Vinicius M Fava1, Aurélie Cobat1, Nguyen Van Thuc2, Ana Carla P Latini3, Mariane M A Stefani4, Andrea F Belone3, Nguyen Ngoc Ba2, Marianna Orlova5, Jérémy Manry1, Marcelo T Mira6, Vu Hong Thai2, Laurent Abel7, Alexandre Alcaïs8, Erwin Schurr1. 1. 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. 2. Hospital for Dermato-Venerology, Ho Chi Minh City, District 3, Vietnam. 3. Lauro de Souza Lima Institute, Bauru, São Paulo. 4. Tropical Pathology and Public Health Institute, Federal University of Goiás, Goiânia. 5. The McGill International TB Centre, Departments of Human Genetics and Medicine, McGill University, Montreal, Quebec, Canada. 6. Core for Advanced Molecular Investigation, Pontifical Catholic University of Paraná, Curitiba, Brazil. 7. 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. 8. 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.
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.
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: Arianne C Richard; John R Ferdinand; Françoise Meylan; Erika T Hayes; Odile Gabay; Richard M Siegel Journal: J Leukoc Biol Date: 2015-07-17 Impact factor: 4.962
Authors: Carolinne Sales-Marques; Cynthia Chester Cardoso; Lucia Elena Alvarado-Arnez; Ximena Illaramendi; Anna Maria Sales; Mariana de Andréa Hacker; Mayara Garcia de Mattos Barbosa; José Augusto da Costa Nery; Roberta Olmo Pinheiro; Euzenir Nunes Sarno; Antonio Guilherme Pacheco; Milton Ozório Moraes Journal: PLoS Negl Trop Dis Date: 2017-07-17
Authors: Vinicius M Fava; Jeremy Manry; Aurélie Cobat; Marianna Orlova; Nguyen Van Thuc; Milton O Moraes; Carolinne Sales-Marques; Mariane M A Stefani; Ana Carla P Latini; Andrea F Belone; Vu Hong Thai; Laurent Abel; Alexandre Alcaïs; Erwin Schurr Journal: PLoS Genet Date: 2017-02-21 Impact factor: 5.917
Authors: Adriana Barbosa de Lima Fonseca; Marise do Vale Simon; Rodrigo Anselmo Cazzaniga; Tatiana Rodrigues de Moura; Roque Pacheco de Almeida; Malcolm S Duthie; Steven G Reed; Amelia Ribeiro de Jesus Journal: Infect Dis Poverty Date: 2017-02-06 Impact factor: 4.520