Leprosy, Susceptibility To, 1

LPRS1 is a locus for susceptibility to paucibacillary leprosy on chromosome 10p13. In addition to information on LPRS1 (see MAPPING), this entry includes a discussion of susceptibility to leprosy in general and information on genetic heterogeneity (see HETEROGENEITY).

Leprosy is a disease of peripheral sensory nerves that results from infection with Mycobacterium leprae, which was first detected in Bergen, Norway, in 1873 by Dr. Armauer Hansen. It can be effectively treated with long-term multidrug therapy. In 2006, more than 250,000 new cases of leprosy were reported to the World Health Organization. Many infected individuals have self-healing indeterminate lesions. Others with initially indeterminate lesions proceed to develop leprosy that can be classified along a clinical and immunologic spectrum from paucibacillary or tuberculoid leprosy to multibacillary or lepromatous leprosy. Most patients fall somewhere between these 2 polar forms of the disease and are classified, using pathology-based criteria developed by Ridley and Jopling (1966), as borderline tuberculoid, midborderline, and borderline lepromatous. The paucibacillary form is associated with strong M. leprae-specific cell-mediated immunity (CMI), whereas the multibacillary form is notable for the lack of antigen-specific CMI. The prevalence of paucibacillary versus multibacillary leprosy varies in different populations. M. leprae cannot be cultured in vitro and grows slowly in the footpads of mice, the liver and spleen of armadillos, and in some nonhuman primates. A genetic component to leprosy susceptibility has long been suspected. While contact with a multibacillary patient increases the relative risk of acquiring disease, most new patients have no known contact with other patients. For further information, see reviews by Fitness et al. (2002), Mira (2006), Moraes et al. (2006), Scollard et al. (2006), and Alter et al. (2008).

The neuropathy of leprosy is caused in part by invasion of peripheral nerves by Mycobacterium leprae. In lepromatous leprosy, protective immune responses are absent and bacteria can spread freely through skin and into peripheral nerves. Spread to deeper tissues is limited because the bacteria reproduce best at temperatures of 27 degrees to 30 degrees C. In tuberculoid leprosy, protective immune responses are present and the disease is more circumscribed, although damage to nerves still results. The Schwann cell is an important target for bacterial invasion of nerves. Rambukkana et al. (1997) demonstrated that M. leprae binds to the G domain of the alpha-2 chain of laminin-2 (LAMA2; 156225). Rambukkana et al. (1998) showed that alpha-dystroglycan (128239) is a cell receptor for the binding of G domain-coated bacteria to Schwann cells.

By immunohistochemistry, Sieling et al. (1999) examined dermal leprosy lesions from patients with the tuberculoid form of the disease, which is associated with high M. leprae-specific cell-mediated immunity (CMI), and observed strong induction of CD1A (188370), CD1B (188360), and CD1C (188340) expression. In contrast, they found that lesions from patients with the lepromatous form of the disease, which is associated with weak or absent specific CMI, did not express CD1 antigens. Moreover, by 2-color immunofluorescence analysis, Sieling et al. (1999) demonstrated that the cells expressing CD1 antigens were CD83 (604534)-positive dendritic cells that were shown to be highly efficient antigen-presenting cells for CD1B-restricted T cells in vitro.

Ng et al. (2000) provided evidence for the involvement of the specific trisaccharide unit of the phenolic glycolipid-1 (PGL1) of Mycobacterium leprae in determining the bacterial predilection to the peripheral nerve. PGL1 binds specifically to the native laminin-2 in the basal lamina of Schwann cell-axon units. This binding is mediated by the LG1, LG4, and LG5 modules present in the naturally cleaved fragments of the peripheral nerve LAMA2 chain, and is inhibited by the synthetic terminal trisaccharide of PGL1. PGL1 is involved in the M. leprae invasion of Schwann cells through the basal lamina in a laminin-2-dependent pathway. The results indicated a novel role of a bacterial glycolipid in determining the nerve predilection of a human pathogen.

Leprosy presents as a clinical and immunologic spectrum of disease. With the use of gene expression profiling, Bleharski et al. (2003) observed that a distinction in gene expression correlated with and accurately classified the clinical form of the disease. Genes belonging to the leukocyte immunoglobulin-like receptor (LIR) family were significantly upregulated in lesions of lepromatous patients suffering from the disseminated form of the infection. In functional studies, LIR7 (604812) suppressed innate host defense mechanisms by shifting monocyte production from interleukin-12 (see 161560) toward interleukin-10 (IL10; 124092) and by blocking antimicrobial activity triggered by Toll-like receptors (e.g., 601194).

