A chromosome 5q31.1 locus associates with tuberculin skin test reactivity in HIV-positive individuals from tuberculosis hyper-endemic regions in east Africa

One in three people has been infected with mycobacterium tuberculosis (mtb),and the risk for mtb infection in hiv-infected individuals is even higher. we hypothesized that hiv-positive individuals living in tuberculosis-endemic regions who do not get infected by mycobacterium tuberculosis are genetically resistant. using an “experiment of nature” design that proved successful in our previous work,we performed a genome-wide association study of tuberculin skin test positivity using 469 hiv-positive patients from prospective study cohorts of tuberculosis from tanzania and uganda to identify genetic loci associated with mtb infection in the context of hiv-infection. among these individuals,244 tested were tuberculin skin test (tst) positive either at enrollment or during the >8 year follow up,while 225 were not. we identified a genome-wide significant association between a dominant model of rs877356 and binary tst status in the combined cohort (odds ratio = 0.2671,p = 1.22x10-8). association was replicated with similar significance when examining tst induration as a continuous trait. the variant lies in the 5q31.1 region,57kb downstream from il9. two-locus analyses of association of variants near rs877356 showed a haplotype comprised of rs877356 and an il9 missense variant,rs2069885,had the most significant association (p = 1.59x10-12). we also replicated previously linked loci on chromosomes 2,5,and 11. il9 is a cytokine produced by mast cells and th2 cells during inflammatory responses,providing a possible link between airway inflammation and protection from mtb infection. our results indicate that studying uninfected,hiv-positive participants with extensive exposure increases the power to detect associations in complex infectious disease. © 2017 sobota et al.