de Leon A, Duppre NC, Hacker MA, Nery JA, Sarno EN, Penna ML. 2011. Leprosy among patient contacts: a multilevel study of risk factors. PLoS Negl Trop Dis 5:e1013.
  17. ^ Liu R, Paxton WA, Choe S, Ceradini D, Martin SR, Horuk R, MacDonald ME, Stuhlmann H, Koup RA, Landau NR. 1996. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell 86:367–377.
  18. ^ Miller LH, Mason SJ, Clyde DF, McGinniss MH. 1976. The resistance factor to Plasmodium vivax in blacks. The Duffy-blood-group genotype, FyFy. N Engl J Med 295:302–304.
  19. ^ Tournamille C, Colin Y, Cartron JP, Le Van Kim C. 1995. Disruption of a GATA motif in the Duffy gene promoter abolishes erythroid gene expression in Duffy-negative individuals. Nat Genet 10:224–228.
  20. ^ Song R, Lisovsky I, Lebouche B, Routy JP, Bruneau J, Bernard NF. 2014. HIV protective KIR3DL1/S1-HLA-B genotypes influence NK cell-mediated inhibition of HIV replication in autologous CD4 targets. PLoS Pathog 10:e1003867.
  21. ^ Allison AC. 1954. Protection afforded by sickle-cell trait against subtertian malareal infection. Br Med J 1:290–294.
  22. a, b Ekambaram V, Sithambaram M. 1977. Self-healing in non-lepromatous leprosy in the area of the ELEP Leprosy Control Project Dharmapuri (Tamil Nadu). Lepr India 49:387–392.
  23. a, b Browne SG. 1974. Self-healing leprosy: report on 2749 patients. Lepr Rev 45:104–111.
  24. ^ Lara CB, Nolasco JO. 1956. Self-healing, or abortive, and residual forms of childhood leprosy and their probable significance. Int J Lepr 24:245–263.
  25. a, b Cole ST, Eiglmeier K, Parkhill J, James KD, Thomson NR, Wheeler PR, Honore N, Garnier T, Churcher C, Harris D, Mungall K, Basham D, Brown D, Chillingworth T, Connor R, Davies RM, Devlin K, Duthoy S, Feltwell T, Fraser A, Hamlin N, Holroyd S, Hornsby T, Jagels K, Lacroix C, Maclean J, Moule S, Murphy L, Oliver K, Quail MA, Rajandream MA, Rutherford KM, Rutter S, Seeger K, Simon S, Simmonds M, Skelton J, Squares R, Squares S, Stevens K, Taylor K, Whitehead S, Woodward JR, Barrell BG. 2001. Massive gene decay in the leprosy bacillus. Nature 409:1007–1011.
  26. ^ Gaschignard J, Grant AV, Thuc NV, Orlova M, Cobat A, Huong NT, Ba NN, Thai VH, Abel L, Schurr E, Alcais A. 2016. Pauci- and multibacillary leprosy: two distinct, genetically neglected diseases. PLoS Negl Trop Dis 10:e0004345.
  27. a, b Fava V, Orlova M, Cobat A, Alcais A, Mira M, Schurr E. 2012. Genetics of leprosy reactions: an overview. Mem Inst Oswaldo Cruz 107 Suppl 1:132–142.
  28. a, b Ranque B, Nguyen VT, Vu HT, Nguyen TH, Nguyen NB, Pham XK, Schurr E, Abel L, Alcais A. 2007. Age is an important risk factor for onset and sequelae of reversal reactions in Vietnamese patients with leprosy. Clin Infect Dis 44:33–40.
  29. ^ Kahawita IP, Walker SL, Lockwood DNJ. 2008. Leprosy type 1 reactions and erythema nodosum leprosum. Anais Brasileiros De Dermatologia 83:75–82.
  30. ^ Scollard DM, Adams LB, Gillis TP, Krahenbuhl JL, Truman RW, Williams DL. 2006. The continuing challenges of leprosy. Clin Microbiol Rev 19:338–381.
  31. ^ Behr MA, Kapur V. 2008. The evidence for Mycobacterium paratuberculosis in Crohn’s disease. Curr Opin Gastroenterol 24:17–21.
  32. ^ Behr MA, Semret M, Poon A, Schurr E. 2004. Crohn’s disease, mycobacteria, and NOD2. Lancet Infect Dis 4:136–137.
  33. ^ Feller M, Huwiler K, Stephan R, Altpeter E, Shang A, Furrer H, Pfyffer GE, Jemmi T, Baumgartner A, Egger M. 2007. Mycobacterium avium subspecies paratuberculosis and Crohn’s disease: a systematic review and meta-analysis. Lancet Infect Dis 7:607–613.
  34. ^ Guzman MG, Halstead SB, Artsob H, Buchy P, Farrar J, Gubler DJ, Hunsperger E, Kroeger A, Margolis HS, Martinez E, Nathan MB, Pelegrino JL, Simmons C, Yoksan S, Peeling RW. 2010. Dengue: a continuing global threat. Nat Rev Microbiol 8:S7–16.
  35. a, b Salzano FM. 1967. Blood groups and leprosy. J Med Genet 4:102–106.
  36. a, b, c Vogel F, Kruger J, Chakravartti MR, Ritter H, Flatz G. 1971. ABO blood groups , Inv serum groups, and serum proteins in leprosy patients from West Bengal (India). Humangenetik 12:284–301.
  37. ^ Prasad KV, Mohamed Ali P. 1966. ABO blood groups and leprosy. Int J Lepr Other Mycobact Dis 34:398–407.
  38. ^ Saha N, Wong HB, Banerjee B, Wong MO. 1971. Distribution of ABO blood groups, G6PD deficiency, and abnormal haemoglobins in leprosy. J Med Genet 8:315–316.
  39. ^ Singh G, Ojha D. 1967. Leprosy and ABO blood groups. J Med Genet 4:107–108.
  40. ^ Vogel F. 1968. ABO blood groups and leprosy. J Med Genet 5:56–57.
  41. ^ Vogel F, Kruger J, Song YK, Flatz G. 1969. ABO blood groups, leprosy, and serum proteins. Humangenetik 7:149–162.
  42. ^ Vogel F, Chakravartti MR. 1966. ABO blood groups and the type of leprosy in an Indian population. Humangenetik 3:186–188.
  43. ^ Barreiro LB, Ben-Ali M, Quach H, Laval G, Patin E, Pickrell JK, Bouchier C, Tichit M, Neyrolles O, Gicquel B, Kidd JR, Kidd KK, Alcais A, Ragimbeau J, Pellegrini S, Abel L, Casanova JL, Quintana-Murci L. 2009. Evolutionary dynamics of human Toll-like receptors and their different contributions to host defense. PLoS Genet 5:e1000562.
