title: HLA class II sequence variants influence tuberculosis risk in populations of European ancestry.
abstract: Mycobacterium tuberculosis infections cause 9 million new tuberculosis cases and 1.5 million deaths annually. To identify variants conferring risk of tuberculosis, we tested 28.3 million variants identified through whole-genome sequencing of 2,636 Icelanders for association with tuberculosis (8,162 cases and 277,643 controls), pulmonary tuberculosis (PTB) and M. tuberculosis infection. We found association of three variants in the region harboring genes encoding the class II human leukocyte antigens (HLAs): rs557011[T] (minor allele frequency (MAF) = 40.2%), associated with M. tuberculosis infection (odds ratio (OR) = 1.14, P = 3.1 × 10(-13)) and PTB (OR = 1.25, P = 5.8 × 10(-12)), and rs9271378[G] (MAF = 32.5%), associated with PTB (OR = 0.78, P = 2.5 × 10(-12))--both located between HLA-DQA1 and HLA-DRB1--and a missense variant encoding p.Ala210Thr in HLA-DQA1 (MAF = 19.1%, rs9272785), associated with M. tuberculosis infection (P = 9.3 × 10(-9), OR = 1.14). We replicated association of these variants with PTB in samples of European ancestry from Russia and Croatia (P < 5.9 × 10(-4)). These findings show that the HLA class II region contributes to genetic risk of tuberculosis, possibly through reduced presentation of protective M. tuberculosis antigens to T cells.
authors.affiliation: deCODE genetics/Amgen Inc., Reykjavik, Iceland.|School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
authors.forename: Gardar
authors.initials: G
authors.lastname: Sveinbjornsson
authors.affiliation: deCODE genetics/Amgen Inc., Reykjavik, Iceland.|School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
authors.forename: Daniel F
authors.identifier: http://orcid.org/0000-0002-5222-9857
authors.initials: DF
authors.lastname: Gudbjartsson
authors.affiliation: deCODE genetics/Amgen Inc., Reykjavik, Iceland.|School of Science and Engineering, Reykjavik University, Reykjavik, Iceland.
authors.forename: Bjarni V
authors.initials: BV
authors.lastname: Halldorsson
authors.affiliation: Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.|Department of Clinical Microbiology, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland.
authors.forename: Karl G
authors.initials: KG
authors.lastname: Kristinsson
authors.affiliation: Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.|Department of Infectious Diseases, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland.
authors.forename: Magnus
authors.initials: M
authors.lastname: Gottfredsson
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Jeffrey C
authors.identifier: http://orcid.org/0000-0002-1152-370X
authors.initials: JC
authors.lastname: Barrett
authors.affiliation: deCODE genetics/Amgen Inc., Reykjavik, Iceland.
authors.forename: Larus J
authors.initials: LJ
authors.lastname: Gudmundsson
authors.affiliation: Division of Communicable Disease Prevention and Control, Primary Health Care of the Capital Area, Reykjavik, Iceland.
authors.forename: Kai
authors.initials: K
authors.lastname: Blondal
authors.affiliation: deCODE genetics/Amgen Inc., Reykjavik, Iceland.
authors.forename: Arnaldur
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authors.affiliation: deCODE genetics/Amgen Inc., Reykjavik, Iceland.
authors.forename: Sigurjon Axel
authors.initials: SA
authors.lastname: Gudjonsson
authors.affiliation: deCODE genetics/Amgen Inc., Reykjavik, Iceland.
authors.forename: Hafdis T
authors.initials: HT
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authors.affiliation: deCODE genetics/Amgen Inc., Reykjavik, Iceland.
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authors.affiliation: deCODE genetics/Amgen Inc., Reykjavik, Iceland.
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authors.affiliation: deCODE genetics/Amgen Inc., Reykjavik, Iceland.
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authors.initials: A
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authors.affiliation: Department of Pulmonology, Clinic of Internal Medicine, Clinical Hospital Center, University of Rijeka, Rijeka, Croatia.
authors.forename: Ljiljana Bulat
authors.initials: LB
authors.lastname: Kardum
authors.affiliation: Laboratory of Molecular Genetics, Department of Oral Biology, Faculty of Dentistry, University of Oslo, Oslo, Norway.|Division of Molecular Medicine, Ruđer Boškovic´ Institute, Zagreb, Croatia.
authors.forename: Jelena
authors.initials: J
authors.lastname: Knežević
authors.affiliation: deCODE genetics/Amgen Inc., Reykjavik, Iceland.|Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
authors.forename: Helgi
authors.initials: H
authors.lastname: Kristjansson
authors.affiliation: Department of Infectious Diseases, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland.
authors.forename: Mar
authors.initials: M
authors.lastname: Kristjansson
authors.affiliation: Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.|Department of Virology, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland.
authors.forename: Arthur
authors.initials: A
authors.lastname: Love
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Yang
authors.initials: Y
authors.lastname: Luo
authors.affiliation: deCODE genetics/Amgen Inc., Reykjavik, Iceland.
authors.forename: Olafur T
authors.initials: OT
authors.lastname: Magnusson
authors.affiliation: deCODE genetics/Amgen Inc., Reykjavik, Iceland.
authors.forename: Patrick
authors.identifier: http://orcid.org/0000-0001-7123-6123
authors.initials: P
authors.lastname: Sulem
authors.affiliation: deCODE genetics/Amgen Inc., Reykjavik, Iceland.
authors.forename: Augustine
authors.initials: A
authors.lastname: Kong
authors.affiliation: deCODE genetics/Amgen Inc., Reykjavik, Iceland.
authors.forename: Gisli
authors.initials: G
authors.lastname: Masson
authors.affiliation: deCODE genetics/Amgen Inc., Reykjavik, Iceland.|Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
authors.forename: Unnur
authors.initials: U
authors.lastname: Thorsteinsdottir
authors.affiliation: Laboratory of Molecular Genetics, Department of Oral Biology, Faculty of Dentistry, University of Oslo, Oslo, Norway.
authors.forename: Zlatko
authors.identifier: http://orcid.org/0000-0002-9970-6497
authors.initials: Z
authors.lastname: Dembic
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Sergey
authors.initials: S
authors.lastname: Nejentsev
authors.affiliation: Division of Communicable Disease Prevention and Control, Primary Health Care of the Capital Area, Reykjavik, Iceland.
authors.forename: Thorsteinn
authors.initials: T
authors.lastname: Blondal
authors.affiliation: deCODE genetics/Amgen Inc., Reykjavik, Iceland.|Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.|Department of Immunology, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland.
authors.forename: Ingileif
authors.identifier: http://orcid.org/0000-0001-8339-150X
authors.initials: I
authors.lastname: Jonsdottir
authors.affiliation: deCODE genetics/Amgen Inc., Reykjavik, Iceland.|Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
authors.forename: Kari
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authors.lastname: Stefansson
mesh_terms: D000483:Alleles; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D015894:Genome, Human; D055106:Genome-Wide Association Study; D059848:HLA-DQ alpha-Chains / Q000235:genetics* / Q000276:immunology; D059811:HLA-DRB1 Chains / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007055:Iceland; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity*; D012307:Risk Factors; D013601:T-Lymphocytes / Q000276:immunology; D014397:Tuberculosis, Pulmonary / Q000235:genetics* / Q000276:immunology / Q000382:microbiology; D044465:White People
chemical_list: D059848:HLA-DQ alpha-Chains; C069050:HLA-DQA1 antigen; D059811:HLA-DRB1 Chains
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