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 = 1.22×10 -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 = 1.59×10 -12 ). We also replicated previously linked loci on chromosomes 2, 5, and 11. IL9 is a cytokine produced by mast cells and T H 2 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. Author summary Approximately one-third of the world’s population has been exposed to Mycobacterium tuberculosis , the bacterium that causes tuberculosis. A small number of those infected develop active disease; however, there is a substantial portion of exposed people who do not even show evidence of an immunological response. These people who appear to resist infection, as measured by a negative tuberculin skin test, represent a subpopulation from which we can learn about resistance. We used a genome-wide approach to study the genetic basis of this resistance in unique cohorts of hypervulnerable, HIV-positive individuals from Uganda and Tanzania, in which exposure was virtually assured. We identified one locus that was highly significantly associated and conferred more than 70% protection from infection. 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. Although 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.
【초록키워드】 Inflammation, Uganda, Inflammatory responses, Tuberculosis, Prospective Study, Genetic, variant, Infection, risk, cytokine, Infectious disease, variants, mast cell, Cohort, Region, Patient, Genome-wide association study, Missense mutation, Mycobacterium tuberculosis, genetic loci, Mast cells, Haplotype, Immunological response, Active disease, association, Evidence, power, Skin test, Odds ratio, evidence of, skin tests, Enrollment, Airway inflammation, locus, causal variant, chromosome, Author, infected individuals, individual, complex, participant, loci, positive, positive individuals, bacterium, chromosomes, combined cohort, HIV-infection, HIV-positive individuals, Mycobacterium, SLC25A48, subpopulation, tuberculin skin test, missense variant, downstream, dominant, uninfected, Genes, approach, Cell, produced, tested, identify, performed, detect, develop, significantly, increase, determine, unique, analysis, cause, replicated, individuals, genome-wide significant, HIV-positive individual, IL9, TST, 【제목키워드】 Tuberculosis, Region, Skin test, locus, chromosome, reactivity, HIV-positive individual,