Host genetics has an important role in leprosy, and variants in the shared promoter region of PARK2 and PACRG were the first major susceptibility factors identified by positional cloning1,2. Here we report the linkage disequilibrium mapping of the second linkage peak of our previous genome-wide scan1, located close to the HLA complex. In both a Vietnamese familial sample and an Indian case-control sample, the low-producing lymphotoxin-α (LTA)+80 A allele was significantly associated with an increase in leprosy risk (P = 0.007 and P = 0.01, respectively). Analysis of an additional case-control sample from Brazil and an additional familial sample from Vietnam showed that the LTA+80 effect was much stronger in young individuals. In the combined sample of 298 Vietnamese familial trios, the odds ratio of leprosy for LTA+80 AA/AC versus CC subjects was 2.11 (P = 0.000024), which increased to 5.63 (P = 0.0000004) in the subsample of 121 trios of affected individuals diagnosed before 16 years of age. In addition to identifying LTA as a major gene associated with early-onset leprosy, our study highlights the critical role of case- and population-specific factors in the dissection of susceptibility variants in complex diseases.
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We thank all affected individuals, their families and population controls for participating in this study. We thank T.J. Hudson, P. Lepage, E.N. Sarno and J.L. Casanova for helpful comments and discussions; A. Montpetit and A. Belisle for assistance with high-throughput genotyping; S. Caillat-Zucman for help in HLA genotyping and L. Simkin for technical assistance. This study was supported by a grant from the Canadian Institutes of Health Research (CIHR) to E.S. A. Alter holds a graduate studentship from the Natural Science and Engineering Research Council of Canada (NSERC). A. Alter and M.O. are supported by the CIHR Strategic Training Centre in the Integrative Biology of Infectious Diseases and Autoimmunity. G.A. is supported by Fondation pour la Recherche Médicale. E.S. is a Chercheur National of the Fonds de Recherche en Santé du Québec and an International Research Scholar of the Howard Hughes Medical Institute. A. Alcaïs and L.A. are supported by the Assistance Publique-Hopitaux de Paris, Programme de Recherche Fondamentale en Microbiologie Maladies Infectieuses et Parasitaires and the Agence Nationale de la Recherche of the Ministère Français de l'Education Nationale de la Recherche et de la Technologie. Requests for materials should be addressed to L.A. (firstname.lastname@example.org) or E.S. (email@example.com).
Characterization of 418 SNPs used in the primary scan of 10.4-Mb interval on human chromosome region 6p21 in 388 unrelated Vietnamese individuals.
Family-based association scan of the 10.4-Mb region on chromosome 6p21 in 194 Vietnamese trios.
rs2071590, rs3128961, rs937662 and rs707928 are associated with leprosy independently of the two PARK2/PACRG SNPs.
Bin structure of 33 informative SNPs spanning the 90-kb target interval in the HLA class III region, analyzed in the Vietnamese sample.
Characterization of 31 SNPs used in the linkage disequilibrium mapping of a 0.82-MB interval covering the whole HLA class III region in 54 unrelated Vietnamese individuals.
Characterization of HLA class I alleles in 37 unrelated Vietnamese individuals.
Multivariate analysis in the Indian sample.