Common polymorphisms in the PKP3-SIGIRR-TMEM16J gene region are associated with susceptibility to tuberculosis

Abstract

Background: Tuberculosis has been associated with genetic variation in host immunity. We hypothesized that single-nucleotide polymorphisms (SNPs) in SIGIRR, a negative regulator of Toll-like receptor/IL-1R signaling, are associated with susceptibility to tuberculosis.

Methods: We used a case-population study design in Vietnam with cases that had either tuberculous meningitis or pulmonary tuberculosis. We genotyped 6 SNPs in the SIGIRR gene region (including the adjacent genes PKP3 and TMEM16J) in a discovery cohort of 352 patients with tuberculosis and 382 controls. Significant associations were genotyped in a validation cohort (339 patients with tuberculosis, 376 controls).

Results: Three SNPs (rs10902158, rs7105848, rs7111432) were associated with tuberculosis in discovery and validation cohorts. The polymorphisms were associated with both tuberculous meningitis and pulmonary tuberculosis and were strongest with a recessive genetic model (odds ratios, 1.5-1.6; P = .0006-.001). Coinheritance of these polymorphisms with previously identified risk alleles in Toll-like receptor 2 and TIRAP was associated with an additive risk of tuberculosis susceptibility.

Conclusions: These results demonstrate a strong association of SNPs in the PKP3-SIGIRR-TMEM16J gene region and tuberculosis in discovery and validation cohorts. To our knowledge, these are the first associations of polymorphisms in this region with any disease.

Figure 1.

The genomic positions of 6 single-nucleotide polymorphisms (SNPs) in the SIGIRR gene region. Exons are shown as black rectangles. D′ and R² values were calculated from control subjects in the discovery cohort. Values are shown numerically and by shading, based on the legend in the middle. The minor allele frequency is shown in the bolded box immediately below each corresponding SNP. SNPs for which significant associations were found in both cohorts are in bold type.