title: A genome wide association study identifies a lncRna as risk factor for pathological inflammatory responses in leprosy.
abstract: Leprosy Type-1 Reactions (T1Rs) are pathological inflammatory responses that afflict a sub-group of leprosy patients and result in peripheral nerve damage. Here, we employed a family-based GWAS in 221 families with 229 T1R-affect offspring with stepwise replication to identify risk factors for T1R. We discovered, replicated and validated T1R-specific associations with SNPs located in chromosome region 10p21.2. Combined analysis across the three independent samples resulted in strong evidence of association of rs1875147 with T1R (p = 4.5x10-8; OR = 1.54, 95% CI = 1.32-1.80). The T1R-risk locus was restricted to a lncRNA-encoding genomic interval with rs1875147 being an eQTL for the lncRNA. Since a genetic overlap between leprosy and inflammatory bowel disease (IBD) has been detected, we evaluated if the shared genetic control could be traced to the T1R endophenotype. Employing the results of a recent IBD GWAS meta-analysis we found that 10.6% of IBD SNPs available in our dataset shared a common risk-allele with T1R (p = 2.4x10-4). This finding points to a substantial overlap in the genetic control of clinically diverse inflammatory disorders.
authors.affiliation: Program in Infectious Diseases and Immunity in Global Health, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.|The McGill International TB Centre, Departments of Human Genetics and Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Vinicius M
authors.identifier: 0000-0001-9142-1713
authors.initials: VM
authors.lastname: Fava
authors.affiliation: Program in Infectious Diseases and Immunity in Global Health, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.|The McGill International TB Centre, Departments of Human Genetics and Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Manry
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U.1163, Paris, France.|University Paris Descartes, Imagine Institute, Paris, France.|Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, United States of America.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Cobat
authors.affiliation: Program in Infectious Diseases and Immunity in Global Health, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.|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: Hospital for Dermato-Venerology, Ho Chi Minh City, Vietnam.
authors.forename: Nguyen
authors.initials: N
authors.lastname: Van Thuc
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: Laboratório de Hanseníase, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, Brazil.
authors.forename: Carolinne
authors.initials: C
authors.lastname: Sales-Marques
authors.affiliation: Tropical Pathology and Public Health Institute, Federal University of Goiás, Goiânia, Brazil.
authors.forename: Mariane M A
authors.identifier: 0000-0002-3731-0817
authors.initials: MM
authors.lastname: Stefani
authors.affiliation: Lauro de Souza Lima Institute, Bauru, Brazil.
authors.forename: Ana Carla P
authors.initials: AC
authors.lastname: Latini
authors.affiliation: Lauro de Souza Lima Institute, Bauru, Brazil.
authors.forename: Andrea F
authors.initials: AF
authors.lastname: Belone
authors.affiliation: Hospital for Dermato-Venerology, Ho Chi Minh City, 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 U.1163, Paris, France.|University Paris Descartes, Imagine Institute, Paris, France.|Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, United States of America.
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 U.1163, Paris, France.|University Paris Descartes, Imagine Institute, Paris, France.|Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, United States of America.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Alcaïs
authors.affiliation: Program in Infectious Diseases and Immunity in Global Health, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.|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: D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000150:complications / Q000235:genetics* / Q000473:pathology; D007918:Leprosy / Q000150:complications / Q000235:genetics* / Q000473:pathology; D008297:Male; D009410:Nerve Degeneration / Q000150:complications / Q000235:genetics / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000235:genetics; D062085:RNA, Long Noncoding / Q000096:biosynthesis / Q000235:genetics*; D012307:Risk Factors; D014744:Vietnam
chemical_list: D062085:RNA, Long Noncoding