title: Age-Dependent Association ofTNFSF15/TNFSF8Variants and Leprosy Type 1 Reaction.
abstract: A current major challenge in leprosy control is the prevention of permanent disabilities. Host pathological inflammatory responses termed type 1 reaction (T1R) are a leading cause of nerve damage for leprosy patients. The environmental or inherited factors that predispose leprosy cases to undergo T1R are not known. However, studies have shown an important contribution of host genetics for susceptibility to T1R. We have previously identified variants encompassing theTNFSF15/TNFSF8genes as T1R risk factors in a Vietnamese sample and replicated this association in a Brazilian sample. However, we failed to validate in Brazilian patients the strong association ofTNFSF15/TNFSF8markers rs6478108 and rs7863183 with T1R that we had observed in Vietnamese patients. Here, we investigated if the lack of validation of these variants was due to age-dependent effects on association using four independent population samples, two from Brazil and two from Vietnam. In the combined analysis across the four samples, we observed a strong association of theTNFSF15/TNFSF8variants rs6478108, rs7863183, and rs3181348 with T1R (pcombined= 1.5E-05,pcombined= 1.8E-05, andpcombined= 6.5E-06, respectively). However, the association of rs6478108 with T1R was more pronounced in leprosy cases under 30 years of age compared to the global sample [odds ratio (OR) = 1.95, 95% confidence interval (CI) = 1.54-2.46,pcombined= 2.5E-08 versus OR = 1.46, 95% CI = 1.23-1.73,pcombined= 1.5E-05]. A multivariable analysis indicated that the association of rs6478108 with T1R was independent of either rs7863183 or rs3181348. These three variants are known regulators of theTNFSF8gene transcription level in multiple tissues. The age dependency of association of rs6478108 and T1R suggests that the genetic control of gene expression varies across the human life span.
authors.affiliation: Program in Infectious Diseases and Immunity in Global Health, Research Institute of the McGill University Health Centre, Montreal, QC, Canada; The McGill International TB Centre, Department of Human Genetics, McGill University, Montreal, QC, Canada.
authors.forename: Vinicius M
authors.initials: VM
authors.lastname: Fava
authors.affiliation: Laboratório de Hanseníase, Instituto Oswaldo Cruz, FIOCRUZ , Rio de Janeiro , Brazil.
authors.forename: Carolinne
authors.initials: C
authors.lastname: Sales-Marques
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163, Paris, France; Imagine Institute, University Paris Descartes, Paris, France; Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Alcaïs
authors.affiliation: Laboratório de Hanseníase, Instituto Oswaldo Cruz, FIOCRUZ , Rio de Janeiro , Brazil.
authors.forename: Milton O
authors.initials: MO
authors.lastname: Moraes
authors.affiliation: Program in Infectious Diseases and Immunity in Global Health, Research Institute of the McGill University Health Centre, Montreal, QC, Canada; The McGill International TB Centre, Department of Human Genetics, McGill University, Montreal, QC, Canada; Department of Medicine, McGill University, Montreal, QC, Canada.
authors.forename: Erwin
authors.initials: E
authors.lastname: Schurr
keywords: Crohn’s disease; TNFSF15; TNFSF8; age at disease diagnosis; association studies; excessive inflammatory response; leprosy; type 1 reaction