title: Association of TNFSF8 regulatory variants with excessive inflammatory responses but not leprosy per se.
abstract: BACKGROUND
  Type 1 reactions (T1R) affect a considerable proportion of patients with leprosy. In those with T1R, the host immune response pathologically overcompensates for the actual infectious threat, resulting in nerve damage and permanent disability. Based on the results of a genome-wide association study of leprosy per se, we investigated the TNFSF15 chromosomal region for a possible contribution to susceptibility to T1R.
  
  
  METHODS
  We performed a high-resolution association scan of the TNFSF15 locus to evaluate the association with T1R in 2 geographically and ethnically distinct populations: a family-based sample from Vietnam and a case-control sample from Brazil, comprising a total of 1768 subjects.
  
  
  RESULTS
  In the Vietnamese sample, 47 single-nucleotide polymorphisms (SNPs) overlapping TNFSF15 and the adjacent TNFSF8 gene were associated with T1R but not with leprosy. Of the 47 SNPs, 39 were cis-expression quantitative trait loci (cis-eQTL) for TNFSF8 including SNPs located within the TNFSF15 gene. In the Brazilian sample, 18 of these cis-eQTL SNPs overlapping the TNFSF8 gene were validated for association with T1R.
  
  
  CONCLUSIONS
  Taken together, these results indicate TNFSF8 and not TNFSF15 as an important T1R susceptibility gene. Our data support the need for infection genetics to go beyond genes for pathogen control to explore genes involved in a commensurate host response.
authors.affiliation: Program in Immunology and Infectious Diseases in Global Health, Research Institute of the McGill University Health Centre The McGill International TB Centre, Departments of Human Genetics and Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Vinicius M
authors.initials: VM
authors.lastname: Fava
authors.affiliation: Program in Immunology and Infectious Diseases in Global Health, Research Institute of the McGill University Health Centre The McGill International TB Centre, Departments of Human Genetics and Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Cobat
authors.affiliation: Hospital for Dermato-Venerology, Ho Chi Minh City, District 3, Vietnam.
authors.forename: Nguyen
authors.initials: N
authors.lastname: Van Thuc
authors.affiliation: Lauro de Souza Lima Institute, Bauru, São Paulo.
authors.forename: Ana Carla P
authors.initials: AC
authors.lastname: Latini
authors.affiliation: Tropical Pathology and Public Health Institute, Federal University of Goiás, Goiânia.
authors.forename: Mariane M A
authors.initials: MM
authors.lastname: Stefani
authors.affiliation: Lauro de Souza Lima Institute, Bauru, São Paulo.
authors.forename: Andrea F
authors.initials: AF
authors.lastname: Belone
authors.affiliation: Hospital for Dermato-Venerology, Ho Chi Minh City, District 3, Vietnam.
authors.forename: Nguyen Ngoc
authors.initials: NN
authors.lastname: Ba
authors.affiliation: The McGill International TB Centre, Departments of Human Genetics and Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Marianna
authors.initials: M
authors.lastname: Orlova
authors.affiliation: Program in Immunology and Infectious Diseases in Global Health, Research Institute of the McGill University Health Centre The McGill International TB Centre, Departments of Human Genetics and Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Jérémy
authors.initials: J
authors.lastname: Manry
authors.affiliation: Core for Advanced Molecular Investigation, Pontifical Catholic University of Paraná, Curitiba, Brazil.
authors.forename: Marcelo T
authors.initials: MT
authors.lastname: Mira
authors.affiliation: Hospital for Dermato-Venerology, Ho Chi Minh City, District 3, Vietnam.
authors.forename: Vu Hong
authors.initials: VH
authors.lastname: Thai
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale University Paris Descartes, Imagine Institute St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, New York.
authors.forename: Laurent
authors.initials: L
authors.lastname: Abel
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale University Paris Descartes, Imagine Institute Centre d'Investigation Clinique, Unité de Recherche Clinique, Necker and Cochin Hospitals, Paris, France St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, New York.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Alcaïs
authors.affiliation: Program in Immunology and Infectious Diseases in Global Health, Research Institute of the McGill University Health Centre The McGill International TB Centre, Departments of Human Genetics and Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Erwin
authors.initials: E
authors.lastname: Schurr
mesh_terms: D053285:CD30 Ligand / Q000235:genetics*; D002874:Chromosome Mapping; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D007918:Leprosy / Q000235:genetics* / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000235:genetics
chemical_list: D053285:CD30 Ligand; C117026:TNFSF15 protein, human; C505774:TNFSF8 protein, human; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15
keywords: TNFSF15; TNFSF8; Type 1 reaction; eQTL; leprosy