Abstract
Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb), and remains a leading public health problem. Previous studies have identified host genetic factors that contribute to Mtb infection outcomes. However, much of the heritability in TB remains unaccounted for and additional susceptibility loci most likely exist. We perform a multistage genome-wide association study on 2949 pulmonary TB patients and 5090 healthy controls (833 cases and 1220 controls were genome-wide genotyped) from Han Chinese population. We discover two risk loci: 14q24.3 (rs12437118, Pcombined = 1.72 × 10−11, OR = 1.277, ESRRB) and 20p13 (rs6114027, Pcombined = 2.37 × 10−11, OR = 1.339, TGM6). Moreover, we determine that the rs6114027 risk allele is related to decreased TGM6 transcripts in PBMCs from pulmonary TB patients and severer pulmonary TB disease. Furthermore, we find that tgm6-deficient mice are more susceptible to Mtb infection. Our results provide new insights into the genetic etiology of TB.
Highlights
Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb), and remains a leading public health problem
The results showed that the rs12437118 was not associated with estrogen-related receptor beta (ESRRB) messenger RNA (mRNA) expression in peripheral blood mononuclear cells (PBMCs) (Fig. 2a)
Tgm[6] confers protection of mice against Mtb infection likely in dose-dependent manner. In this three-stage genome-wide association studies (GWAS) of TB, we identified two loci on 14q24.3 derived from ESRRB and on 20p13 derived from TGM6 that were significantly associated with TB risk in a Chinese Han population
Summary
Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb), and remains a leading public health problem. Previous studies have identified host genetic factors that contribute to Mtb infection outcomes. Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis (Mtb), remains the leading cause of death by infection in the world[1], with 10.4 million new cases and 1.7 million deaths in 20162. Four common variants associated with TB have been identified through genome-wide association studies (GWAS) in African and/or Russian populations[7,8,9]. The human leukocyte antigens (HLA) class II region was found to contribute to genetic risk of TB in Europeans[14] Another GWAS performed in an Asian population did not identify susceptibility loci that reached the threshold for genome-wide significance[15,16], likely because of smaller sample sizes. Our findings provide shed light on the genetic etiology and pathogenesis of TB
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