Chromosome 6q25 is linked to susceptibility to leprosy in a Vietnamese population

Leprosy, a chronic infectious disease caused by Mycobacterium leprae, affects an estimated 700,000 persons each year1. Clinically, leprosy can be categorized as paucibacillary or multibacillary disease2. These clinical forms develop in persons that are intrinsically susceptible to leprosy per se, that is, leprosy independent of its specific clinical manifestation3. We report here on a genome-wide search for loci controlling susceptibility to leprosy per se in a panel of 86 families including 205 siblings affected with leprosy from Southern Vietnam. Using model-free linkage analysis, we found significant evidence for a susceptibility gene on chromosome region 6q25 (maximum likelihood binomial (MLB) lod score 4.31; P =5 × 10‐6). We confirmed this by family-based association analysis in an independent panel of 208 Vietnamese leprosy simplex families. Of seven microsatellite markers underlying the linkage peak, alleles of two markers (D6S1035 and D6S305) showed strong evidence for association with leprosy (P = 6.7 × 10 ‐4 and P = 5.9 × 10 ‐5 , respectively). Persons who experience sustained exposure to M. leprae may develop a single skin lesion due to M. leprae infection that often goes undetected and is self-healing 2 . Among those that do not self-heal and do not receive treatment, the disease may progress to a spectrum of clinical presentations 4 . Currently, approximately 60% of new cases present with paucibacillary leprosy, characterized by low numbers of skin lesions and absence of histologically detectable M. leprae in those lesions. The remaining 40% of new cases present as multibacillary cases, characterized by high numbers of skin lesions that often contain readily detectable leprosy bacilli 1 . The two-step nature of leprosy pathogenesis is reflected by an apparent two-stage genetic control of the disease in which some loci affect intrinsic susceptibility to leprosy (leprosy per se) and others modify the clinical form of the disease 3 . Effective chemotherapeutic treatment is available for leprosy, and the only known M. leprae reservoir of biological significance is humans. Yet the world-wide incidence of leprosy has shown little decrease over the last 15 years. The reason for this continued high incidence is unknown, indicating that important aspects of the intricate relationship between M. leprae and its human host are not yet known. Tw in studies and family segregation analyses suggest the existence of a strong genetic component for susceptibility to leprosy in human populations 5,6 . Variants in VDR 7 , HLA-DR2 specificities 8 , TAP1 and TAP2 (ref. 9), SLC11A1 (also called NRAMP1; refs. 10,11) and TNF 12 are linked or associated with leprosy or its subtypes. But none of these genes can account for either the large genetic effect detected in several complex analy