Abstract
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.
Highlights
One third of the world’s population has been infected with Mycobacterium tuberculosis (MTB) [1, 2]
The most significant variant, rs8773656, was near IL9 and SLC25A48, and a haplotype including this variant and a missense mutation in IL9 was even more significantly associated with negative skin tests. It is impossible based solely on our data to determine the causal variant or genes, IL9 is an attractive candidate as its product has previously been associated with bronchial hyperresponsiveness, thereby providing a possible link between inflammation and protection from Mycobacterium tuberculosis infection
Using two recently concluded prospective cohorts of tuberculosis disease from Tanzania and Uganda, with available TST and IFN-γ results, we identified a variant on chromosome 5q31.1, near SLC25A48 and IL9 that imparts resistance to MTB infection in immunocompromised individuals
Summary
One third of the world’s population has been infected with Mycobacterium tuberculosis (MTB) [1, 2]. Subsequent tuberculosis disease (TB) occurs during the lifespan of about 10% of those infected[1,2,3]. Tuberculosis is a major cause of morbidity and mortality worldwide, with 1.5 million deaths and 9.6 million new cases of active disease reported in 2014[1]. Tuberculosis is the primary cause of death in people co-infected with the human immunodeficiency virus (HIV), and 400,000 of the global TB deaths in 2014 occurred in this patient population [1, 4]. The immunosuppression from HIV facilitates progression to active disease directly following infection, or by the reactivation of a latent MTB infection[5, 6]. About 10–20% of people living in areas hyperendemic for MTB, which virtually guarantees repeated exposure, appear to be resistant to infection[7,8,9,10]
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