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Leprosy is a chronic infection of the skin and peripheral nerves caused by Mycobacterium leprae. Despite recent improvements in disease control, leprosy remains an important cause of infectious disability globally. Large-scale genetic association studies in Chinese, Vietnamese and Indian populations have identified over 30 susceptibility loci for leprosy. There is a significant burden of leprosy in Africa, however it is uncertain whether the findings of published genetic association studies are generalizable to African populations. To address this, we conducted a genome-wide association study (GWAS) of leprosy in Malawian (327 cases, 436 controls) and Malian (247 cases, 368 controls) individuals. In that analysis, we replicated four risk loci previously reported in China, Vietnam and India; MHC Class I and II, LACC1 and SLC29A3. We further identified a novel leprosy susceptibility locus at 10q24 (rs2015583; combined p = 8.81 × 10-9; OR = 0.51 [95% CI 0.40 - 0.64]). Using publicly-available data we characterise regulatory activity at this locus, identifying ACTR1A as a candidate mediator of leprosy risk. This locus shows evidence of recent positive selection and demonstrates pleiotropy with established risk loci for inflammatory bowel disease and childhood-onset asthma. A shared genetic architecture for leprosy and inflammatory bowel disease has been previously described. We expand on this, strengthening the hypothesis that selection pressure driven by leprosy has shaped the evolution of autoimmune and atopic disease in modern populations. More broadly, our data highlights the importance of defining the genetic architecture of disease across genetically diverse populations, and that disease insights derived from GWAS in one population may not translate to all affected populations., Competing Interests: The authors have declared that no competing interests exist.

We present a large case-control candidate gene study of leprosy susceptibility. Thirty-eight polymorphic sites from 13 genes were investigated for their role in susceptibility to leprosy by comparing 270 cases with 452 controls in Karonga district, northern Malawi. Homozygotes for a silent T-->C change in codon 352 of the vitamin D receptor gene appeared to be at high risk (odds ratio [OR] = 4.3, 95% confidence interval [CI] = 1.6-11.4, P = 0.004), while homozygotes for the McCoy b blood group defining variant K1590E in exon 29 of the complement receptor 1 (formerly CD35) gene appeared to be protected (OR = 0.3, 95% CI = 0.1-0.8, P = 0.02). Borderline evidence for association with leprosy susceptibility was found for seven polymorphic sites in an additional six genes. Some of these apparent associations may be false-positive results from multiple comparisons, and several associations suggested by studies in other populations were not replicated here. These data provide evidence of inter-population heterogeneity in leprosy susceptibility.

Leprosy is a chronic disease caused by infection with Mycobacterium leprae, which is manifested across a wide clinical spectrum. There is evidence that susceptibility both to leprosy per se and to the clinical type of leprosy is influenced by host genetic factors. This paper describes the application of an identity by descent regression search for genetic determinants of leprosy type among families from Karonga District, Northern Malawi. Suggestive evidence was found for linkage to leprosy type on chr 21q22 (P<0.001). The methodological implications of the approach and the findings are discussed.

The relative recurrence risk ratio lambdaR (and particularly the sibling recurrence risk ratio, lambdaS) is often of interest to those wanting to quantify the genetic contribution towards risk of disease or to discriminate between different genetic models. However, estimating lambdaR for complex diseases for which genetic and environmental risk factors are both involved is not straightforward. Ignoring environmental factors may lead to inflated estimates of lambdaR. We present a marginal model which uses a copula function to model the association in cumulative incidence rates between pairs of relatives. This model is applicable to present-state data and allows estimation of risk of disease in a pair of relatives (and hence lambdaR), given measured environmental covariates. We apply the model to leprosy among sibling pairs from the Karonga district, Malawi. If risk factors are ignored, the apparent lambdaS in this population is over 3. Accounting for known nongenetic risk factors reduces it to just under 2., (Copyright 2003 Wiley-Liss, Inc.)

Leprosy is a chronic disease caused by infection with Mycobacterium leprae. Susceptibility to leprosy is influenced by both genetic and non-genetic factors and the disease is known to cluster in families. One measure of genetic effect is the relative recurrence risk ratio, lambdaR. Estimates of this parameter can be inflated if environmental risk factors which also cluster in families, such as household contact, are not properly accounted for. We present the results of fitting a cross ratio model that allows estimation of the odds ratio of disease conditional on disease or no disease in a given relative, given measured covariates. From this model we can predict fitted values for lambdaR that represent the familial risk not accounted for by other covariates including observed household contact. If all covariates could be measured, this would be the 'genetic relative risk ratio'. We find lambdaR > 1 for all relative pairs except grandparent-grandchild, and lambdaR > 2 for siblings. Though not in itself evidence for a strong genetic susceptibility to leprosy, this result is consistent with much other evidence which suggests susceptibility to leprosy is under the control of many factors, the strongest of which may be non-genetic, with host genetics playing a small but significant role.

Data on household and dwelling contact with known leprosy cases were available on more than 80,000 initially disease-free individuals followed up during the 1980s in a rural district of northern Malawi. A total of 331 new cases of leprosy were diagnosed among them. Individuals recorded as living in household or dwelling contact with multibacillary patients at the start of follow-up were at approximately five- to eightfold increased risk of leprosy, respectively, compared with individuals not living in such households or dwellings. Individuals living in household or dwelling contact with paucibacillary cases were both at approximately twofold increased risk. The higher risk associated with multibacillary contact and the fact that dwelling contact entailed a greater risk than household contact if the association was with multibacillary, but not with paucibacillary, disease suggest that paucibacillary cases may not themselves be sources of transmission, but rather just markers that a household has had contact with some (outside) source of infection. When household contact was considered alone, the risks of disease were appreciably higher for younger than for older contacts and for male compared with female contacts. Despite the elevated risk of leprosy associated with household or dwelling contact, only 15% of all incidence cases arose among recognized household contacts. Given the dynamic nature of household membership and consequent misclassification of contact status, the true contribution to overall incidence of contact within household or dwelling settings is likely to be much higher than this, perhaps 30% or higher. Considering the predilection of males for infectious multibacillary forms of the disease, the transmission of Mycobacterium leprae at an early age, in particular to males, may be of particular importance for the persistence of leprosy in endemic communities. Although residential contact with a multibacillary case is the strongest known determinant of leprosy risk, the vast majority of such contacts never manifest disease, which indicates a crucial role for genetic and/or environmental factors in the transmission of M. leprae infection and/or the pathogenesis of clinical leprosy.