02521nas a2200529   4500000000100000008004100001260001300042653001500055653001000070653001700080653001200097653001100109653002500120653001000145653003800155653001100193653001000204653001200214653002700226653002200253653001600275653003600291653002000327653001700347653001200364100001400376700001200390700001300402700001300415700001400428700001200442700001900454700001300473700001200486700001000498700001400508700001400522700001300536700001200549700001300561700001100574245012500585300001100710490000700721520124900728022001401977       2007                            d  c2007 Apr10aAdolescent10aAdult10aAge of Onset10aAlleles10aBrazil10aCase-Control Studies10aChild10aGenetic Predisposition to Disease10aHumans10aIndia10aleprosy10aLinkage Disequilibrium10aLymphotoxin-alpha10aMiddle Aged10aPolymorphism, Single Nucleotide10aResearch Design10aRisk Factors10aVietnam1 aAlcaïs A1 aAlter A1 aAntoni G1 aOrlova M1 aNguyen VT1 aSingh M1 aVanderborght P1 aKatoch K1 aMira MT1 aVu HT1 aNgyuen TH1 aNguyen NB1 aMoraes M1 aMehra N1 aSchurr E1 aAbel L00aStepwise replication identifies a low-producing lymphotoxin-alpha allele as a major risk factor for early-onset leprosy.  a517-220 v393 a<p>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 cloning. Here we report the linkage disequilibrium mapping of the second linkage peak of our previous genome-wide scan, located close to the HLA complex. In both a Vietnamese familial sample and an Indian case-control sample, the low-producing lymphotoxin-alpha (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.</p>  a1061-4036