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Meta-Analysis
. 2016 Mar;48(3):318-22.
doi: 10.1038/ng.3498. Epub 2016 Feb 1.

HLA Class II Sequence Variants Influence Tuberculosis Risk in Populations of European Ancestry

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Free PMC article
Meta-Analysis

HLA Class II Sequence Variants Influence Tuberculosis Risk in Populations of European Ancestry

Gardar Sveinbjornsson et al. Nat Genet. .
Free PMC article

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.

Conflict of interest statement

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

Figures

Figure 1
Figure 1
Regional association plot of the HLA 6p21 loci for pulmonary tuberculosis (N=3,686), all tuberculosis (N=8,162) and M. tuberculosis infected w/wo TB (N=14,723). The -log10 P values (y axis) of each SNP are presented on the basis of their chromosomal positions (x axis). Only P values below 1×10-3 are plotted.The horizontal dotted lines represend significance thresholds for missense and non-coding variants.

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