Replication of Associations with Electrocardio-graphic Traits in African Americans from Clinical and Epidemiologic Studies.

The NAv1.5 sodium channel α subunit is the predominant α-subunit expressed in the heart and is associated with cardiac arrhythmias. We tested five previously identified variants (rs7374138, rs7637849, rs7637849, rs7629265, and rs11129796) for an association with PR interval and QRS duration in two unique study populations: the Third National Health and Nutrition Examination Survey (NHANES III, n= 552) accessed by the Epidemiologic Architecture for Genes Linked to Environment (EAGLE) and a combined dataset (n= 455) from two biobanks linked to electronic medical records from Vanderbilt University (BioVU) and Northwestern University (NUgene) as part of the electronic Medical Records & Genomics (eMERGE) network.

Lipid trait-associated genetic variation is associated with gallstone disease in the diverse Third National Health and Nutrition Examination Survey (NHANES III).

Background: Gallstone disease is one of the most common digestive disorders, affecting more than 30 million Americans. Previous twin studies suggest a heritability of 25% for gallstone formation. To date, one genome-wide association study (GWAS) has been performed in a population of European-descent.

Assessment of a pharmacogenomic marker panel in a polypharmacy population identified from electronic medical records.

Background: The ADME Core Panel assays 184 variants across 34 pharmacogenes, many of which are difficult to accurately genotype with standard multiplexing methods.

Methods: We genotyped 326 frequently medicated individuals of European descent in Vanderbilt's biorepository linked to de-identified electronic medical records, BioVU, on the ADME Core Panel to assess quality and performance of the assay. We compared quality control metrics and determined the extent of direct and indirect marker overlap between the ADME Core Panel and the Illumina Omni1-Quad.

Characterization of the Metabochip in diverse populations from the International HapMap Project in the Epidemiologic Architecture for Genes Linked to Environment (EAGLE) project.

Genome-wide association studies (GWAS) have identified hundreds of genomic regions associated with common human disease and quantitative traits. A major research avenue for mature genotype-phenotype associations is the identification of the true risk or functional variant for downstream molecular studies or personalized medicine applications. As part of the Population Architecture using Genomics and Epidemiology (PAGE) study, we as Epidemiologic Architecture for Genes Linked to Environment (EAGLE) are fine-mapping GWAS-identified genomic regions for common diseases and quantitative traits.

Serum vitamins A and E as modifiers of lipid trait genetics in the National Health and Nutrition Examination Surveys as part of the Population Architecture using Genomics and Epidemiology (PAGE) study.

Both environmental and genetic factors impact lipid traits. Environmental modifiers of known genotype-phenotype associations may account for some of the "missing heritability" of these traits. To identify such modifiers, we genotyped 23 lipid-associated variants identified previously through genome-wide association studies (GWAS) in 2,435 non-Hispanic white, 1,407 non-Hispanic black, and 1,734 Mexican-American samples collected for the National Health and Nutrition Examination Surveys (NHANES).

CLCNKB-T481S and essential hypertension in a Ghanaian population.

Objective: Prior to the discovery of chloride channel Kb with a variant threonine change to serine at position 481 (CLCNKB-T481S) there were no variants or clinical disorders associated with gain-of-function defects in thick ascending limb of the kidney channels or transporters. CLCNKB-T481S is a novel gain-of-function variant that has been associated with essential hypertension. This finding has not been replicated until our current study.

Functional BSND variants in essential hypertension.

Background: Defects in the handling of renal salt reabsorption may contribute to interindividual differences in blood-pressure regulation and susceptibility to hypertension. Sodium chloride reabsorption in the thick ascending limb (TAL) is dependent in part on the chloride channel, ClC-Kb (encoded by CLCNKB), and its accessory subunit, barttin (encoded by BSND).

Methods: We investigated genetic variations in BSND in a screening population, and genotyped a homogenous cohort of normotensive and hypertensive Ghanaian subjects, in addition to four ethnically defined control populations.

Haplotype diversity in four genes (CLCNKA, CLCNKB, BSND, NEDD4L) involved in renal salt reabsorption.

Objective: Differences exist among various populations with regards to hypertension prevalence, severity, progression and response to therapy. Such differences may be due to genetic or environmental factors. We characterized the genetic variation and haplotype diversity of four hypertension candidate genes (CLCNKA, CLCNKB, BSND, NEDD4L) in four different ethnic groups (Caucasian Americans, African-Americans, Han Chinese, and Mexican-Americans).

Kinetic isotope effects of nucleoside hydrolase from Escherichia coli.

rihC is one of a group of three ribonucleoside hydrolases found in Escherichia coli (E. coli). The enzyme catalyzes the hydrolysis of selected nucleosides to ribose and the corresponding base.

Functional interaction between extracellular sodium, potassium and inactivation gating in HERG channels.

We have studied the interaction between extracellular K(+) (K(+)(o)) and extracellular Na(+) (Na(+)(o)) in human ether-à-go-go related gene (HERG)-encoded K(+) channels expressed in Chinese hamster ovary (CHO-K1) cells, using the whole-cell voltage clamp technique. Prior studies indicate that Na(+)(o) potently inhibits HERG current (IC(50) 3 mm) by binding to an outer pore site, and also speeds recovery from inactivation. In this study, we sought to explore the relationship between the Na(+)(o) effect on recovery and Na(+)(o) inhibition of HERG current, and to determine whether inactivation gating plays a critical role in Na(+)(o) inhibition of HERG current.