  44. ^ Krutzik SR, Ochoa MT, Sieling PA, Uematsu S, Ng YW, Legaspi A, Liu PT, Cole ST, Godowski PJ, Maeda Y, Sarno EN, Norgard MV, Brennan PJ, Akira S, Rea TH, Modlin RL. 2003. Activation and regulation of Toll-like receptors 2 and 1 in human leprosy. Nat Med 9:525–532.
  45. ^ Mattos KA, Oliveira VG, D’Avila H, Rodrigues LS, Pinheiro RO, Sarno EN, Pessolani MC, Bozza PT. 2011. TLR6-driven lipid droplets in Mycobacterium leprae-infected Schwann cells: immunoinflammatory platforms associated with bacterial persistence. J Immunol 187:2548–2558.
  46. a, b, c Wong SH, Gochhait S, Malhotra D, Pettersson FH, Teo YY, Khor CC, Rautanen A, Chapman SJ, Mills TC, Srivastava A, Rudko A, Freidin MB, Puzyrev VP, Ali S, Aggarwal S, Chopra R, Reddy BS, Garg VK, Roy S, Meisner S, Hazra SK, Saha B, Floyd S, Keating BJ, Kim C, Fairfax BP, Knight JC, Hill PC, Adegbola RA, Hakonarson H, Fine PE, Pitchappan RM, Bamezai RN, Hill AV, Vannberg FO. 2010. Leprosy and the adaptation of human toll-like receptor 1. PLoS Pathog 6:e1000979.
  47. a, b, c, d Marques Cde S, Brito-de-Souza VN, Guerreiro LT, Martins JH, Amaral EP, Cardoso CC, Dias-Batista IM, Silva WL, Nery JA, Medeiros P, Gigliotti P, Campanelli AP, Virmond M, Sarno EN, Mira MT, Lana FC, Caffarena ER, Pacheco AG, Pereira AC, Moraes MO. 2013. Toll-like receptor 1 N248S single-nucleotide polymorphism is associated with leprosy risk and regulates immune activation during mycobacterial infection. J Infect Dis 208:120–129.
  48. a, b Misch EA, Macdonald M, Ranjit C, Sapkota BR, Wells RD, Siddiqui MR, Kaplan G, Hawn TR. 2008. Human TLR1 deficiency is associated with impaired mycobacterial signaling and protection from leprosy reversal reaction. PLoS Negl Trop Dis 2:e231.
  49. a, b, c, d Zhang F, Liu H, Chen S, Low H, Sun L, Cui Y, Chu T, Li Y, Fu X, Yu Y, Yu G, Shi B, Tian H, Liu D, Yu X, Li J, Lu N, Bao F, Yuan C, Liu J, Liu H, Zhang L, Sun Y, Chen M, Yang Q, Yang H, Yang R, Zhang L, Wang Q, Liu H, Zuo F, Zhang H, Khor CC, Hibberd ML, Yang S, Liu J, Zhang X. 2011. Identification of two new loci at IL23R and RAB32 that influence susceptibility to leprosy. Nat Genet 43:1247–1251.
  50. ^ Johnson CM, Lyle EA, Omueti KO, Stepensky VA, Yegin O, Alpsoy E, Hamann L, Schumann RR, Tapping RI. 2007. Cutting edge: A common polymorphism impairs cell surface trafficking and functional responses of TLR1 but protects against leprosy. J Immunol 178:7520–7524.
  51. ^ Hart BE, Tapping RI. 2012. Differential trafficking of TLR1 I602S underlies host protection against pathogenic mycobacteria. J Immunol 189:5347–5355.
  52. ^ Schuring RP, Hamann L, Faber WR, Pahan D, Richardus JH, Schumann RR, Oskam L. 2009. Polymorphism N248S in the human Toll-like receptor 1 gene is related to leprosy and leprosy reactions. J Infect Dis 199:1816–1819.
  53. ^ Ma X, Liu Y, Gowen BB, Graviss EA, Clark AG, Musser JM. 2007. Full-exon resequencing reveals toll-like receptor variants contribute to human susceptibility to tuberculosis disease. PLoS One 2:e1318.
  54. ^ Hamann L, Bedu-Addo G, Eggelte TA, Schumann RR, Mockenhaupt FP. 2010. The toll-like receptor 1 variant S248N influences placental malaria. Infect Genet Evol 10:785–789.
  55. ^ Bochud PY, Hawn TR, Siddiqui MR, Saunderson P, Britton S, Abraham I, Argaw AT, Janer M, Zhao LP, Kaplan G, Aderem A. 2008. Toll-like receptor 2 (TLR2) polymorphisms are associated with reversal reaction in leprosy. J Infect Dis 197:253–261.
  56. ^ Oliveira RB, Ochoa MT, Sieling PA, Rea TH, Rambukkana A, Sarno EN, Modlin RL. 2003. Expression of Toll-like receptor 2 on human Schwann cells: a mechanism of nerve damage in leprosy. Infect Immun 71:1427–1433.
  57. a, b Bochud PY, Sinsimer D, Aderem A, Siddiqui MR, Saunderson P, Britton S, Abraham I, Tadesse Argaw A, Janer M, Hawn TR, Kaplan G. 2009. Polymorphisms in Toll-like receptor 4 (TLR4) are associated with protection against leprosy. Eur J Clin Microbiol Infect Dis 28:1055–1065.
  58. a, b Suryadevara NC, Neela VS, Kovvali S, Pydi SS, Jain S, Siva Sai KS, Valluri VL, Spurgeon AM. 2013. Genetic association of G896A polymorphism of TLR4 gene in leprosy through family-based and case-control study designs. Trans R Soc Trop Med Hyg 107:777–782.
  59. ^ Akdis M, Burgler S, Crameri R, Eiwegger T, Fujita H, Gomez E, Klunker S, Meyer N, O’Mahony L, Palomares O, Rhyner C, Ouaked N, Schaffartzik A, Van De Veen W, Zeller S, Zimmermann M, Akdis CA. 2011. Interleukins, from 1 to 37, and interferon-gamma: receptors, functions, and roles in diseases. J Allergy Clin Immunol 127:701–721 e701–770.
  60. ^ Modlin RL, Hofman FM, Horwitz DA, Husmann LA, Gillis S, Taylor CR, Rea TH. 1984. In situ identification of cells in human leprosy granulomas with monoclonal antibodies to interleukin 2 and its receptor. J Immunol 132:3085–3090.
  61. ^ Hsieh CS, Macatonia SE, Tripp CS, Wolf SF, O’Garra A, Murphy KM. 1993. Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science 260:547–549.
  62. ^ Morahan G, Kaur G, Singh M, Rapthap CC, Kumar N, Katoch K, Mehra NK, Huang D. 2007. Association of variants in the IL12B gene with leprosy and tuberculosis. Tissue Antigens 69(Suppl 1):234–236.
