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

Gardar Sveinbjornsson; Daniel F Gudbjartsson; Bjarni V Halldorsson; Karl G Kristinsson; Magnus Gottfredsson; Jeffrey C Barrett; Larus J Gudmundsson; Kai Blondal; Arnaldur Gylfason; Sigurjon Axel Gudjonsson; Hafdis T Helgadottir; Adalbjorg Jonasdottir; Aslaug Jonasdottir; Ari Karason; Ljiljana Bulat Kardum; Jelena Knežević; Helgi Kristjansson; Mar Kristjansson; Arthur Love; Yang Luo; Olafur T Magnusson; Patrick Sulem; Augustine Kong; Gisli Masson; Unnur Thorsteinsdottir; Zlatko Dembic; Sergey Nejentsev; Thorsteinn Blondal; Ingileif Jonsdottir; Kari Stefansson

doi:https://doi.org/10.1038/ng.3498

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

Gardar Sveinbjornsson, Daniel F Gudbjartsson, Bjarni V Halldorsson, Karl G Kristinsson, Magnus Gottfredsson, Jeffrey C Barrett, Larus J Gudmundsson, Kai Blondal, Arnaldur Gylfason, Sigurjon Axel Gudjonsson, Hafdis T Helgadottir, Adalbjorg Jonasdottir, Aslaug Jonasdottir, Ari Karason, Ljiljana Bulat Kardum, Jelena Knežević, Helgi Kristjansson, Mar Kristjansson, Arthur Love, Yang LuoOlafur T Magnusson, Patrick Sulem, Augustine Kong, Gisli Masson, Unnur Thorsteinsdottir, Zlatko Dembic, Sergey Nejentsev, Thorsteinn Blondal, Ingileif Jonsdottir, Kari Stefansson

Research output: Contribution to journal › Article › Academic › peer-review

103 Citations (Scopus)

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.

Original language	English
Pages (from-to)	318-22
Number of pages	5
Journal	Nature Genetics
Volume	48
Issue number	3
DOIs	https://doi.org/10.1038/ng.3498
Publication status	Published - Mar 2016
Externally published	Yes

Keywords

Alleles
European Continental Ancestry Group
Gene Frequency
Genetic Predisposition to Disease
Genetic Variation
Genome, Human
Genome-Wide Association Study
HLA-DQ alpha-Chains/genetics
HLA-DRB1 Chains/genetics
Humans
Iceland
Mycobacterium tuberculosis/genetics
Risk Factors
T-Lymphocytes/immunology
Tuberculosis, Pulmonary/genetics

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https://doi.org/10.1038/ng.3498

Cite this

Sveinbjornsson, G., Gudbjartsson, D. F., Halldorsson, B. V., Kristinsson, K. G., Gottfredsson, M., Barrett, J. C., Gudmundsson, L. J., Blondal, K., Gylfason, A., Gudjonsson, S. A., Helgadottir, H. T., Jonasdottir, A., Jonasdottir, A., Karason, A., Kardum, L. B., Knežević, J., Kristjansson, H., Kristjansson, M., Love, A., ... Stefansson, K. (2016). HLA class II sequence variants influence tuberculosis risk in populations of European ancestry. Nature Genetics, 48(3), 318-22. https://doi.org/10.1038/ng.3498

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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.",

keywords = "Alleles, European Continental Ancestry Group, Gene Frequency, Genetic Predisposition to Disease, Genetic Variation, Genome, Human, Genome-Wide Association Study, HLA-DQ alpha-Chains/genetics, HLA-DRB1 Chains/genetics, Humans, Iceland, Mycobacterium tuberculosis/genetics, Risk Factors, T-Lymphocytes/immunology, Tuberculosis, Pulmonary/genetics",

author = "Gardar Sveinbjornsson and Gudbjartsson, {Daniel F} and Halldorsson, {Bjarni V} and Kristinsson, {Karl G} and Magnus Gottfredsson and Barrett, {Jeffrey C} and Gudmundsson, {Larus J} and Kai Blondal and Arnaldur Gylfason and Gudjonsson, {Sigurjon Axel} and Helgadottir, {Hafdis T} and Adalbjorg Jonasdottir and Aslaug Jonasdottir and Ari Karason and Kardum, {Ljiljana Bulat} and Jelena Kne{\v z}evi{\'c} and Helgi Kristjansson and Mar Kristjansson and Arthur Love and Yang Luo and Magnusson, {Olafur T} and Patrick Sulem and Augustine Kong and Gisli Masson and Unnur Thorsteinsdottir and Zlatko Dembic and Sergey Nejentsev and Thorsteinn Blondal and Ingileif Jonsdottir and Kari Stefansson",

year = "2016",

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doi = "https://doi.org/10.1038/ng.3498",

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journal = "Nature Genetics",

issn = "1061-4036",

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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 2016, 'HLA class II sequence variants influence tuberculosis risk in populations of European ancestry', Nature Genetics, vol. 48, no. 3, pp. 318-22. https://doi.org/10.1038/ng.3498

TY - JOUR

T1 - HLA class II sequence variants influence tuberculosis risk in populations of European ancestry

AU - Sveinbjornsson, Gardar

AU - Gudbjartsson, Daniel F

AU - Halldorsson, Bjarni V

AU - Kristinsson, Karl G

AU - Gottfredsson, Magnus

AU - Barrett, Jeffrey C

AU - Gudmundsson, Larus J

AU - Blondal, Kai

AU - Gylfason, Arnaldur

AU - Gudjonsson, Sigurjon Axel

AU - Helgadottir, Hafdis T

AU - Jonasdottir, Adalbjorg

AU - Jonasdottir, Aslaug

AU - Karason, Ari

AU - Kardum, Ljiljana Bulat

AU - Knežević, Jelena

AU - Kristjansson, Helgi

AU - Kristjansson, Mar

AU - Love, Arthur

AU - Luo, Yang

AU - Magnusson, Olafur T

AU - Sulem, Patrick

AU - Kong, Augustine

AU - Masson, Gisli

AU - Thorsteinsdottir, Unnur

AU - Dembic, Zlatko

AU - Nejentsev, Sergey

AU - Blondal, Thorsteinn

AU - Jonsdottir, Ingileif

AU - Stefansson, Kari

PY - 2016/3

Y1 - 2016/3

N2 - 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.

AB - 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.

KW - Alleles

KW - European Continental Ancestry Group

KW - Gene Frequency

KW - Genetic Predisposition to Disease

KW - Genetic Variation

KW - Genome, Human

KW - Genome-Wide Association Study

KW - HLA-DQ alpha-Chains/genetics

KW - HLA-DRB1 Chains/genetics

KW - Humans

KW - Iceland

KW - Mycobacterium tuberculosis/genetics

KW - Risk Factors

KW - T-Lymphocytes/immunology

KW - Tuberculosis, Pulmonary/genetics

U2 - https://doi.org/10.1038/ng.3498

DO - https://doi.org/10.1038/ng.3498

M3 - Article

C2 - 26829749

SN - 1061-4036

VL - 48

SP - 318

EP - 322

JO - Nature Genetics

JF - Nature Genetics

IS - 3

ER -