A genome wide association study of pulmonary tuberculosis susceptibility in Indonesians.

BACKGROUND: There is reason to expect strong genetic influences on the risk of developing active pulmonary tuberculosis (TB) among latently infected individuals. Many of the genome wide linkage and association studies (GWAS) to date have been conducted on African populations. In order to identify additional targets in genetically dissimilar populations, and to enhance our understanding of this disease, we performed a multi-stage GWAS in a Southeast Asian cohort from Indonesia. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Mycobacterium tuberculosis Beijing genotype strains associated with febrile response to treatment.

DNA fingerprinting has demonstrated predominance of the Beijing genotype among Mycobacterium tuberculosis strains isolated in Southeast Asia. We prospectively examined the occurrence of Beijing genotype strains in tuberculosis patients in Indonesia. Early in treatment, patients infected with Beijing genotype strains more often had fever unrelated to disease severity, toxicity, or drug resistance, indicating that Beijing genotype strains may have specific pathogenic properties

Polymorphisms in SP110 are not associated with pulmonary tuberculosis in Indonesians.

Despite being high transmissible, Mycobacterium tuberculosis (M. tuberculosis) infection causes active disease in only 5-10% of disease-susceptible individuals. This has instigated interest in studying potentially underlying genetic host factors and mechanisms in tuberculosis (TB). The recent identification of the Intracellular pathogen resistance 1 (Ipr1) gene, which plays a major role in controlling M. tuberculosis susceptibility and infection severity in mice (Pan et al., 2005), has prompted studies on its human homolog; SP110 in humans. Association of SP110 SNPs with pulmonary TB were first reported in a study on West African families (Tosh et al., 2006). Subsequent attempts to replicate these findings in other populations, including another West African (Ghanaian) cohort (Thye et al., 2006), however, were unsuccessful. Here we have genotyped 20 SNPs located in the SP110 gene, including the previously TB associated variants; rs2114592 and rs3948464, for the first time in a South East Asian cohort from Indonesia. Our study did not reveal any statistically significant associations between SP110 SNPs and pulmonary TB. In addition, a meta-analysis of the two previously TB associated SNPs revealed that these are not associated with TB, further confirming the lack of convincing evidence for SP110 to be implicated in TB susceptibility, as yet in humans

Prognostic Significance of Left Anterior Hemiblock in Patients With Suspected Coronary Artery Disease

ObjectivesThis study was designed to assess the functional and prognostic significance of left anterior hemiblock (LAHB) in patients with no history of myocardial infarction referred for dobutamine stress echocardiography (DSE).BackgroundThe significance of isolated LAHB in patients with suspected coronary artery disease (CAD) is unclear.MethodsWe studied 1,187 patients with suspected CAD and no history of myocardial infarction who underwent DSE and were followed for occurrence of cardiac death.ResultsLeft anterior hemiblock was detected on baseline electrocardiogram in 159 patients (13%). Ischemia occurred more frequently in patients with LAHB (43% vs. 33%, p = 0.02). During a mean follow-up of 5.0 ± 2.5 years, 125 patients (11%) died of cardiac causes. The annual cardiac death rate was 4.9% in patients with LAHB and 1.9% for patients without (p < 0.0001). Patients with both LAHB and an abnormal DSE had the highest annual cardiac death rate (6.3%). In a Cox multivariable analysis, independent predictors of cardiac death were age, smoking, history of heart failure, diabetes, and ischemia. Left anterior hemiblock was independently associated with increased risk of cardiac death among patients with normal DSE (hazard ratio 1.8, 95% confidence interval 1.1 to 3.8) and in patients with abnormal DSE (hazard ratio 1.7, 95% confidence interval 1.1 to 2.7).ConclusionsIn patients with suspected CAD referred for stress testing, LAHB is associated with increased risk of cardiac death. This risk is persistent after adjustment for major clinical data and abnormalities on the stress echocardiogram. Therefore, isolated LAHB should not be considered a benign electrocardiographic abnormality in these patients