  63. ^ Alvarado-Navarro A, Montoya-Buelna M, Munoz-Valle JF, Lopez-Roa RI, Guillen-Vargas C, Fafutis-Morris M. 2008. The 3’UTR 1188 A/C polymorphism in the interleukin-12p40 gene (IL-12B) is associated with lepromatous leprosy in the west of Mexico. Immunol Lett 118:148–151.
  64. a, b Chopra R, Kalaiarasan P, Ali S, Srivastava AK, Aggarwal S, Garg VK, Bhattacharya SN, Bamezai RN. 2014. PARK2 and proinflammatory/anti-inflammatory cytokine gene interactions contribute to the susceptibility to leprosy: a case-control study of North Indian population. BMJ Open 4:e004239.
  65. a, b Ali S, Srivastava AK, Chopra R, Aggarwal S, Garg VK, Bhattacharya SN, Bamezai RN. 2013. IL12B SNPs and copy number variation in IL23R gene associated with susceptibility to leprosy. J Med Genet 50:34–42.
  66. a, b Liu H, Irwanto A, Tian H, Fu X, Yu Y, Yu G, Low H, Chu T, Li Y, Shi B, Chen M, Sun Y, Yuan C, Lu N, You J, Bao F, Li J, Liu J, Liu H, Liu D, Yu X, Zhang L, Yang Q, Wang N, Niu G, Ma S, Zhou Y, Wang C, Chen S, Zhang X, Liu J, Zhang F. 2012. Identification of IL18RAP/IL18R1 and IL12B as leprosy risk genes demonstrates shared pathogenesis between inflammation and infectious diseases. Am J Hum Genet 91:935–941.
  67. ^ Ohyama H, Ogata K, Takeuchi K, Namisato M, Fukutomi Y, Nishimura F, Naruishi H, Ohira T, Hashimoto K, Liu T, Suzuki M, Uemura Y, Matsushita S. 2005. Polymorphism of the 5’ flanking region of the IL-12 receptor beta2 gene partially determines the clinical types of leprosy through impaired transcriptional activity. J Clin Pathol 58:740–743.
  68. ^ Silva GA, Santos MP, Motta-Passos I, Boechat AL, Malheiro A, Ramasawmy R, Naveca FG, de Paula L. 2014. Polymorphisms assessment in the promoter region of IL12RB2 in Amazon leprosy patients. Hum Immunol 75:592–596.
  69. ^ Lee SB, Kim BC, Jin SH, Park YG, Kim SK, Kang TJ, Chae GT. 2003. Missense mutations of the interleukin-12 receptor beta 1(IL12RB1) and interferon-gamma receptor 1 (IFNGR1) genes are not associated with susceptibility to lepromatous leprosy in Korea. Immunogenetics 55:177–181.
  70. a, b Alvarado-Arnez LE, Amaral EP, Sales-Marques C, Duraes SM, Cardoso CC, Nunes Sarno E, Pacheco AG, Lana FC, Moraes MO. 2015. Association of IL10 polymorphisms and leprosy: a meta-analysis. PLoS One 10:e0136282.
  71. a, b Pereira AC, Brito-de-Souza VN, Cardoso CC, Dias-Baptista IM, Parelli FP, Venturini J, Villani-Moreno FR, Pacheco AG, Moraes MO. 2009. Genetic, epidemiological and biological analysis of interleukin-10 promoter single-nucleotide polymorphisms suggests a definitive role for –819C/T in leprosy susceptibility. Genes Immun 10:174–180.
  72. ^ Franceschi DS, Mazini PS, Rudnick CC, Sell AM, Tsuneto LT, Ribas ML, Peixoto PR, Visentainer JE. 2009. Influence of TNF and IL10 gene polymorphisms in the immunopathogenesis of leprosy in the south of Brazil. Int J Infect Dis 13:493–498.
  73. ^ Cardona-Castro N, Sanchez-Jimenez M, Rojas W, Bedoya-Berrio G. 2012. IL-10 gene promoter polymorphisms and leprosy in a Colombian population sample. Biomedica 32:71–76.
  74. ^ Garcia P, Alencar D, Pinto P, Santos N, Salgado C, Sortica VA, Hutz MH, Ribeiro-dos-Santos A, Santos S. 2013. Haplotypes of the IL10 gene as potential protection factors in leprosy patients. Clin Vaccine Immunol 20:1599–1603.
  75. ^ Malhotra D, Darvishi K, Sood S, Sharma S, Grover C, Relhan V, Reddy BS, Bamezai RN. 2005. IL-10 promoter single nucleotide polymorphisms are significantly associated with resistance to leprosy. Hum Genet 118:295–300.
  76. ^ Gao X, Chen J, Tong Z, Yang G, Yao Y, Xu F, Zhou J. 2015. Interleukin-10 promoter gene polymorphisms and susceptibility to tuberculosis: a meta-analysis. PLoS One 10:e0127496.
  77. ^ Liang B, Guo Y, Li Y, Kong H. 2014. Association between IL-10 gene polymorphisms and susceptibility of tuberculosis: evidence based on a meta-analysis. PLoS One 9:e88448.
  78. ^ Gibson AW, Edberg JC, Wu J, Westendorp RG, Huizinga TW, Kimberly RP. 2001. Novel single nucleotide polymorphisms in the distal IL-10 promoter affect IL-10 production and enhance the risk of systemic lupus erythematosus. J Immunol 166:3915–3922.
  79. ^ Chaitanya VS, Jadhav RS, Lavania M, Singh M, Valluri V, Sengupta U. 2014. Interleukin-17F single-nucleotide polymorphism (7488T>C) and its association with susceptibility to leprosy. Int J Immunogenet 41:131–137.
  80. ^ Escamilla-Tilch M, Estrada-Garcia I, Granados J, Arenas-Guzman R, Ramos-Payan R, Perez-Suarez TG, Salazar MI, Perez-Lucas RL, Estrada-Parra S, Torres-Carrillo NM. 2014. Lack of Association of the polymorphisms IL-17A (–197G/A) and IL-17F (+7488A/G) with multibacillary leprosy in Mexican patients. Int J Genomics 2014:920491.
  81. a, b Sousa AL, Fava VM, Sampaio LH, Martelli CM, Costa MB, Mira MT, Stefani MM. 2012. Genetic and immunological evidence implicates interleukin 6 as a susceptibility gene for leprosy type 2 reaction. J Infect Dis 205:1417–1424.
  82. ^ Fishman D, Faulds G, Jeffery R, Mohamed-Ali V, Yudkin JS, Humphries S, Woo P. 1998. The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Invest 102:1369–1376.
  83. ^ Fujita T. 2002. Evolution of the lectin-complement pathway and its role in innate immunity. Nat Rev Immunol 2:346–353.
