title: Stepwise replication identifies a low-producing lymphotoxin-alpha allele as a major risk factor for early-onset leprosy.
abstract: 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.
authors.affiliation: Laboratoire de Génétique Humaine des Maladies Infectieuses, Institut National de la Santé et de la Recherche Médicale, U550, 75015 Paris, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Alcaïs
authors.forename: Andrea
authors.initials: A
authors.lastname: Alter
authors.forename: Guillemette
authors.initials: G
authors.lastname: Antoni
authors.forename: Marianna
authors.initials: M
authors.lastname: Orlova
authors.forename: Van Thuc
authors.initials: VT
authors.lastname: Nguyen
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Singh
authors.forename: Patrícia R
authors.initials: PR
authors.lastname: Vanderborght
authors.forename: Kiran
authors.initials: K
authors.lastname: Katoch
authors.forename: Marcelo T
authors.initials: MT
authors.lastname: Mira
authors.forename: Hong Thai
authors.initials: HT
authors.lastname: Vu
authors.forename: Thu Huong
authors.initials: TH
authors.lastname: Ngyuen
authors.forename: Ngoc Ba
authors.initials: NB
authors.lastname: Nguyen
authors.forename: Milton
authors.initials: M
authors.lastname: Moraes
authors.forename: Narinder
authors.initials: N
authors.lastname: Mehra
authors.forename: Erwin
authors.initials: E
authors.lastname: Schurr
authors.forename: Laurent
authors.initials: L
authors.lastname: Abel
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000483:Alleles; D001938:Brazil / Q000453:epidemiology; D016022:Case-Control Studies; D002648:Child; D020022:Genetic Predisposition to Disease; D006801:Humans; D007194:India / Q000453:epidemiology; D007918:Leprosy / Q000453:epidemiology / Q000235:genetics*; D015810:Linkage Disequilibrium; D008233:Lymphotoxin-alpha / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012107:Research Design; D012307:Risk Factors; D014744:Vietnam / Q000453:epidemiology
chemical_list: D008233:Lymphotoxin-alpha