A Locus at 5q33.3 Confers Resistance to Tuberculosis in Highly Susceptible Individuals

Abstract

Immunosuppression resulting from HIV infection increases the risk of progression to active tuberculosis (TB) both in individuals newly exposed to Mycobacterium tuberculosis (MTB) and in those with latent infections. We hypothesized that HIV-positive individuals who do not develop TB, despite living in areas where it is hyperendemic, provide a model of natural resistance. We performed a genome-wide association study of TB resistance by using 581 HIV-positive Ugandans and Tanzanians enrolled in prospective cohort studies of TB; 267 of these individuals developed active TB, and 314 did not. A common variant, rs4921437 at 5q33.3, was significantly associated with TB (odds ratio = 0.37, p = 2.11 × 10(-8)). This variant lies within a genomic region that includes IL12B and is embedded in an H3K27Ac histone mark. The locus also displays consistent patterns of linkage disequilibrium across African populations and has signals of strong selection in populations from equatorial Africa. Along with prior studies demonstrating that therapy with IL-12 (the cytokine encoded in part by IL12B, associated with longer survival following MTB infection in mice deficient in CD4 T cells), our results suggest that this pathway might be an excellent target for the development of new modalities for treating TB, especially for HIV-positive individuals. Our results also indicate that studying extreme disease resistance in the face of extensive exposure can increase the power to detect associations in complex infectious disease.

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

“…By applying the “experiment of nature” strategy outlined in a genetic study of tuberculosis disease with the same cohorts [19], we hypothesized that these immunosuppressed patients who live in MTB endemic areas but do not get infected have strong innate resistance. This hypothesis and approach were validated as we identified a novel association between protection from MTB infection and rs877356 with a large effect size.…”

“…A complete description of the study cohorts and genetic analysis methods is provided in our previous work [19]. …”

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.…”

“…GWAS is based on the premise that causal variants will be in linkage disequilibrium (LD) with the markers present on single nucleotide polymorphism (SNP) arrays. Since 2005, when the first GWAS was published [1], associations have been detected between numerous common genetic variants and several infectious diseases including TB [2–5]. …”

Human Genomics of Mycobacterium tuberculosis Infection and Disease

“…In a prospective study with 581 HIV-positive Ugandans and Tanzanians, 267 subjects developed active TB and 314 remained disease-free within 8 years of follow-up. In a GWAS approach, a significant association was shown between the common variant rs4951437 and protection from TB disease: OR=0.37 ( p = 2.1 × 10 −8 ) (56). The SNP is located in an intron of the UBLCP1 gene, 51kb downstream of the 3’UTR of IL12B , and falls within an H3K27Ac histone mark, indicating its potential role as a regulatory element.…”