A genome wide association study of pulmonary tuberculosis susceptibility in Indonesians

In stage 1, we used the Affymetrix 100 K SNP GeneChip marker set to genotype 259 Indonesian samples. After quality control filtering, 108 cases and 115 controls were analyzed for association of 95,207 SNPs. In stage 2, we attempted validation of 2,453 SNPs with promising associations from the first stage, in 1,189 individuals from the same Indonesian cohort, and finally in stage 3 we selected 251 SNPs from this stage to test TB association in an independent Caucasian cohort (n = 3,760) from Russia.Our study suggests evidence of association (P = 0.0004-0.0067) for 8 independent loci (nominal significance P < 0.05), which are located within or near the following genes involved in immune signaling: JAG1, DYNLRB2, EBF1, TMEFF2, CCL17, HAUS6, PENK and TXNDC4.Mechanisms of immune defense suggested by some of the identified genes exhibit biological plausibility and may suggest novel pathways involved in the host containment of infection with TB.Tuberculosis (TB) remains one of the leading causes of infection-associated mortality, with close to 10 million new cases and 2 million deaths annually [1,2]. Although Mycobacterium tuberculosis has infected around a third of the world's population, only 3-10% of those infected develop active disease during their lifetime [3]. More than 90% of infected individuals remain asymptomatic with a latent infection. This indicates that host immune/defense pathways are often highly effective in controlling this disease. Because the infection causes such a burden of disease in those unable to contain the infection, it is important to discover underlying mechanisms to aid the development of more effective interventions such as better vaccines and novel treatments for latent and active infection. Similarly, it is important to identify predictive biomarkers that might identify individuals who are most susceptible to developing active TB disease.Studies of heritability using twins and other familial designs have convincingly implicated a genetic