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PMID: 26829749 Published · ppublish English Journal Article Meta-Analysis Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

HLA class II sequence variants influence tuberculosis risk in populations of European ancestry.

Nature genetics ·Vol. 48 ·No. 3 ·2016-03-00 ·Pages 318-22

Sveinbjornsson G, Gudbjartsson DF, Halldorsson BV, Kristinsson KG, Gottfredsson M, Barrett JC, Gudmundsson LJ, Blondal K, Gylfason A, Gudjonsson SA, Helgadottir HT, Jonasdottir A, Jonasdottir A, Karason A, Kardum LB, Knežević J, Kristjansson H, Kristjansson M, Love A, Luo Y, Magnusson OT, Sulem P, Kong A, Masson G, Thorsteinsdottir U, Dembic Z, Nejentsev S, Blondal T, Jonsdottir I, Stefansson K

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.

MeSH Terms
Alleles Gene Frequency Genetic Predisposition to Disease Genetic Variation Genome, Human Genome-Wide Association Study HLA-DQ alpha-Chains/genetics,immunology HLA-DRB1 Chains/genetics,immunology Humans Iceland Mycobacterium tuberculosis/genetics,immunology,pathogenicity Risk Factors T-Lymphocytes/immunology Tuberculosis, Pulmonary/genetics,immunology,microbiology Whites
Chemicals
HLA-DQ alpha-Chains HLA-DQA1 antigen HLA-DRB1 Chains
Authors & Affiliations
30 authors, click to expand affiliations / ORCID
Sveinbjornsson Gardar
deCODE genetics/Amgen Inc., Reykjavik, Iceland. | School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
Gudbjartsson Daniel F ORCID
deCODE genetics/Amgen Inc., Reykjavik, Iceland. | School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
Halldorsson Bjarni V
deCODE genetics/Amgen Inc., Reykjavik, Iceland. | School of Science and Engineering, Reykjavik University, Reykjavik, Iceland.
Kristinsson Karl G
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.
Gottfredsson Magnus
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.
Barrett Jeffrey C ORCID
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
Gudmundsson Larus J
deCODE genetics/Amgen Inc., Reykjavik, Iceland.
Blondal Kai
Division of Communicable Disease Prevention and Control, Primary Health Care of the Capital Area, Reykjavik, Iceland.
Gylfason Arnaldur
deCODE genetics/Amgen Inc., Reykjavik, Iceland.
Gudjonsson Sigurjon Axel
deCODE genetics/Amgen Inc., Reykjavik, Iceland.
Helgadottir Hafdis T
deCODE genetics/Amgen Inc., Reykjavik, Iceland.
Jonasdottir Adalbjorg
deCODE genetics/Amgen Inc., Reykjavik, Iceland.
Jonasdottir Aslaug
deCODE genetics/Amgen Inc., Reykjavik, Iceland.
Karason Ari
deCODE genetics/Amgen Inc., Reykjavik, Iceland.
Kardum Ljiljana Bulat
Department of Pulmonology, Clinic of Internal Medicine, Clinical Hospital Center, University of Rijeka, Rijeka, Croatia.
Knežević Jelena
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.
Kristjansson Helgi
deCODE genetics/Amgen Inc., Reykjavik, Iceland. | Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
Kristjansson Mar
Department of Infectious Diseases, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland.
Love Arthur
Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland. | Department of Virology, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland.
Luo Yang
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
Magnusson Olafur T
deCODE genetics/Amgen Inc., Reykjavik, Iceland.
Sulem Patrick ORCID
deCODE genetics/Amgen Inc., Reykjavik, Iceland.
Kong Augustine
deCODE genetics/Amgen Inc., Reykjavik, Iceland.
Masson Gisli
deCODE genetics/Amgen Inc., Reykjavik, Iceland.
Thorsteinsdottir Unnur
deCODE genetics/Amgen Inc., Reykjavik, Iceland. | Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
Dembic Zlatko ORCID
Laboratory of Molecular Genetics, Department of Oral Biology, Faculty of Dentistry, University of Oslo, Oslo, Norway.
Nejentsev Sergey
Department of Medicine, University of Cambridge, Cambridge, UK.
Blondal Thorsteinn
Division of Communicable Disease Prevention and Control, Primary Health Care of the Capital Area, Reykjavik, Iceland.
Jonsdottir Ingileif ORCID
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.
Stefansson Kari
deCODE genetics/Amgen Inc., Reykjavik, Iceland. | Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
Conflict of Interest

Authors affiliated with deCODE genetics/AMGEN Inc. declare competing financial interests as employees.

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Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1546-1718
DOI
10.1038/ng.3498
Published
2016-03-00
Epub
2016-00-01
Pages
318-22
Language
English
Region
United States
NLM ID
9216904
PMCID
PMC5081101
Subset
IM
Grants
Wellcome Trust · 088838/Z/09/Z · United Kingdom
PHS HHS · HHSN266200400064C · United States
Wellcome Trust · 088838 · United Kingdom
Wellcome Trust · 095198 · United Kingdom
Wellcome Trust · 095198/Z/10/Z · United Kingdom
External Links
PubMed source DOI: 10.1038/ng.3498 PMC Full Text View journal details
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