HLA class II sequence variants influence tuberculosis risk in populations of European ancestry
Copyright policy )HLA class II sequence variants influence tuberculosis risk in populations of European ancestry
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.
- University of Cambridge United Kingdom
- Institut Pasteur France
- National University Hospital of Iceland Iceland
- University Of Cambridge
- Wellcome Trust United Kingdom
BIOMEDICINE AND HEALTHCARE. Clinical Medical Sciences., T-Lymphocytes, Iceland, Article, HLA-DQ alpha-Chains, White People, TMD12, Gene Frequency, Risk Factors, Humans, Genetic Predisposition to Disease, HLA class II ; tuberculosis ; variants, Tuberculosis, Pulmonary, Alleles, PAD12, variants, Genome, Human, HLA-DR Antigens/genetics, BIOMEDICINA I ZDRAVSTVO. Kliničke medicinske znanosti., BIOMEDICINE AND HEALTHCARE. Basic Medical Sciences., Berklar, Genetic Variation, Mycobacterium tuberculosis, Arfgengi, Tuberculosis, Pulmonary/genetics, Europe, BAC12, HLA class II, tuberculosis, NAF12, BIOMEDICINA I ZDRAVSTVO. Temeljne medicinske znanosti., Genome-Wide Association Study, HLA-DRB1 Chains
BIOMEDICINE AND HEALTHCARE. Clinical Medical Sciences., T-Lymphocytes, Iceland, Article, HLA-DQ alpha-Chains, White People, TMD12, Gene Frequency, Risk Factors, Humans, Genetic Predisposition to Disease, HLA class II ; tuberculosis ; variants, Tuberculosis, Pulmonary, Alleles, PAD12, variants, Genome, Human, HLA-DR Antigens/genetics, BIOMEDICINA I ZDRAVSTVO. Kliničke medicinske znanosti., BIOMEDICINE AND HEALTHCARE. Basic Medical Sciences., Berklar, Genetic Variation, Mycobacterium tuberculosis, Arfgengi, Tuberculosis, Pulmonary/genetics, Europe, BAC12, HLA class II, tuberculosis, NAF12, BIOMEDICINA I ZDRAVSTVO. Temeljne medicinske znanosti., Genome-Wide Association Study, HLA-DRB1 Chains
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