Deciphering Genetic Susceptibility to Tuberculous Meningitis

Abstract

Tuberculous meningitis (TBM) is the most severe form of extrapulmonary tuberculosis (TB) that arises when a caseating meningeal granuloma discharges its contents into the subarachnoid space. It accounts for ~1% of all disease caused by Mycobacterium tuberculosis and the age of peak incidence is from 2–4 years. The exact pathogenesis of TBM is still not fully understood and the mechanism(s) by which the bacilli initially invade the blood-brain-barrier are still to be elucidated. This study investigated the involvement of the host genome in TBM susceptibility, by considering common variants (minor allele frequency (MAF) >5%) using microarray genotyping and rare variants (MAF <1%) via exome sequencing. A total of 123 TBM cases, 400 pulmonary TB (pTB) cases and 477 healthy controls were genotyped on the MEGA array. A genome-wide association study (GWAS) comparing 114 TBM cases to 395 healthy controls showed no association with TBM susceptibility. A second analysis comparing 114 TBM cases to 382 pTB cases was conducted to investigate variants associated with different TB phenotypes. No significant associations were found with progression from pTB to TBM. Ten TBM cases and 10 healthy controls were exome sequenced. Gene set association tests SKAT-O and SKAT Common Rare were used to assess the association of rare SNPs and the cumulative effect of both common and rare SNPs with susceptibility to TBM, respectively. Ingenuity Pathway Analysis (IPA) of the top-hits of the SKAT-O analysis showed that NOD2 and CYP4F2 are both important in TBM pathogenesis and highlighted these as targets for future study. For the SKAT Common Rare analysis Centriolar Coiled-Coil Protein 110 (CCP110) was nominally associated (p = 5.89x10−6) with TBM susceptibility. In addition, several top-hit genes ascribed to the development of the central nervous system (CNS) and innate immune system regulation were identified. Exome sequencing and GWAS of our TBM cohort has identified a single previously undescribed association of CCP110 with TBM susceptibility. These results advance our understanding of TBM in terms of both variants and genes that influence susceptibility. In addition, several candidate genes involved in innate immunity have been identified for further genotypic and functional investigation.

Recent advances in understanding the human host immune response in tuberculous meningitis

“…Even within the same geographical region, identifying polymorphisms can be limited by genetic differences. This was demonstrated recently in a genome-wide association study (GWAS) of South African children with TBM versus healthy controls and PTB cases which did not find any associations with TBM susceptibility (120). The authors attribute this to the sample size, age differences and the ethnic heterogeneity of the study population.…”

A nod to the bond between NOD2 and mycobacteria

“…In another study, intronic SNPs in NOD2 (rs6500328 and rs2111234) were associated with an Mtb resister phenotype (persistently negative for disease and immune conversion) but not TB per se [ 121 , 122 ]. Recently, NOD2 was associated with TB meningitis via SKAT-O analysis [ 123 ]. Intronic/synonymous SNPs were not evaluated for expression changes in NOD2 in these studies, which remains a possibility.…”