Schwann cells are thought to be the primary host cells for Mycobacterium leprae, and demyelination is a common pathologic feature in leprosy and other neurodegenerative diseases. Using immunoblot and immunofluorescence analyses, Tapinos et al. (2006) observed marked, early phosphorylation of ERK1 (MAPK1; 176948)/ERK2 (MAPK3; 601795) accompanied by demyelination in the absence of apoptosis after exposure of rat and human Schwann cell cultures to M. leprae. The M. leprae-induced ERK1/ERK2 activation was mediated by binding of M. leprae to the extracellular domain of ERBB2 (164870), leading to its phosphorylation without ERBB3 (190151) heterodimerization. Tapinos et al. (2006) concluded that M. leprae binds ERBB2 directly and induces excessive ERK1/ERK2 signaling, which subsequently causes demyelination. They proposed that ERBB2 or other receptor tyrosine kinases may serve as key sites for initiating demyelination.

Tanigawa et al. (2009) found that CORO1A (605000) suppressed TLR signaling following expression in a human monocytic cell line. TLR2 (603028)-mediated activation of the innate immune response resulted in suppression of CORO1A expression. However, in cells infected with M. leprae, TLR2-mediated CORO1A suppression was inhibited, as was NFKB (see 164011) activation. Tanigawa et al. (2009) proposed that the balance between TLR2-mediated signaling and CORO1A expression is key in determining the fate of M. leprae after infection.

M. leprae survives and replicates within lipid droplets stored in the enlarged phagosomes of histiocytes, a typical feature of lepromatous leprosy thought to be an important nutrient source for the bacillus. Using immunohistochemistry, Tanigawa et al. (2008) demonstrated that the lipid droplet-associated proteins ADRP (PLIN2; 103195) and PLIN1 (170290) localized to the enlarged phagosomes of macrophages in lepromatous leprosy lesions. ADRP expression was induced in a monocyte cell line when live, but not dead, M. leprae was added. M. leprae could also inhibit the normal suppression of ADRP and PLIN1 expression mediated by peptidoglycan, a TLR2 ligand. Tanigawa et al. (2008) proposed that M. leprae can actively induce and support ADRP/PLIN1 expression to facilitate intraphagosomal lipid accumulation and a suitable environment for survival within macrophages.

Independently, Mattos et al. (2010) demonstrated the presence of ADRP in foamy macrophages of lepromatous leprosy patients and in human monocytes and mouse macrophages. In addition, lipid bodies containing ADRP were taken up from infected cells by neighboring uninfected macrophages in a partially TLR2- and TLR6 (605403)-dependent manner. Flow cytometric analysis indicated a correlation between lipid body formation and prostaglandin E2 production. Mattos et al. (2010) concluded that M. leprae-induced lipid bodies are intracellular sites for eicosanoid synthesis and proposed that foamy cells may be critical in subverting the immune response in lepromatous leprosy.

Behr et al. (2010) reviewed several studies implicating stimulation of antiinflammatory molecules and inhibition of autophagy by virulent mycobacteria as a means to evade the host immune system.

Using RT-PCR and immunohistochemistry, Teles et al. (2013) demonstrated increased expression of the type I interferon IFNB (IFNB1; 147640) in lesions of lepromatous leprosy (L-lep) patients compared with tuberculoid leprosy (T-lep) patients. Expression of an IFNB receptor, IFNAR1 (107450), was also increased in L-lep lesions. Increased expression of IFNB was associated with increased expression of IL10, and IFNB alone induced IL10 expression in mononuclear cells in vitro. There was an inverse correlation between IL10 expression and expression of the antimicrobial peptides CAMP (600474) and DEFB4 (DEFB4A; 602215). Measurement of uncultivable Mycobacterium leprae viability based on the ratio of M. leprae 16S rRNA to M. leprae repetitive element DNA indicated that IFNG (147570) induced antimicrobial activity against M. leprae in monocytes by about 35%, which was abrogated by the addition of either IFNB or IL10. Teles et al. (2013) concluded that the type I interferon gene expression program prominently expressed in L-lep lesions inhibits the IFNG-induced antimicrobial response against M. leprae through an intermediary, IL10.

