Stepwise replication identifies a low-producing lymphotoxin-α allele as a major risk factor for early-onset leprosy

• Published in: Nature genetics Vol. 39; no. 4; pp. 517 - 522
• Main Authors: Alcaïs, Alexandre, Alter, Andrea, Antoni, Guillemette, Orlova, Marianna, Van Thuc, Nguyen, Singh, Meenakshi, Vanderborght, Patrícia R, Katoch, Kiran, Mira, Marcelo T, Thai, Vu Hong, Huong, Ngyuen Thu, Ba, Nguyen Ngoc, Moraes, Milton, Mehra, Narinder, Schurr, Erwin, Abel, Laurent
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.04.2007; Nature Publishing Group
• Subjects: Adolescent; Adult; Age of Onset; Agriculture; Alleles; Animal Genetics and Genomics; Bacterial diseases; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Brazil - epidemiology; Cancer Research; Case-Control Studies; Child; Diagnosis; Fundamental and applied biological sciences. Psychology; Gene Function; Genetic aspects; Genetic Predisposition to Disease; Genetics of eukaryotes. Biological and molecular evolution; Health aspects; Human bacterial diseases; Human Genetics; Humans; India - epidemiology; Infectious diseases; Leprosy; Leprosy - epidemiology; Leprosy - genetics; letter; Linkage Disequilibrium; Lymphotoxin-alpha - genetics; Medical sciences; Middle Aged; Physiological aspects; Polymorphism, Single Nucleotide; Research Design; Risk Factors; Tropical bacterial diseases; Tuberculosis and atypical mycobacterial infections; Tumor necrosis factor; Vietnam - epidemiology; Brazil; Vietnam; India; Canada; Infection; Skin disease; Allele; Risk factor; Bacteriosis; Leprosy; Early; Replication; Identification; Mycobacterial infection
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng2000

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 1 , 2 . Here we report the linkage disequilibrium mapping of the second linkage peak of our previous genome-wide scan 1 , 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.