Genome-wide SNP-based linkage analysis of tuberculosis in Thais

Abstract

Tuberculosis, a potentially fatal infectious disease, affects millions of individuals annually worldwide. Human protective immunity that contains tuberculosis after infection has not been clearly defined. To gain insight into host genetic factors, nonparametric linkage analysis was performed using high-throughput microarray-based single nucleotide polymorphism (SNP) genotyping platform, a GeneChip array comprised 59 860 bi-allelic markers, in 93 Thai families with multiple siblings, 195 individuals affected with tuberculosis. Genotyping revealed a region on chromosome 5q showing suggestive evidence of linkage with tuberculosis (Z(lr) statistics ¼ 3.01, logarithm of odds (LOD) score ¼ 2.29, empirical P-value ¼ 0.0005), and two candidate regions on chromosomes 17p and 20p by an ordered subset analysis using minimum age at onset of tuberculosis as the covariate (maximum LOD score ¼ 2.57 and 3.33, permutation P-value ¼ 0.0187 and 0.0183, respectively). These results imply a new evidence of genetic risk factors for tuberculosis in the Asian population. The significance of these ordered subset results supports a clinicopathological concept that immunological impairment in the disease differs between young and old tuberculosis patients. The linkage information from a specific ethnicity may provide unique candidate regions for the identification of the susceptibility genes and further help elucidate the immunopathogenesis of tuberculosis.

Genome-wide association studies of tuberculosis in Asians identify distinct at-risk locus for young tuberculosis

“…16 Thus, the failure of the initial GWAS in Asian TB is not due to the problem of SNP coverage in the current microarray genotyping platform. Taking into consideration the caveats that might affect the power of a GWAS in identifying genetic risks to common diseases 17 and our experience of the increasing power of linkage analysis of TB by the subset-ordered analysis based on the age at onset of TB sibpairs, 10 we hypothesized that a gene-environmental effect (G X E) interaction, such as bacille calmette guerin (BCG) vaccination, exposure to different strains of M. tuberculosis, 18 or misclassification, might cause heterogeneity in TB. All of these factors contribute to different age effects on TB development.…”

“…Based on the epidemiological classification of TB and our findings that subset-ordered linkage analysis in TB sibpairs identified chromosome 17p and chromosome 20p as candidate loci that were enriched in young TB sibpairs 10 and the results are quite different from traditional linkage analyses of TB, 11,12 we hypothesized that subdividing (or classifying) patients based on their diseasedevelopment model would enrich genetic heritability in each subset and reduce genetic heterogeneity by reducing misclassification bias. In the present study, genome-wide association analyses of TB were conducted in two East Asian populations (Japanese and Thai).…”

Innate Immune Gene Polymorphisms in Tuberculosis

“…Host genetic factors explain, at least in part, why some people are more or less susceptible to infection. Several lines of evidence, including twin studies (48,148,242), genome-wide linkage studies (21,49,136,144,148,217), and recently published genome-wide association studies (GWAS) (135,172,229), demonstrate that host genetics strongly influences susceptibility to TB. However, assessing the contributions and functional consequences of specific genetic variations (polymorphisms) in the human genome to host susceptibility or resistance to TB remains a longstanding challenge of population genetics research, with many questions unanswered.…”

Association analysis of susceptibility candidate region on chromosome 5q31 for tuberculosis

“…11 The region has been of particular interest because it carries a cluster of Th2 cytokines and related genes including IL4, IL5, IL13, RAD50, KIF3A, SLC22A4 and SLC22A5. Such results have allowed us to conduct fine-mapping of the tuberculosis susceptibility locus in this region in Thai trio families.…”

“…Of the 203 complete trio families, 15 were part of multi-case families in a previous linkage study. 11 Tuberculosis was diagnosed on the basis of clinical presentation and bacteriological confirmation by sputum culture for M. tuberculosis or at least two out of three positive sputum smears for acid-fast bacilli. Diagnosis of tuberculosis in a few cases was obtained from records in the tuberculosis surveillance system accompanied by a current abnormal chest x-ray.…”