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

Abstract

Mycobacterium tuberculosis (M. tuberculosis) infections cause 9.0 million new tuberculosis (TB) cases and 1.5 million deaths annually1. To search for sequence variants that confer risk of TB we tested 28.3 million variants identified through whole-genome sequencing of 2,636 Icelanders for association with TB (8,162 cases and 277,643 controls), pulmonary TB (PTB), and M. tuberculosis infection. We found association of three sequence variants in the HLA class II region: rs557011[T] (MAF=40.2%) with M. tuberculosis infection (OR =1.14, P=3.1×10-13) and PTB (OR=1.25, P=5.8×10-12) and rs9271378[G] (MAF=32.5%) with PTB (OR=0.78, P=2.5×10-12), both located between HLA-DQA1 and HLA-DRB1. Finally, a missense variant p.Ala210Thr in HLA-DQA1, (MAF=19.1%, rs9272785) shows association with M. tuberculosis infection (P=9.3×10-9, OR=1.14). The association of these variants with PTB was replicated in large samples of European ancestry from Russia and Croatia (P< 5.9×10-4). These findings demonstrate that the HLA class II region contributes to the complex genetic risk of tuberculosis, possibly through reduced presentation of protective M. tuberculosis antigens to T cells.

Transcriptional Classification and Functional Characterization of Human Airway Macrophage and Dendritic Cell Subsets

“…The average cell yield from lavage of a pair of lungs was 5.43 × 10 9 total cells. As several studies have suggested that HLA type I (A, B, and C) and type II (DR, DQ, and DP) variants associate with the pathogenesis of autoimmune disorders and infections (40–43), we genotyped donor lungs for HLA alleles. High diversity was observed in HLA variants at HLA -A, -B, and -C loci from all seven donors, with only one donor carrying homozygosity.…”

A post-GWAS analysis of predicted regulatory variants and tuberculosis susceptibility

“…However, the power to detect a common variant with an odds ratio of 2 was 98%. Validation of these results in other case-control cohorts as well as the inclusion of recent GWAS results [5,12,14] is desirable, but complicated by the lack of available TB case-control cohorts with a similar genetic structure to that of the SAC population. In addition, since there was a priori evidence for an association, replication is arguably not necessary as this study attempted to fine-map the potential causal variants in loci identified by previous TB GWAS.…”

The MHC locus and genetic susceptibility to autoimmune and infectious diseases

“…We note that fewer MHC associations have been found for infectious diseases than for autoimmune diseases, mainly because of the smaller cohort sizes for infectious diseases. Thus, extensive fine-mapping studies (and imputation) have yet to be performed, with the exception of a few studies on infections such as human immunodeficiency virus (HIV) [62], human hepatitis B virus (HBV) [63, 64], human hepatitis C virus (HCV) [65], human papilloma virus (HPV) seropositivity [66], and tuberculosis [67]. …”