Beiguelman (1968) reviewed the evidence for an inherited basis of vulnerability to leprosy and the familial pattern of the Mitsuda (late lepromin) reaction. The following observations suggest heritable susceptibility to leprosy: (1) The disease fails to manifest itself in most exposed persons, even heavily exposed persons. (2) The frequency of leprosy among relatives of index cases is higher when the subjects are from a consanguineous marriage. (3) Different racial stocks living in the same area show different prevalence rates. (4) Even in populations with a high frequency, familial aggregation is demonstrable, i.e., the distribution in sibships is not random. (5) The distribution of polar types (typical lepromatous or malignant versus typical tuberculoid or benign) is not at random among affected sib pairs. (6) One polar form cannot be converted into the other by environmental agents.

Beiguelman and Quagliato (1965) studied the familial distribution of the Mitsuda reaction and presented evidence that could be interpreted as supporting monogenic determination.

De Vries et al. (1976) found that sibs with the same type of leprosy showed a significant excess of identical HLA haplotypes.

Shields et al. (1987) studied the distribution of leprosy in an isolated population in Papua New Guinea. Leprosy was found to be strongly familial within the Karimui. Segregation analysis could not differentiate between a mendelian genetic and a purely environmental hypothesis. The basic social unit within this population was not the family but the community, and thus the spread of an infectious disease would be expected to be communal and not familial.

Abel et al. (1987) concluded that 1 or more recessive major genes control susceptibility to leprosy per se (LPS) and to nonlepromatous leprosy (NLL), a subtype of leprosy. Their studies were performed in 27 large pedigrees observed in the Caribbean island Desirade. Linkage analyses performed with LPS and NLL as independent traits excluded tight HLA linkage for NLL. Abel and Demenais (1988) presented the full data, which, in conjunction with experimental data in previous studies, led them to conclude that the gene for susceptibility to leprosy per se and that for susceptibility to nonlepromatous leprosy may be different, acting at successive stages of the immune response to infection with Mycobacterium leprae. They thought that the 2 types of susceptibilities may be recessive and codominant, respectively.

Feitosa et al. (1995) examined data on 10,886 cases of leprosy distributed among 1,568 families in the Campinas area of Sao Paulo, Brazil. Complex segregation analysis suggested the presence of a recessive major gene controlling susceptibility to leprosy per se, with a frequency of approximately 0.05, although there were deviations from the expected Mendelian segregation proportions. They could find no evidence, however, to suggest a unique genetic determinant for either the lepromatous or tuberculoid subtypes.

LPRS1 on Chromosome 10p13

Siddiqui et al. (2001) reported a genetic linkage scan of the genomes of 224 families from South India, containing 245 independent affected sib pairs with leprosy, mainly of the paucibacillary type. In a 2-stage genome scan using 396 microsatellite markers, Siddiqui et al. (2001) found significant linkage (maximum multipoint lod score = 4.09, p = 0.00002) to chromosome 10p13, corresponding to marker D10S1661. Siddiqui et al. (2001) did not observe significant linkage from microsatellite markers within the MHC region (see 142800) or flanking the NRAMP1 gene (SLC11A1; 600266), indicating that neither of these regions encodes a major susceptibility locus in this population. The estimated locus-specific lambda-S (the ratio of the risk for sibs of patients to that for the general population) for the peak linkage on chromosome 10p13 in the South Indian population is 1.66. Thus, this locus may make an appreciable contribution to the total genetic component.

Clinically, leprosy can be categorized as paucibacillary or multibacillary disease (Jacobson and Krahenbuhl, 1999). Mira et al. (2003) performed a linkage homogeneity test for the 6q25 (LPRS2; 607572) and 10p13 regions across leprosy phenotypes. They carried out linkage analysis on 3 subsamples that included families with only paucibacillary cases, with only multibacillary cases, or with both pauci- and multibacillary cases. They found no heterogeneity of linkage between clinical form of leprosy and the 6q25 region, and the estimated proportion of alleles shared identical by descent (IBD) by affected sib pairs was similar among the 3 categories. In the same analysis using the 10p13 region, reported by Siddiqui et al. (2001) to be linked to paucibacillary leprosy, Mira et al. (2003) detected significant evidence for heterogeneity of linkage according to clinical form of leprosy, with a marked difference in the estimated proportion of alleles shared IBD by affected sibs. Linkage to 10p13 was represented largely by families with paucibacillary leprosy. Mira et al. (2003) concluded that the 6q25 locus (LPRS2) controls leprosy per se, whereas the locus on 10p13 (LPRS1) is related to paucibacillary leprosy.