  84. ^ de Messias-Reason IJ, Boldt AB, Moraes Braga AC, Von Rosen Seeling Stahlke E, Dornelles L, Pereira-Ferrari L, Kremsner PG, Kun JF. 2007. The association between mannan-binding lectin gene polymorphism and clinical leprosy: new insight into an old paradigm. J Infect Dis 196:1379–1385.
  85. a, b, c Zhang DF, Huang XQ, Wang D, Li YY, Yao YG. 2013. Genetic variants of complement genes ficolin-2, mannose-binding lectin and complement factor H are associated with leprosy in Han Chinese from Southwest China. Hum Genet 132:629–640.
  86. a, b Sapkota BR, Macdonald M, Berrington WR, Misch EA, Ranjit C, Siddiqui MR, Kaplan G, Hawn TR. 2010. Association of TNF, MBL, and VDR polymorphisms with leprosy phenotypes. Hum Immunol 71:992–998.
  87. ^ Vasconcelos LR, Fonseca JP, do Carmo RF, de Mendonca TF, Pereira VR, Lucena-Silva N, Pereira LM, Moura P, Cavalcanti Mdo S. 2011. Mannose-binding lectin serum levels in patients with leprosy are influenced by age and MBL2 genotypes. Int J Infect Dis 15:e551–557.
  88. a, b Ip WK, Takahashi K, Ezekowitz RA, Stuart LM. 2009. Mannose-binding lectin and innate immunity. Immunol Rev 230:9–21.
  89. ^ Boldt AB, Goeldner I, Stahlke ER, Thiel S, Jensenius JC, de Messias-Reason IJ. 2013. Leprosy association with low MASP-2 levels generated by MASP2 haplotypes and polymorphisms flanking MAp19 exon 5. PLoS One 8:e69054.
  90. ^ de Messias IJ, Santamaria J, Brenden M, Reis A, Mauff G. 1993. Association of C4B deficiency (C4B*Q0) with erythema nodosum in leprosy. Clin Exp Immunol 92:284–287.
  91. ^ Endo Y, Matsushita M, Fujita T. 2011. The role of ficolins in the lectin pathway of innate immunity. Int J Biochem Cell Biol 43:705–712.
  92. ^ de Messias-Reason I, Kremsner PG, Kun JF. 2009. Functional haplotypes that produce normal ficolin-2 levels protect against clinical leprosy. J Infect Dis 199:801–804.
  93. ^ Aranow C. 2011. Vitamin D and the immune system. J Investig Med 59:881–886.
  94. ^ Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, Ochoa MT, Schauber J, Wu K, Meinken C, Kamen DL, Wagner M, Bals R, Steinmeyer A, Zugel U, Gallo RL, Eisenberg D, Hewison M, Hollis BW, Adams JS, Bloom BR, Modlin RL. 2006. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 311:1770–1773.
  95. ^ Roy S, Frodsham A, Saha B, Hazra SK, Mascie-Taylor CG, Hill AV. 1999. Association of vitamin D receptor genotype with leprosy type. J Infect Dis 179:187–191.
  96. ^ Goulart LR, Ferreira FR, Goulart IM. 2006. Interaction of TaqI polymorphism at exon 9 of the vitamin D receptor gene with the negative lepromin response may favor the occurrence of leprosy. FEMS Immunol Med Microbiol 48:91–98.
  97. ^ Mandal D, Reja AH, Biswas N, Bhattacharyya P, Patra PK, Bhattacharya B. 2015. Vitamin D receptor expression levels determine the severity and complexity of disease progression among leprosy reaction patients. New Microbes New Infect 6:35–39.
  98. a, b Tobin DM, Vary JC, Jr., Ray JP, Walsh GS, Dunstan SJ, Bang ND, Hagge DA, Khadge S, King MC, Hawn TR, Moens CB, Ramakrishnan L. 2010. The lta4h locus modulates susceptibility to mycobacterial infection in zebrafish and humans. Cell 140:717–730.
  99. ^ Prado-Montes de Oca E, Velarde-Felix JS, Rios-Tostado JJ, Picos-Cardenas VJ, Figuera LE. 2009. SNP 668C (-44) alters a NF-kappaB1 putative binding site in non-coding strand of human beta-defensin 1 (DEFB1) and is associated with lepromatous leprosy. Infect Genet Evol 9:617–625.
  100. ^ Noon LA, Lloyd AC. 2005. Hijacking the ERK signaling pathway: Mycobacterium leprae shuns MEK to drive the proliferation of infected Schwann cells. Sci STKE 2005:pe52.
  101. ^ Wibawa T, Soebono H, Matsuo M. 2002. Association of a missense mutation of the laminin alpha2 gene with tuberculoid type of leprosy in Indonesian patients. Trop Med Int Health 7:631–636.
  102. ^ Schoenborn JR, Wilson CB. 2007. Regulation of interferon-gamma during innate and adaptive immune responses. Adv Immunol 96:41–101.
  103. ^ Cardoso CC, Pereira AC, Brito-de-Souza VN, Dias-Baptista IM, Maniero VC, Venturini J, Vilani-Moreno FR, de Souza FC, Ribeiro-Alves M, Sarno EN, Pacheco AG, Moraes MO. 2010. IFNG +874 T>A single nucleotide polymorphism is associated with leprosy among Brazilians. Hum Genet 128:481–490.
  104. ^ Silva GA, Naveca FG, Ramasawmy R, Boechat AL. 2014. Association between the IFNG +874A/T gene polymorphism and leprosy resistance: a meta-analysis. Cytokine 65:130–133.
  105. ^ Xue L, Morris SW, Orihuela C, Tuomanen E, Cui X, Wen R, Wang D. 2003. Defective development and function of Bcl10-deficient follicular, marginal zone and B1 B cells. Nat Immunol 4:857–865.
  106. a, b Liu H, Bao F, Irwanto A, Fu X, Lu N, Yu G, Yu Y, Sun Y, Low H, Li Y, Liany H, Yuan C, Li J, Liu J, Chen M, Liu H, Wang N, You J, Ma S, Niu G, Zhou Y, Chu T, Tian H, Chen S, Zhang X, Liu J, Zhang F. 2013. An association study of TOLL and CARD with leprosy susceptibility in Chinese population. Hum Mol Genet 22:4430–4437.
  107. ^ Araki T, Milbrandt J. 1996. Ninjurin, a novel adhesion molecule, is induced by nerve injury and promotes axonal growth. Neuron 17:353–361.
  108. ^ Graca CR, Paschoal VD, Cordeiro-Soubhia RM, Tonelli-Nardi SM, Machado RL, Kouyoumdjian JA, Baptista Rossit AR. 2012. NINJURIN1 single nucleotide polymorphism and nerve damage in leprosy. Infect Genet Evol 12:597–600.
