Polymorphisms of NOD2 and the risk of tuberculosis: a validation study in the Chinese population

Abstract

A genome-wide association study (GWAS) of leprosy reported four specific genetic polymorphisms of NOD2 that were associated with susceptibility to Mycobacterium leprae in China. Considering the role of NOD2 in innate immune defence, we performed a study in a Chinese population to determine whether the same SNPs of NOD2 that were associated with disease caused by M. leprae were also associated with disease caused by Mycobacterium tuberculosis. We performed a frequency-matched case-control study in 1043 patients with pulmonary tuberculosis and 808 unaffected controls. All subjects were >15 years old and were Han Chinese from Jiangsu Province. We extracted DNA from a blood sample from each study participant. SNPs of rs3135499, rs7194886, rs8057341 and rs9302752 in the NOD2 gene were genotyped using a TaqMan-based allelic discrimination system. Using all possible patients with tuberculosis as cases, no significant association was found between the four specific SNPs and the risk of tuberculosis. In a subgroup analysis restricted to cases with bacteriologically confirmed tuberculosis (sputum culture positive), the variant genotype of rs7194886 was significantly associated with an altered risk of tuberculosis. Compared with the CC genotype, individuals carrying the CT/TT genotype of rs7194886 had an increased risk [odds ratio (OR) 1.35, 95% confidence interval (CI) (1.05-1.72)]. The association was stronger among tobacco smokers and males. By haplotype analysis, rs9302752C-rs7194886T was associated with an increased risk of bacteriologically confirmed tuberculosis (sputum culture positive) (P = 0.039), but it was not significant after correcting for multiple comparisons. In summary, genetic polymorphisms of the SNP rs7194886 in the NOD2 gene, which were discovered in the GWAS of leprosy, might also be associated with the pulmonary tuberculosis in the Chinese population.

The Role of NOD2 in Murine and Human Melioidosis

“…rs7194886 is an intergenic variant upstream of NOD2 that is associated with leprosy in a genome wide association study in Chinese subjects and with type I reversal reactions and erythema nodosum leprosum in a candidate gene analysis in Nepalese subjects (22, 23). rs7194886 is not associated with leprosy in Vietnamese subjects (24); however, the variant is associated with tuberculosis in Chinese individuals (37). Thus, there is increasing evidence of its importance in mycobacterial infection in Asian populations.…”

LRRK2 and RIPK2 Variants in the NOD 2-Mediated Signaling Pathway Are Associated with Susceptibility to Mycobacterium leprae in Indian Populations

“…Mutations in the gene encoding NOD2 in humans have been associated with Crohn’s disease (CD) [26], Blau syndrome (BS) [27], and early onset sarcoidosis (EOS) [28]. In addition, the studied NOD2 variant (rs9302752A/G) was associated with susceptibility to tuberculosis and leprosy in Chinese and Vietnamese population [7], [29], [30]. NOD2 signaling pathways are activated by a CARD effector domain that causes inflammation by the activation of NF-kB and MAP kinase pathways [10].…”

Receptor-mediated recognition of mycobacterial pathogens

“…An association has also been found between TB susceptibility and the NOD2 synonymous Arg5878Arg SNP in the Chinese Han population (Zhao et al ., ). This association was further validated in a larger Chinese population (Pan et al ., ). Genetic associations between allelic variants of NOD2 and susceptibility to infection have also been reported for other mycobacterial species.…”