Genome-wide meta-analysis of variant-by-diuretic interactions as modulators of lipid traits in persons of European and African ancestry.

Hypertension (HTN) is a significant risk factor for cardiovascular morbidity and mortality. Metabolic abnormalities, including adverse cholesterol and triglycerides (TG) profiles, are frequent comorbid findings with HTN and contribute to cardiovascular disease. Diuretics, which are used to treat HTN and heart failure, have been associated with worsening of fasting lipid concentrations. Genome-wide meta-analyses with 39,710 European-ancestry (EA) individuals and 9925 African-ancestry (AA) individuals were performed to identify genetic variants that modify the effect of loop or thiazide diuretic use on blood lipid concentrations. Both longitudinal and cross sectional data were used to compute cohort-specific interaction results, which were then combined through meta-analysis in each ancestry. These ancestry-specific results were further combined through trans-ancestry meta-analysis. Analysis of EA data identified two genome-wide significant (p < 5 × 10-8) loci with single nucleotide variant (SNV)-loop diuretic interaction on TG concentrations (including COL11A1). Analysis of AA data identified one genome-wide significant locus adjacent to BMP2 with SNV-loop diuretic interaction on TG concentrations. Trans-ancestry analysis strengthened evidence of association for SNV-loop diuretic interaction at two loci (KIAA1217 and BAALC). There were few significant SNV-thiazide diuretic interaction associations on TG concentrations and for either diuretic on cholesterol concentrations. Several promising loci were identified that may implicate biologic pathways that contribute to adverse metabolic side effects from diuretic therapy.

Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology.

Thiazide diuretics, commonly used antihypertensives, may cause QT interval (QT) prolongation, a risk factor for highly fatal and difficult to predict ventricular arrhythmias. We examined whether common single-nucleotide polymorphisms (SNPs) modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, trans-ethnic and cross-phenotype genome-wide analyses of European (66%), African American (15%) and Hispanic (19%) populations (N=78 199), leveraging longitudinal data, incorporating corrected standard errors to account for underestimation of interaction estimate variances and evaluating evidence for pathway enrichment. Although no loci achieved genome-wide significance (P<5 × 10-8), we found suggestive evidence (P<5 × 10-6) for SNPs modifying the thiazide-QT association at 22 loci, including ion transport loci (for example, NELL1, KCNQ3). The biologic plausibility of our suggestive results and simulations demonstrating modest power to detect interaction effects at genome-wide significant levels indicate that larger studies and innovative statistical methods are warranted in future efforts evaluating thiazide-SNP interactions.

Large-scale pharmacogenomic study of sulfonylureas and the QT, JT and QRS intervals: CHARGE Pharmacogenomics Working Group.

Sulfonylureas, a commonly used class of medication used to treat type 2 diabetes, have been associated with an increased risk of cardiovascular disease. Their effects on QT interval duration and related electrocardiographic phenotypes are potential mechanisms for this adverse effect. In 11 ethnically diverse cohorts that included 71 857 European, African-American and Hispanic/Latino ancestry individuals with repeated measures of medication use and electrocardiogram (ECG) measurements, we conducted a pharmacogenomic genome-wide association study of sulfonylurea use and three ECG phenotypes: QT, JT and QRS intervals. In ancestry-specific meta-analyses, eight novel pharmacogenomic loci met the threshold for genome-wide significance (P<5 × 10-8), and a pharmacokinetic variant in CYP2C9 (rs1057910) that has been associated with sulfonylurea-related treatment effects and other adverse drug reactions in previous studies was replicated. Additional research is needed to replicate the novel findings and to understand their biological basis.

Comparison of PRAS II, RapID ANA, and API 20A systems for identification of anaerobic bacteria.

This study evaluated the PRAS II, RapID ANA, and API 20A systems for the identification of anaerobic bacteria. A total of 80 isolates (68 fresh clinical isolates and 12 stock cultures) were examined and included 25 Bacteriodes spp., 7 Fusobacterium spp., 12 Clostridium spp., 2 Veillonella spp., 16 gram-positive cocci, and 18 gram-positive nonsporeforming bacilli. All isolates were initially identified by the procedures outlined in Holdeman et al. (ed.), Anaerobe Laboratory Manual, Virginia Polytechnic Institute and State University, Blacksburg, Va., 1977; identifications from the PRAS II, RapID ANA, and API 20A systems were compared with these initial identifications. If no supplemental tests were required, the RapID ANA and API 20A systems had incubation times of 4 and 24 h, respectively; the PRAS II system generally required 2 to 5 days of incubation, depending on the growth rate of the isolate. PRAS II identified 74% correct to species level, 14% correct to genus only, and 6% incorrect; 6% could not be identified. PRAS II data were reevaluated according to a revised data base that was provided after completion of the study; PRAS II (revised) identified 82% correct to species, 12% correct to genus only, and 6% incorrect. RapID ANA identified 62% correct to the species level, 28% correct to genus only, and 10% incorrect. API 20A identified 71% correct to the species level, 10% correct to genus only, and 3% incorrect; 16% could not identified. The API 20A is a more established system for identification of anaerobic bacteria; PRAS II and RapID ANA appear to be promising new methods for the identification of anaerobic bacteria.

Medium for selective isolation and presumptive identification of the Bacteroides fragilis group.

We developed and evaluated a new medium (FRAG agar) for the selective isolation and presumptive identification of the Bacteroides fragilis group. This medium contains 1% D-glucuronic acid as a fermentable carbon source, a reduced peptone content, gentamicin, and 20% bile. Presumptive identification of the B. fragilis group was based on growth, fermentation, and typical colony morphology. A total of 75 stock culture isolates of the B. fragilis group grew well on this medium, and 69 showed evidence of fermentation. Of 90 other anaerobes, none grew well or fermented glucuronic acid. In a clinical trial of 100 specimens sent for anaerobic culture, FRAG agar inhibited 71 of 71 anaerobes not belonging to the B. fragilis group, as well as 104 of 110 facultative organisms. A total of 33 isolates of the B. fragilis group were recovered on the selective medium, whereas only 23 were recovered by routine methods. Of 23 cultures positive for the B. fragilis group on routine plates, 22 were positive on FRAG agar.