  109. ^ Cardoso CC, Martinez AN, Guimaraes PE, Mendes CT, Pacheco AG, de Oliveira RB, Teles RM, Illarramendi X, Sampaio EP, Sarno EN, Dias-Neto E, Moraes MO. 2007. Ninjurin 1 asp110ala single nucleotide polymorphism is associated with protection in leprosy nerve damage. J Neuroimmunol 190:131–138.
  110. a, b Cezar-de-Mello PF, Toledo-Pinto TG, Marques CS, Arnez LE, Cardoso CC, Guerreiro LT, Antunes SL, Jardim MM, Covas Cde J, Illaramendi X, Dias-Baptista IM, Rosa PS, Duraes SM, Pacheco AG, Ribeiro-Alves M, Sarno EN, Moraes MO. 2014. Pre-miR-146a (rs2910164 G>C) single nucleotide polymorphism is genetically and functionally associated with leprosy. PLoS Negl Trop Dis 8:e3099.
  111. ^ Liu PT, Wheelwright M, Teles R, Komisopoulou E, Edfeldt K, Ferguson B, Mehta MD, Vazirnia A, Rea TH, Sarno EN, Graeber TG, Modlin RL. 2012. MicroRNA-21 targets the vitamin D-dependent antimicrobial pathway in leprosy. Nat Med 18:267–273.
  112. ^ Skamene E, Gros P, Forget A, Patel PJ, Nesbitt MN. 1984. Regulation of resistance to leprosy by chromosome 1 locus in the mouse. Immunogenetics 19:117–124.
  113. ^ Vidal S, Tremblay ML, Govoni G, Gauthier S, Sebastiani G, Malo D, Skamene E, Olivier M, Jothy S, Gros P. 1995. The Ity/Lsh/Bcg locus: natural resistance to infection with intracellular parasites is abrogated by disruption of the Nramp1 gene. J Exp Med 182:655–666.
  114. ^ Mohamed HS, Ibrahim ME, Miller EN, White JK, Cordell HJ, Howson JM, Peacock CS, Khalil EA, El Hassan AM, Blackwell JM. 2004. SLC11A1 (formerly NRAMP1) and susceptibility to visceral leishmaniasis in The Sudan. Eur J Hum Genet 12:66–74.
  115. ^ Gallant CJ, Malik S, Jabado N, Cellier M, Simkin L, Finlay BB, Graviss EA, Gros P, Musser JM, Schurr E. 2007. Reduced in vitro functional activity of human NRAMP1 (SLC11A1) allele that predisposes to increased risk of pediatric tuberculosis disease. Genes Immun 8:691–698.
  116. ^ Abel L, Sanchez FO, Oberti J, Thuc NV, Van Hoa L, Lap VD, Skamene E, Lagrange PH, Schurr E. 1998. Susceptibility to leprosy is linked to the human NRAMP1 gene. Journal of Infectious Diseases 177:133–145.
  117. ^ Hatta M, Ratnawati, Tanaka M, Ito J, Shirakawa T, Kawabata M. 2010. NRAMP1/SLC11A1 gene polymorphisms and host susceptibility to Mycobacterium tuberculosis and M. leprae in South Sulawesi, Indonesia. Southeast Asian J Trop Med Public Health 41:386–394.
  118. ^ Meisner SJ, Mucklow S, Warner G, Sow SO, Lienhardt C, Hill AV. 2001. Association of NRAMP1 polymorphism with leprosy type but not susceptibility to leprosy per se in west Africans. Am J Trop Med Hyg 733–735:733–735.
  119. ^ Teixeira MA, Silva NL, Ramos Ade L, Hatagima A, Magalhaes V. 2010. NRAMP1 gene polymorphisms in individuals with leprosy reactions attended at two reference centers in Recife, northeastern Brazil. Rev Soc Bras Med Trop 43:281–286.
  120. ^ Alcais A, Sanchez FO, Thuc NV, Lap VD, Oberti J, Lagrange PH, Schurr E, Abel L. 2000. Granulomatous reaction to intradermal injection of lepromin (Mitsuda reaction) is linked to the human NRAMP1 gene in Vietnamese leprosy sibships. J Infect Dis 181:302–308.
  121. a, b Ranque B, Alter A, Mira M, Thuc NV, Thai VH, Huong NT, Ba NN, Khoa PX, Schurr E, Abel L, Alcais A. 2007. Genomewide linkage analysis of the granulomatous mitsuda reaction implicates chromosomal regions 2q35 and 17q21. J Infect Dis 196:1248–1252.
  122. ^ Ferreira FR, Goulart LR, Silva HD, Goulart IM. 2004. Susceptibility to leprosy may be conditioned by an interaction between the NRAMP1 promoter polymorphisms and the lepromin response. Int J Lepr Other Mycobact Dis 72:457–467.
  123. ^ Siddiqui MR, Meisner S, Tosh K, Balakrishnan K, Ghei S, Fisher SE, Golding M, Shanker Narayan NP, Sitaraman T, Sengupta U, Pitchappan R, Hill AV. 2001. A major susceptibility locus for leprosy in India maps to chromosome 10p13. Nat Genet 27:439–441.
  124. a, b, c Mira MT, Alcais A, Van Thuc N, Thai VH, Huong NT, Ba NN, Verner A, Hudson TJ, Abel L, Schurr E. 2003. Chromosome 6q25 is linked to susceptibility to leprosy in a Vietnamese population. Nat Genet 33:412–415.
  125. ^ Alter A, de Leseleuc L, Van Thuc N, Thai VH, Huong NT, Ba NN, Cardoso CC, Grant AV, Abel L, Moraes MO, Alcais A, Schurr E. 2010. Genetic and functional analysis of common MRC1 exon 7 polymorphisms in leprosy susceptibility. Hum Genet 127:337–348.
  126. a, b Wang D, Feng JQ, Li YY, Zhang DF, Li XA, Li QW, Yao YG. 2012. Genetic variants of the MRC1 gene and the IFNG gene are associated with leprosy in Han Chinese from Southwest China. Hum Genet 131:1251–1260.
  127. a, b, c Grant AV, Cobat A, Van Thuc N, Orlova M, Huong NT, Gaschignard J, Alter A, Ba NN, Thai VH, Abel L, Alcais A, Schurr E. 2014. CUBN and NEBL common variants in the chromosome 10p13 linkage region are associated with multibacillary leprosy in Vietnam. Hum Genet 133:883–893.
  128. a, b Mira MT, Alcais A, Nguyen VT, Moraes MO, Di Flumeri C, Vu HT, Mai CP, Nguyen TH, Nguyen NB, Pham XK, Sarno EN, Alter A, Montpetit A, Moraes ME, Moraes JR, Dore C, Gallant CJ, Lepage P, Verner A, Van De Vosse E, Hudson TJ, Abel L, Schurr E. 2004. Susceptibility to leprosy is associated with PARK2 and PACRG. Nature 427:636–640.
