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GWAS Highlights Chromosome 8 Variants Associated with TB Susceptibility

NEW YORK (GenomeWeb) – In Nature Genetics, an international team led by investigators at the University of Cambridge described variants in the chromosome 8 gene ASAP1 that appear to influence individuals' susceptibility to tuberculosis.

Using genotyping data from nearly 15,100 individuals with or without pulmonary tuberculosis, the researchers narrowed in on tuberculosis infection-associated variants in the intronic region of ASAP1. At least one of the SNPs coincided with diminished dendritic cell expression of the gene, which codes for a cell scaffold protein that activates a so-called Arf GTPase enzyme.

Because infection with Mycobacterium tuberculosis itself seems to drive down expression of ASAP1 in the same cell type, the team proposed that the susceptibility variants might contribute to disease by further interfering with the function of the dendritic cells.

"[O]ur results suggest that impaired migration of M. tuberculosis-infected [dendritic cells] caused by the genetically determined reduction of ASAP1 expression may contribute to TB pathogenesis," senior author Sergey Nejentsev, a medicine researcher at the University of Cambridge, and colleagues wrote.

The team proposed that slower-than-usual dendritic cell migration to the lymph nodes might postpone early responses to M. tuberculosis. Likewise, it speculated that reduced ASAP1 expression may contribute to late-stage disease or latent TB reactivation by hindering dendritic cell movement.

Roughly one-tenth of those infected by the M. tuberculosis parasite go on to develop active TB, the researchers noted, suggesting other factors — including host genetics — can affect disease risk.

At least two potential TB infection risk loci were described in past GWAS, though the authors of the current analysis argued that there are likely other susceptibility variants that remain undetected.

"To date, GWAS of susceptibility to TB and other infectious diseases have identified fewer associated loci than have studies of many other complex diseases," the team noted. "This indicates that the effects of common polymorphisms predisposing to infection are usually small, and current GWAS may be statistically underpowered."

For their new GWAS, the researchers started with information at some 7.6 million directly genotyped or imputed SNPs in 5,530 HIV-negative Russian individuals with pulmonary TB and 5,607 unaffected controls from the same population, all tested using the Affymetrix Genome-wide Human SNP array 6.0.

While chromosome 18 variants described in a prior TB GWAS of African individuals were not over-represented in the Russians with TB, they did see an apparent association involving a chromosome 11 locus identified in a past study of South African cases and controls.

The team also detected new variants in ASAP1 introns that reached genome-wide significant associations with TB in the discovery group.

Seven SNPs at the locus were subsequently confirmed through targeted TaqMan genotyping on another 1,085 Russians with TB and 2,865 population-matched controls and through a combined analysis of the discovery and replication cohorts. 

When the researchers scoured existing data for TB cases and controls from Ghana and Gambia, they noticed far lower populations of the ASAP1 SNPs, which made it trickier to pick up a clear TB association at the locus. Still, results in those populations suggest that intronic variants in the gene are linked to TB susceptibility.

A series of follow-up experiments in white blood cells from healthy donors provided clues to ASAP1's potential role in TB risk, highlighting the dip in dendritic cell expression of ASAP1 when the TB-associated SNP rs10956514 is present or following typical M. tuberculosis infection.