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

Nat Genet 2016 Mar 1;48(3):318-22. Epub 2016 Feb 1.

deCODE genetics/Amgen Inc., Reykjavik, Iceland.

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.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5081101PMC
http://dx.doi.org/10.1038/ng.3498DOI Listing
March 2016
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References

(Supplied by CrossRef)

GJ Fox et al.
Adv. Exp. Med. Biol. 2013

GW Comstock et al.
Am. Rev. Respir. Dis. 1978

S Sigurdsson et al.
Laeknabladid 2005

S Sigurdsson et al.
Laeknabladid 1976

GH Bothamley et al.
Eur. Respir. J. 2008

DF Gudbjartsson et al.
Nat. Genet. 2015

MA DePristo et al.
Nat. Genet. 2011

A Cobat et al.
J. Exp. Med. 2009

A Cobat et al.
J. Infect. Dis. 2015

V Emilsson et al.
Nature 2008

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