  129. ^ Malhotra D, Darvishi K, Lohra M, Kumar H, Grover C, Sood S, Reddy BS, Bamezai RN. 2006. Association study of major risk single nucleotide polymorphisms in the common regulatory region of PARK2 and PACRG genes with leprosy in an Indian population. Eur J Hum Genet 14:438–442.
  130. a, b, c, d Alter A, Fava VM, Huong NT, Singh M, Orlova M, Van Thuc N, Katoch K, Thai VH, Ba NN, Abel L, Mehra N, Alcais A, Schurr E. 2013. Linkage disequilibrium pattern and age-at-diagnosis are critical for replicating genetic associations across ethnic groups in leprosy. Hum Genet 132:107–116.
  131. ^ Chopra R, Ali S, Srivastava AK, Aggarwal S, Kumar B, Manvati S, Kalaiarasan P, Jena M, Garg VK, Bhattacharya SN, Bamezai RN. 2013. Mapping of PARK2 and PACRG overlapping regulatory region reveals LD structure and functional variants in association with leprosy in unrelated Indian population groups. PLoS Genet 9:e1003578.
  132. ^ Ali S, Vollaard AM, Widjaja S, Surjadi C, van de Vosse E, van Dissel JT. 2006. PARK2/PACRG polymorphisms and susceptibility to typhoid and paratyphoid fever. Clin Exp Immunol 144:425–431.
  133. a, b de Leseleuc L, Orlova M, Cobat A, Girard M, Huong NT, Ba NN, Thuc NV, Truman R, Spencer JS, Adams L, Thai VH, Alcais A, Schurr E. 2013. PARK2 mediates interleukin 6 and monocyte chemoattractant protein 1 production by human macrophages. PLoS Negl Trop Dis 7:e2015.
  134. ^ Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N. 1998. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392:605–608.
  135. ^ Lucking CB, Durr A, Bonifati V, Vaughan J, De Michele G, Gasser T, Harhangi BS, Meco G, Denefle P, Wood NW, Agid Y, Brice A, French Parkinson’s Disease Genetics Study G, European Consortium on Genetic Susceptibility in Parkinson’s D. 2000. Association between early-onset Parkinson’s disease and mutations in the parkin gene. N Engl J Med 342:1560–1567.
  136. ^ Behr MA, Schurr E. 2013. Cell biology: a table for two. Nature 501:498–499.
  137. ^ Gutierrez MG, Master SS, Singh SB, Taylor GA, Colombo MI, Deretic V. 2004. Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell 119:753–766.
  138. ^ Manzanillo PS, Ayres JS, Watson RO, Collins AC, Souza G, Rae CS, Schneider DS, Nakamura K, Shiloh MU, Cox JS. 2013. The ubiquitin ligase parkin mediates resistance to intracellular pathogens. Nature 501:512–516.
  139. a, b Mira MT, Alcais A, di Pietrantonio T, Thuc NV, Phuong MC, Abel L, Schurr E. 2003. Segregation of HLA/TNF region is linked to leprosy clinical spectrum in families displaying mixed leprosy subtypes. Genes Immun 4:67–73.
  140. a, b Miller EN, Jamieson SE, Joberty C, Fakiola M, Hudson D, Peacock CS, Cordell HJ, Shaw MA, Lins-Lainson Z, Shaw JJ, Ramos F, Silveira F, Blackwell JM. 2004. Genome-wide scans for leprosy and tuberculosis susceptibility genes in Brazilians. Genes Immun 5:63–67.
  141. a, b Alcais A, Alter A, Antoni G, Orlova M, Nguyen VT, Singh M, Vanderborght PR, Katoch K, Mira MT, Vu HT, Ngyuen TH, Nguyen NB, Moraes M, Mehra N, Schurr E, Abel L. 2007. Stepwise replication identifies a low-producing lymphotoxin-alpha allele as a major risk factor for early-onset leprosy. Nat Genet 39:517–522.
  142. a, b, c Alter A, Huong NT, Singh M, Orlova M, Van Thuc N, Katoch K, Gao X, Thai VH, Ba NN, Carrington M, Abel L, Mehra N, Alcais A, Schurr E. 2011. Human leukocyte antigen class I region single-nucleotide polymorphisms are associated with leprosy susceptibility in Vietnam and India. J Infect Dis 203:1274–1281.
  143. ^ Roach DR, Briscoe H, Saunders B, France MP, Riminton S, Britton WJ. 2001. Secreted lymphotoxin-alpha is essential for the control of an intracellular bacterial infection. J Exp Med 193:239–246.
  144. ^ Bopst M, Garcia I, Guler R, Olleros ML, Rulicke T, Muller M, Wyss S, Frei K, Le Hir M, Eugster HP. 2001. Differential effects of TNF and LTalpha in the host defense against M. bovis BCG. Eur J Immunol 31:1935–1943.
  145. ^ Knight JC, Keating BJ, Kwiatkowski DP. 2004. Allele-specific repression of lymphotoxin-alpha by activated B cell factor-1. Nat Genet 36:394–399.
  146. ^ Jarduli LR, Sell AM, Reis PG, Sippert EA, Ayo CM, Mazini PS, Alves HV, Teixeira JJ, Visentainer JE. 2013. Role of HLA, KIR, MICA, and cytokines genes in leprosy. Biomed Res Int 2013:989837.
  147. ^ Roy S, McGuire W, Mascie-Taylor CG, Saha B, Hazra SK, Hill AV, Kwiatkowski D. 1997. Tumor necrosis factor promoter polymorphism and susceptibility to lepromatous leprosy. J Infect Dis 176:530–532.
  148. ^ Santos AR, Suffys PN, Vanderborght PR, Moraes MO, Vieira LM, Cabello PH, Bakker AM, Matos HJ, Huizinga TW, Ottenhoff TH, Sampaio EP, Sarno EN. 2002. Role of tumor necrosis factor-alpha and interleukin-10 promoter gene polymorphisms in leprosy. J Infect Dis 186:1687–1691.
  149. ^ Vanderborght PR, Matos HJ, Salles AM, Vasconcellos SE, Silva-Filho VF, Huizinga TW, Ottenhoff TH, Sampaio EP, Sarno EN, Santos AR, Moraes MO. 2004. Single nucleotide polymorphisms (SNPs) at –238 and –308 positions in the TNFalpha promoter: clinical and bacteriological evaluation in leprosy. Int J Lepr Other Mycobact Dis 72:143–148.
