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 the dominant model of rs877356 and binary TST status in the combined cohort (OR=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 T¬H2 cells during inflammatory responses, providing a possible link between airway inflammation and protection from MTB infection. Our results indicate that studying uninfected participants with extensive exposure increases the power to detect associations in complex infectious disease.

Populations in sub-Saharan Africa are shifting from rural to increasingly urban. Although the burden of cardiovascular disease is expected to increase with this changing landscape, few large studies have assessed a wide range of risk factors in urban and rural populations, particularly in West Africa. We conducted a cross-sectional, population-based survey of 3317 participants from Ghana (≥18 years old), of whom 2265 (57% female) were from a mid-sized city (Sunyani, population ~250,000) and 1052 (55% female) were from surrounding villages (populations <5000). We measured canonical cardiovascular disease risk factors (BMI, blood pressure, fasting glucose, lipids) and fibrinolytic markers (PAI-1 and t-PA), and assessed how their distributions and related clinical outcomes (including obesity, hypertension and diabetes) varied with urban residence and sex. Urban residence was strongly associated with obesity (OR: 7.8, 95% CI: 5.3–11.3), diabetes (OR 3.6, 95% CI: 2.3–5.7), and hypertension (OR 3.2, 95% CI: 2.6–4.0). Among the quantitative measures, most affected were total cholesterol (+0.81 standard deviations, 95% CI 0.73–0.88), LDL cholesterol (+0.89, 95% CI: 0.79–0.99), and t-PA (+0.56, 95% CI: 0.48–0.63). Triglycerides and HDL cholesterol profiles were similarly poor in both urban and rural environments, but significantly worse among rural participants after BMI-adjustment. For most of the risk factors, the strength of the association with urban residence did not vary with sex. Obesity was a major exception, with urban women at particularly high risk (26% age-standardized prevalence) compared to urban men (7%). Overall, urban residents had substantially worse cardiovascular risk profiles, with some risk factors at levels typically seen in the developed world.