LPRS2 on Chromosome 6q25-q27

See 607572 for information on LPRS2, a leprosy susceptibility locus on chromosome 6q25-q27.

LPRS3 on Chromosome 4q32

See 246300 for information on LPRS3, a form of leprosy susceptibility associated with a polymorphism in the TLR2 gene (603028) on chromosome 4q32.

LPRS4 on Chromosome 6p21.3

See 610988 for information on LPRS4, a leprosy susceptibility locus on chromosome 6p21.3. A polymorphism in the LTA gene (153440) is associated with susceptibility to early-onset leprosy and accounts, in part, for susceptibility to leprosy linked to chromosome 6p21.3 (LPRS4).

LPRS5 on Chromosome 4p14

See 613223 for information on LPRS5, a form of leprosy susceptibility associated with a polymorphism in the TLR1 gene (601194) on chromosome 4p14. A polymorphism in the TLR1 gene is also associated with protection against leprosy.

LPRS6 on Chromosome 13q14.11

See 613407 for information on LPRS6, a leprosy susceptibility locus on chromosome 13q14.11.

Associations Pending Confirmation

Kaur et al. (1997) studied COL3A1 (120180) and CTLA4 (123890) polymorphisms with respect to susceptibility to leprosy in a New Delhi population. These loci were selected because they are located on human chromosome 2q31-q33, a region that appears to have homology of synteny to the region of the mouse genome carrying the Bcg locus, which influences susceptibility to intracellular parasites. The 250-bp polymorphism of COL3A1, when present in the homozygous form, was associated with the multibacillary form of leprosy (p less than 0.05; relative risk = 5.5), although the results did not reach statistical significance. A 312-bp COL3A1 allele was significantly associated with nonresponsiveness to M. leprae antigens in vitro (p = 0.01). The 104-bp allele of CTLA4 was not found in any of the 25 leprosy patients. This suggested a possible correlation of homozygosity for this allele with health, and its absence as a possible risk factor for leprosy (p less than 0.05; relative risk = 25.83).

By sib-pair linkage analyses of 168 members of twenty 2-generation multiplex leprosy (approximately 50% multibacillary) families of Vietnamese and Chinese descent, Abel et al. (1998) determined that there was a significant (p less than 0.02) nonrandom segregation of an 'extended' chromosome 2 haplotype. The extended haplotype included NRAMP1 (SLC11A1; 600266), a RFLP within the TNP1 gene (190231), and 3 highly polymorphic chromosome 2 D-segment markers (D2S1471, D2S173, and D2S104). Analysis of an intragenic haplotype of 6 diallelic NRAMP1 polymorphisms showed that the association approached statistical significance (p less than 0.06). Both the extended and the intragenic haplotype sharing were stronger and statistically significant among the 16 Vietnamese families. Monte Carlo simulations suggested that leprosy susceptibility might be associated with NRAMP1 and additional genetic loci.

The Mitsuda test, unlike the 3-day tuberculin test for diagnosis of tuberculosis infection, measures the response 3 or 4 weeks after the intradermal injection of heat-killed M. leprae (or lepromin) and has a high prognostic value for susceptibility (when negative) or resistance (when positive) to the multibacillary or lepromatous form of leprosy. By linkage analysis between the NRAMP1 genome region and the extent of the Mitsuda skin reaction in 118 sibs (half with leprosy) of families with leprosy in Vietnam, Alcais et al. (2000) observed significant linkage between NRAMP1 and the Mitsuda reaction either as a quantitative or a categorical trait, independent of leprosy status. Alcais et al. (2000) found that lepromatous subjects (22 individuals) had small (2.2 mm) mean reaction sizes, whereas tuberculoid (22 individuals), indeterminate (15 individuals), and healthy (59 individuals) subjects had larger reactions (7.5, 6.2, and 6.4 mm, respectively).

A region of mouse chromosome 11 that is syntenic with human chromosome 17q11-q21 is known to carry a susceptibility gene(s) for intramacrophage pathogens. To examine this region in humans, Jamieson et al. (2004) studied 92 multicase tuberculosis (607948) families (627 individuals) and 72 multicase leprosy families (372 individuals) from Brazil. Multipoint nonparametric analysis using 16 microsatellites showed 2 peaks of linkage for leprosy at D17S250 and D17S1795 and a single peak for tuberculosis at D17S250. Combined analysis showed significant linkage at D17S250, equivalent to an allele sharing lod score of 2.48 (p of 0.0004). Jamieson et al. (2004) typed 49 informative SNPs in candidate genes, and family-based allelic testing that was robust to family clustering showed significant associations with tuberculosis susceptibility at 4 genes, NOS2A (163730), CCL18 (603757), CCL4 (182284), and STAT5B (604260), separated by intervals up to several Mb. Stepwise conditional logistic regression analysis using a case/pseudo-control data set showed that the 4 genes contributed separate main effects, consistent with a cluster of susceptibility genes across chromosome 17q11.2 that regulate mycobacterial infections.

