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.

Keywords: East Africa; HIV; IL12B; UBLCP1; histone acetylation; selection.

Figure 1

Results for Imputed SNPs in a 50 kb Region around rs4921437 from an Additive Genetic Model for Association with TB in the Combined Cohort The imputed SNP with the most significant association, rs10515780, is in a purple. Colors represent LD (measured with r²) between available variants and rs10515780. Annotation of chromatin-state segmentation in the zoomed region around rs4921437 is from the UCSC Genome Browser (hg19) for nine human cell types (chr5: 158,680,000–158,700,000). Bright red indicates an active promoter, light red indicates a weak promoter, yellow represents a weak or poised enhancer, light green represents a weak transcribed state, and dark green indicates transcriptional transition or elongation. An H3K27Ac histone mark aligns with the most significant SNPs.