  150. ^ Cardoso CC, Pereira AC, Brito-de-Souza VN, Duraes SM, Ribeiro-Alves M, Nery JA, Francio AS, Vanderborght PR, Parelli FP, Alter A, Salgado JL, Sampaio EP, Santos AR, Oliveira ML, Sarno EN, Schurr E, Mira MT, Pacheco AG, Moraes MO. 2011. TNF –308G>A single nucleotide polymorphism is associated with leprosy among Brazilians: a genetic epidemiology assessment, meta-analysis, and functional study. J Infect Dis 204:1256–1263.
  151. ^ Silva GA, Ramasawmy R, Boechat AL, Morais AC, Carvalho BK, Sousa KB, Souza VC, Cunha MG, Barletta-Naveca RH, Santos MP, Naveca FG. 2015. Association of TNF –1031 C/C as a potential protection marker for leprosy development in Amazonas state patients, Brazil. Hum Immunol 76:137–141.
  152. ^ Algood HM, Lin PL, Flynn JL. 2005. Tumor necrosis factor and chemokine interactions in the formation and maintenance of granulomas in tuberculosis. Clin Infect Dis 41 Suppl 3:S189–193.
  153. ^ Ali S, Chopra R, Aggarwal S, Srivastava AK, Kalaiarasan P, Malhotra D, Gochhait S, Garg VK, Bhattacharya SN, Bamezai RN. 2012. Association of variants in BAT1-LTA-TNF-BTNL2 genes within 6p21.3 region show graded risk to leprosy in unrelated cohorts of Indian population. Hum Genet 131:703–716.
  154. ^ Tosh K, Ravikumar M, Bell JT, Meisner S, Hill AV, Pitchappan R. 2006. Variation in MICA and MICB genes and enhanced susceptibility to paucibacillary leprosy in South India. Hum Mol Genet 15:2880–2887.
  155. ^ Zhang FR, Liu H, Irwanto A, Fu XA, Li Y, Yu GQ, Yu YX, Chen MF, Low HQ, Li JH, Bao FF, Foo JN, Bei JX, Jia XM, Liu J, Liany H, Wang N, Niu GY, Wang ZZ, Shi BQ, Tian HQ, Liu HX, Ma SS, Zhou Y, You JB, Yang Q, Wang C, Chu TS, Liu DC, Yu XL, Sun YH, Ning Y, Wei ZH, Chen SL, Chen XC, Zhang ZX, Liu YX, Pulit SL, Wu WB, Zheng ZY, Yang RD, Long H, Liu ZS, Wang JQ, Li M, Zhang LH, Wang H, Wang LM, Xiao P, Li JL, Huang ZM, Huang JX, Li Z, Liu J, Xiong L, Yang J, Wang XD, Yu DB, Lu XM, Zhou GZ, Yan LB, Shen JP, Zhang GC, Zeng YX, de Bakker PIW, Chen SM, Liu JJ. 2013. HLA-B*13:01 and the dapsone hypersensitivity syndrome. N Engl J Med 369:1620–1628.
  156. ^ Kulkarni S, Martin MP, Carrington M. 2008. The Yin and Yang of HLA and KIR in human disease. Semin Immunol 20:343–352.
  157. ^ Jarduli LR, Alves HV, de Souza-Santana FC, Marcos EV, Pereira AC, Dias-Baptista IM, Fava VM, Mira MT, Moraes MO, Virmond Mda C, Visentainer JE. 2014. Influence of KIR genes and their HLA ligands in the pathogenesis of leprosy in a hyperendemic population of Rondonopolis, Southern Brazil. BMC Infect Dis 14:438.
  158. ^ Escamilla-Tilch M, Torres-Carrillo NM, Payan RR, Aguilar-Medina M, Salazar MI, Fafutis-Morris M, Arenas-Guzman R, Estrada-Parra S, Estrada-Garcia I, Granados J. 2013. Association of genetic polymorphism of HLA-DRB1 antigens with the susceptibility to lepromatous leprosy. Biomed Rep 1:945–949.
  159. ^ Hsieh NK, Chu CC, Lee NS, Lee HL, Lin M. 2010. Association of HLA-DRB1*0405 with resistance to multibacillary leprosy in Taiwanese. Hum Immunol 71:712–716.
  160. ^ Zhang F, Liu H, Chen S, Wang C, Zhu C, Zhang L, Chu T, Liu D, Yan X, Liu J. 2009. Evidence for an association of HLA-DRB1*15 and DRB1*09 with leprosy and the impact of DRB1*09 on disease onset in a Chinese Han population. BMC Med Genet 10:133.
  161. ^ da Silva SA, Mazini PS, Reis PG, Sell AM, Tsuneto LT, Peixoto PR, Visentainer JE. 2009. HLA-DR and HLA-DQ alleles in patients from the south of Brazil: markers for leprosy susceptibility and resistance. BMC Infect Dis 9:134.
  162. ^ Vanderborght PR, Pacheco AG, Moraes ME, Antoni G, Romero M, Verville A, Thai VH, Huong NT, Ba NN, Schurr E, Sarno EN, Moraes MO. 2007. HLA-DRB1*04 and DRB1*10 are associated with resistance and susceptibility, respectively, in Brazilian and Vietnamese leprosy patients. Genes Immun 8:320–324.
  163. ^ Zerva L, Cizman B, Mehra NK, Alahari SK, Murali R, Zmijewski CM, Kamoun M, Monos DS. 1996. Arginine at positions 13 or 70-71 in pocket 4 of HLA-DRB1 alleles is associated with susceptibility to tuberculoid leprosy. J Exp Med 183:829–836.
  164. ^ de Vries RR, Mehra NK, Vaidya MC, Gupte MD, Meera Khan P, Van Rood JJ. 1980. HLA-linked control of susceptibility to tuberculoid leprosy and association with HLA-DR types. Tissue Antigens 16:294–304.
  165. ^ Ulvestad E, Williams K, Bo L, Trapp B, Antel J, Mork S. 1994. HLA class II molecules (HLA-DR, -DP, -DQ) on cells in the human CNS studied in situ and in vitro. Immunology 82:535–541.
  166. ^ Tosh K, Meisner S, Siddiqui MR, Balakrishnan K, Ghei S, Golding M, Sengupta U, Pitchappan RM, Hill AV. 2002. A region of chromosome 20 is linked to leprosy susceptibility in a South Indian population. J Infect Dis 186:1190–1193.
  167. ^ Jamieson SE, Miller EN, Black GF, Peacock CS, Cordell HJ, Howson JM, Shaw MA, Burgner D, Xu W, Lins-Lainson Z, Shaw JJ, Ramos F, Silveira F, Blackwell JM. 2004. Evidence for a cluster of genes on chromosome 17q11-q21 controlling susceptibility to tuberculosis and leprosy in Brazilians. Genes Immun 5:46–57.
