GWAS for discovery and replication of genetic loci associated with sudden cardiac arrest in patients with coronary artery disease.

Background: Epidemiologic evidence suggests a heritable component to risk for sudden cardiac arrest independent of risk for myocardial infarction. Recent candidate gene association studies for community sudden cardiac arrests have focused on a limited number of biological pathways and yielded conflicting results. We sought to identify novel gene associations for sudden cardiac arrest in patients with coronary artery disease by performing a genome-wide association study.

Association of TGFBR2 polymorphism with risk of sudden cardiac arrest in patients with coronary artery disease.

Background: Transforming growth factor ss (TGFss) signaling has been shown to promote myocardial fibrosis and remodeling with coronary artery disease (CAD), and previous studies show a major role for fibrosis in the initiation of malignant ventricular arrhythmias (VA) and sudden cardiac arrest (SCA). Common single nucleotide polymorphisms (SNPs) in TGFss pathway genes may be associated with SCA.

Objective: We examined the association of common SNPs among 12 candidate genes in the TGFss pathway with the risk of SCA.

Narcolepsy is strongly associated with the T-cell receptor alpha locus.

Narcolepsy with cataplexy, characterized by sleepiness and rapid onset into REM sleep, affects 1 in 2,000 individuals. Narcolepsy was first shown to be tightly associated with HLA-DR2 (ref. 3) and later sublocalized to DQB1*0602 (ref.

Multiple polymorphisms in the TNFAIP3 region are independently associated with systemic lupus erythematosus.

The TNFAIP3 (tumor necrosis factor alpha-induced protein 3) gene encodes a ubiquitin editing enzyme, A20, that restricts NF-kappaB-dependent signaling and prevents inflammation. We show that three independent SNPs in the TNFAIP3 region (rs13192841, rs2230926 and rs6922466) are associated with systemic lupus erythematosus (SLE) among individuals of European ancestry. These findings provide critical links between A20 and the etiology of SLE.

Marking embryonic stem cells with a 2A self-cleaving peptide: a NKX2-5 emerald GFP BAC reporter.

Background: Fluorescent reporters are useful for assaying gene expression in living cells and for identifying and isolating pure cell populations from heterogeneous cultures, including embryonic stem (ES) cells. Multiple fluorophores and genetic selection markers exist; however, a system for creating reporter constructs that preserve the regulatory sequences near a gene's native ATG start site has not been widely available.

Methodology: Here, we describe a series of modular marker plasmids containing independent reporter, bacterial selection, and eukaryotic selection components, compatible with both Gateway recombination and lambda prophage bacterial artificial chromosome (BAC) recombineering techniques.

Common genetic variation in KCNH2 is associated with QT interval duration: the Framingham Heart Study.

Background: QT prolongation is associated with increased risk of sudden cardiac death in the general population and in people exposed to QT-prolonging drugs. Mutations in the KCNH2 gene encoding the HERG potassium channel cause 30% of long-QT syndrome, and binding to this channel leads to drug-induced QT prolongation. We tested common KCNH2 variants for association with continuous QT interval duration.

Vascular stiffness and genetic variation at the endothelial nitric oxide synthase locus: the Framingham Heart study.

Arterial stiffness is a moderately heritable trait that is affected by alterations in the bioavailability of NO. Previous studies have found associations between variants in the gene for endothelial NO synthase (NOS3) and arterial properties. We previously identified a linkage peak for forward pressure wave amplitude in the immediate vicinity of NOS3.

Clinical and genetic correlates of aldosterone-to-renin ratio and relations to blood pressure in a community sample.

Aldosterone:renin ratio (ARR) is used to screen for hyperaldosteronism. Data regarding correlates of ambulatory ARR in the community and its relation to hypertension incidence are limited. We defined clinical correlates of ARR, determined its heritability, tested for association and linkage, and related ARR to blood pressure (BP) progression in nonhypertensive individuals among 3326 individuals from the Framingham Heart Study (53% women; mean age: 59 years).

Contribution of clinical correlates and 13 C-reactive protein gene polymorphisms to interindividual variability in serum C-reactive protein level.

Background: Serum C-reactive protein (CRP) level is a heritable complex trait that predicts incident cardiovascular disease. We investigated the clinical and genetic sources of interindividual variability in serum CRP.

Methods And Results: We studied serum CRP in 3301 Framingham Heart Study (FHS) participants (mean age 61 years, 53% women).

Common genetic variation at the endothelial nitric oxide synthase locus and relations to brachial artery vasodilator function in the community.

Background: Sequence variants at the endothelial nitric oxide synthase (NOS3) locus have been associated with endothelial function measures, but replication has been limited.

Methods And Results: In reference pedigrees, we characterized linkage disequilibrium structure at the NOS3 locus using 33 common single nucleotide polymorphisms (SNPs). Eighteen SNPs that capture underlying common variation were genotyped in unrelated Framingham Heart Study participants (49.