In a 2-stage genomewide scan of 71 multicase leprosy families (365 individuals) in Brazil, Miller et al. (2004) found suggestive evidence for linkage to chromosomes 6p21.32, 17q22, and 20p13. Peak lod scores for these regions were 3.23 (p of 5.8 x 10(-5)), 2.38 (p of 0.0005), and 1.51 (p of 0.004), respectively. The peak lod score for chromosome 6p21.32 was obtained at HLA-DQA (146880).

Zhang et al. (2009) performed a genomewide association study (GWAS) to identify leprosy susceptibility loci in 706 patients and 1,225 controls, all of whom were self-identified Han Chinese from eastern China. Diagnosis was made on the basis of the consensus of at least 2 dermatologists. Patients and controls reported an absence of M. tuberculosis and other chronic infections. Controls lacked a history of leprosy in themselves and their families, as well as autoimmune and systemic disorders. The initial GWAS revealed 93 SNPs that showed strongest association with leprosy. Genotyping of these 93 SNPs in 3 replication studies showed highly significant associations (P less than 1.00 x 10(-10) for all analyses combined) with SNPs in or near the CCDC122 (613408), C13ORF31 (613409), NOD2 (605956), TNFSF15 (604052), and RIPK2 (603455) genes and the HLA-DR (see 142857)/HLA-DQ (see 604305) locus, as well as a weaker association (P = 5.10 x 10(-5)) with a SNP in the LRRK2 gene (609007). These replication studies included 3,254 patients and 5,955 controls who were predominantly Han Chinese from eastern China, as well as some individuals from non-Han ethnic groups from southern China. All the SNPs, with the possible exception of that in LRRK2, were associated with both multibacillary and paucibacillary forms of leprosy. However, the associations between SNPs in C13ORF1, LRRK2, NOD2, and RIPK2 were stronger for multibacillary than paucibacillary leprosy. Zhang et al. (2009) concluded that genes in the NOD2 signaling pathway, which regulates the innate immune response, are associated with susceptibility to infection with M. leprae. See LPRS6 (613407) for further information on the leprosy susceptibility locus on chromosome 13q14.11, which includes the CCDC122 and C13ORF31 genes.

In an editorial, Schurr and Gros (2009) stated that Zhang et al. (2009) not only identified genes and biologic pathways that might be targeted for pharmacologic intervention in leprosy, but also in Crohn disease (266600). They noted that some cases of Crohn disease may have a mycobacterial cause, and that variation in NOD2 and TNFSF15, both of which were identified as leprosy susceptibility loci by Zhang et al. (2009), is associated with Crohn disease (see IBD1, 266600, and IBD16, 612259, respectively). Greenstein and Brown (2010) concurred with Schurr and Gros (2009) and noted that cattle with a Nod2 defect are more likely to contract Johne disease, a ruminant counterpart to Crohn disease.

Zhang et al. (2011) performed an expanded GWAS analysis by combining their previous data set of 706 Chinese Han individuals with leprosy and 1,225 Chinese Han controls (Zhang et al., 2009) with an additional 4,367 Chinese Han controls. Consistent with their previous GWAS, they observed strong associations within the HLA-DR and HLA-DQA1 loci and with the previously identified genes outside of the MHC loci, including NOD2 and RIPK2. An expanded analysis revealed additional associations with SNPs in novel loci, and Zhang et al. (2011) genotyped the top 24 SNPs within 22 loci in 3 independent replication samples totaling 3,301 individuals with leprosy and 5,229 controls from Chinese Han populations from north and south China, as well as southern Chinese minority populations. Two novel loci showed genomewide significance: rs2275606 near the RAB32 gene (612906) on chromosome 6q24.3 (combined P = 3.94 x 10-14; odds ratio = 1.30), and rs3762318 near the IL23R gene (607562) on chromosome 1p31.3 (combined P = 3.27 x 10-11; odds ratio = 0.69). A SNP near the CYLD gene (605018) on chromosome 16q12.1, rs16948876, also showed genomewide significance (combined P = 1.64 x 10-10; odds ratio = 1.56), but the authors noted that further study was needed to confirm whether it was an independent association. In addition, Zhang et al. (2011) presented evidence for interaction between SNPs in NOD2 (rs9302752) and RIPK2 (rs40457) and suggested that independent studies were needed to validate the finding. Zhang et al. (2011) concluded that the identification of IL23R as a leprosy susceptibility gene establishes the involvement of innate immunity in the pathogenesis of leprosy, whereas the identification of RAB32 as a leprosy susceptibility gene suggests that autophagy may be involved in host defense against M. leprae infection.