  168. ^ Rambukkana A. 2010. Usage of signaling in neurodegeneration and regeneration of peripheral nerves by leprosy bacteria. Prog Neurobiol 91:102–107.
  169. ^ Rego JL, Oliveira JM, Santana Nde L, Machado PR, Castellucci LC. 2015. The role of ERBB2 gene polymorphisms in leprosy susceptibility. Braz J Infect Dis 19:206–208.
  170. ^ Araujo SR, Jamieson SE, Dupnik KM, Monteiro GR, Nobre ML, Dias MS, Trindade Neto PB, Queiroz Mdo C, Gomes CE, Blackwell JM, Jeronimo SM. 2014. Examining ERBB2 as a candidate gene for susceptibility to leprosy (Hansen’s disease) in Brazil. Mem Inst Oswaldo Cruz 109:182–188.
  171. a, b Yang Q, Liu H, Low HQ, Wang H, Yu Y, Fu X, Yu G, Chen M, Yan X, Chen S, Huang W, Liu J, Zhang F. 2012. Chromosome 2p14 is linked to susceptibility to leprosy. PLoS One 7:e29747.
  172. ^ Manry J, Quintana-Murci L. 2013. A genome-wide perspective of human diversity and its implications in infectious disease. Cold Spring Harb Perspect Med 3:a012450.
  173. ^ Monot M, Honore N, Garnier T, Araoz R, Coppee JY, Lacroix C, Sow S, Spencer JS, Truman RW, Williams DL, Gelber R, Virmond M, Flageul B, Cho SN, Ji B, Paniz-Mondolfi A, Convit J, Young S, Fine PE, Rasolofo V, Brennan PJ, Cole ST. 2005. On the origin of leprosy. Science 308:1040–1042.
  174. ^ Zhang FR, Huang W, Chen SM, Sun LD, Liu H, Li Y, Cui Y, Yan XX, Yang HT, Yang RD, Chu TS, Zhang C, Zhang L, Han JW, Yu GQ, Quan C, Yu YX, Zhang Z, Shi BQ, Zhang LH, Cheng H, Wang CY, Lin Y, Zheng HF, Fu XA, Zuo XB, Wang Q, Long H, Sun YP, Cheng YL, Tian HQ, Zhou FS, Liu HX, Lu WS, He SM, Du WL, Shen M, Jin QY, Wang Y, Low HQ, Erwin T, Yang NH, Li JY, Zhao X, Jiao YL, Mao LG, Yin G, Jiang ZX, Wang XD, Yu JP, Hu ZH, Gong CH, Liu YQ, Liu RY, Wang DM, Wei D, Liu JX, Cao WK, Cao HZ, Li YP, Yan WG, Wei SY, Wang KJ, Hibberd ML, Yang S, Zhang XJ, Liu, JJ. 2009. Genomewide association study of leprosy. N Engl J Med 361:2609–2618.
  175. a, b, c Wong SH, Hill AV, Vannberg FO, India-Africa-United Kingdom Leprosy Genetics C. 2010. Genomewide association study of leprosy. N Engl J Med 362:1446–1447; author reply 1447–1448.
  176. a, b, c Grant AV, Alter A, Huong NT, Orlova M, Van Thuc N, Ba NN, Thai VH, Abel L, Schurr E, Alcais A. 2012. Crohn’s disease susceptibility genes are associated with leprosy in the Vietnamese population. J Infect Dis 206:1763–1767.
  177. a, b Sales-Marques C, Salomao H, Fava VM, Alvarado-Arnez LE, Amaral EP, Cardoso CC, Dias-Batista IM, da Silva WL, Medeiros P, da Cunha Lopes Virmond M, Lana FC, Pacheco AG, Moraes MO, Mira MT, Pereira Latini AC. 2014. NOD2 and CCDC122-LACC1 genes are associated with leprosy susceptibility in Brazilians. Hum Genet 133:1525–1532.
  178. ^ Berrington WR, Macdonald M, Khadge S, Sapkota BR, Janer M, Hagge DA, Kaplan G, Hawn TR. 2010. Common polymorphisms in the NOD2 gene region are associated with leprosy and its reactive states. J Infect Dis 201:1422–1435.
  179. ^ Wang D, Xu L, Lv L, Su LY, Fan Y, Zhang DF, Bi R, Yu D, Zhang W, Li XA, Li YY, Yao YG. 2015. Association of the LRRK2 genetic polymorphisms with leprosy in Han Chinese from Southwest China. Genes Immun 16:112–119.
  180. ^ Marcinek P, Jha AN, Shinde V, Sundaramoorthy A, Rajkumar R, Suryadevara NC, Neela SK, van Tong H, Balachander V, Valluri VL, Thangaraj K, Velavan TP. 2013. LRRK2 and RIPK2 variants in the NOD 2-mediated signaling pathway are associated with susceptibility to Mycobacterium leprae in Indian populations. PLoS One 8:e73103.
  181. a, b, c Fava VM, Cobat A, Van Thuc N, Latini AC, Stefani MM, Belone AF, Ba NN, Orlova M, Manry J, Mira MT, Thai VH, Abel L, Alcais A, Schurr E. 2015. Association of TNFSF8 regulatory variants with excessive inflammatory responses but not leprosy per se. J Infect Dis 211:968–977.
  182. ^ Fava VM, Manry J, Cobat A, Orlova M, Van Thuc N, Ba NN, Thai VH, Abel L, Alcais A, Schurr E, Canadian Lrrk2 in Inflammation Team (CLINT). 2016. A missense LRRK2 variant is a risk factor for excessive inflammatory responses in leprosy. PLoS Negl Trop Dis 10:e0004412.
  183. ^ Schurr E, Gros P. 2009. A common genetic fingerprint in leprosy and Crohn’s disease? N Engl J Med 361:2666–2668.
  184. a, b Liu H, Irwanto A, Fu X, Yu G, Yu Y, Sun Y, Wang C, Wang Z, Okada Y, Low H, Li Y, Liany H, Chen M, Bao F, Li J, You J, Zhang Q, Liu J, Chu T, Andiappan AK, Wang N, Niu G, Liu D, Yu X, Zhang L, Tian H, Zhou G, Rotzschke O, Chen S, Zhang X, Liu J, Zhang F. 2015. Discovery of six new susceptibility loci and analysis of pleiotropic effects in leprosy. Nat Genet 47:267–271.
  185. a, b Cobat A, Abel L, Alcais A, Schurr E. 2014. A general efficient and flexible approach for genome-wide association analyses of imputed genotypes in family-based designs. Genet Epidemiol 38:560–571.
erythema nodosum leprosum
multibacillary leprosy
paucibacillary leprosy
lepromatous leprosy
tuberculoid leprosy
reversal reaction
Type 2
Type 1
MB
RR
BB
BL
BT
LL
TT
PB