By evaluating 4 TLR4 (603030) SNPs in 441 Ethiopian leprosy patients and 197 healthy controls, Bochud et al. (2009) found that the minor alleles of the 896G-A (D299G; 603030.0001) and 1196C-T (T399I; 603030.0002) SNPs were associated with a significant protective effect against the disease. TLR4 SNPs were not significantly associated with disease type. Stimulation of untyped monocytes with M. leprae partially inhibited their subsequent cytokine response to lipopolysaccharide. Bochud et al. (2009) proposed that TLR4 polymorphisms are associated with susceptibility to leprosy, possibly due to M. leprae-mediated modulation of TLR4 signaling.

Given the altered balance of pro- and antiinflammatory eicosanoids in zebrafish with mutations in leukotriene A4 hydrolase (LTA4H; 151570), Tobin et al. (2010) hypothesized that LTA4H polymorphisms may alter the response to human mycobacterial infections that cause tuberculosis (TB; see 607948) and leprosy. Comparison of 692 Vietnamese HIV-seronegative pulmonary and meningeal TB patients with 759 healthy controls revealed fewer heterozygotes at each of 6 LTA4H SNPs (rs1978331, rs17677715, rs2247570, rs2660898, rs2660845, and rs2540475) in TB patients. Comparison of frequencies of heterozygotes versus homozygotes among TB patients and controls yielded odds ratios (ORs) less than 1 at all 6 SNPs. Adjusting for multiple comparisons, association of heterozygosity with lower incidence of TB was significant at rs1978331 and rs2660898 (P = 0.011 and 0.0003, respectively, after Bonferroni correction), the 2 SNPs intragenic in LTA4H with common minor allele frequencies. Among 53 meningeal TB patients heterozygous at both rs1978331 and rs2660898, only 4% died within 300 days after diagnosis. In contrast, mortality was 16% among 156 meningeal TB patients homozygous at these SNPs. Evaluation of 335 paucibacillary leprosy patients, 121 multibacillary (MB) leprosy patients with erythema nodosum leprosum (ENL), and 443 MB leprosy patients without ENL from Nepal showed that LTA4H heterozygosity at rs1978331 and rs2660898 was significantly associated with a lower incidence of MB leprosy without ENL (OR = 0.62 and P = 0.001 for rs1978331, and OR = 0.70 and P = 0.021 for rs2660898). Tobin et al. (2010) concluded that LTA4H heterozygosity is associated with protection from TB infection, lower mortality among patients with severe TB infection, and protection from development of severe leprosy disease among exposed individuals. They proposed that LTA4H heterozygosity may reflect an optimal balance, or rheostat mechanism, of pro- and antiinflammatory eicosanoids (i.e., LTB4 and LXA4, respectively).

Liu et al. (2012) conducted a multistage genetic association study of 133 inflammatory bowel disease susceptibility loci in 4,971 leprosy patients and 5,503 controls from a Chinese population. They identified associations at rs2058660 on chromosome 2q12.1 (P = 4.57 x 10(-19); OR = 1.30) and rs6871626 on chromosome 5q33.3 (P = 3.95 x 10(-18); OR = 0.75), implicating IL18RAP (604509)/IL18R1 (604494) and IL12B (161561), respectively, as susceptibility genes for leprosy. Liu et al. (2012) proposed that these genes have an important role in transcriptional regulation of IFNG (147570) production in leprosy and that there are shared genetic susceptibility genes between infectious and inflammatory diseases.

Monot et al. (2005) used comparative genomics to demonstrate that all extant cases of leprosy were attributable to a single clone whose dissemination worldwide can be retraced from analysis of very rare single-nucleotide polymorphisms. The disease seems to have originated in Eastern Africa or the Near East and spread with successive human migrations. Europeans or North Africans introduced leprosy into West Africa and the Americas in the past 500 years.