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Introduction: Dyslipidemia [i.e., elevated levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG); decreased level of high-density lipoprotein cholesterol (HDL-C)] is one of the risk factors for cardiovascular disease (CVD). Genetics play an important role in inter-individual variation of lipid levels. ATP-binding cassette A1 (ABCA1), a membrane transporter, mediates cellular phospholipid and cholesterol efflux. Mutations in ABCA1 gene cause Tangier’s disease (OMIM #205400) presented with HDL-C deficiency, as well as, increased risk for developing CVD. In this study, we aimed to identify both common [minor allele frequency (MAF)≥5%] and uncommon (MAFABCA1 associated with inter-individual variation in major lipid traits. Methods: We resequenced 50 exons and exon-intron boundaries of ABCA1 in a selected set of 95 individuals with extreme HDL-C levels (≤10 th and ≥90 th %tile), and subsequently genotyped selected variants in the entire sample of 623 US Non-Hispanic Whites. With resequencing, we identified 404 variants, and for genotyping we selected 250 variants (216 from sequencing data, 34 from HapMap-CEU data). A total of 182 successfully genotyped and QC-passed bi-allelic variants were tested for association with plasma lipid levels. Results: Gene-based test showed evidence of association between ABCA1 and TG ( p =0.0108). Single-site association analyses demonstrated 26 common variants nominally associated ( p p =0.0005; rs2066716 (Thr1427Thr) with TG levels, p =0.0016] remained significant. Furthermore, rs2066716 (Thr1427Thr) was among 11 out of 26 lipid-associated ABCA1 variants for which the replication data were available in an independent sample ( n =744) and it remained significantly associated with TG levels in the meta-analysis (meta- p =0.0088). Rare variant analyses revealed association of multiple sets of rare variants with lipid traits. Conclusions: Our findings support the genetic contribution of ABCA1 , both common and rare variants, to lipid levels in humans.

Introduction: Cystic fibrosis is among the most common inherited disorders, with ∼ 3% of Caucasians being heterozygous for the common CFTR ΔF508 mutation. Cardiomyopathy is a major cause of morbidity and mortality. While a small preliminary study suggested that cardiomyopathy patients heterozygous for the CFTR ΔF508 mutation have poorer outcomes, the finding has not been replicated and it is not known whether the poor outcomes are related to sudden death and/or heart failure progression. Methods: We screened 1347 Caucasian cardiomyopathy subjects (EF 21%, 82% male, 75% ischemic) with implantable cardioverter defibrillators (ICDs) from the prospective, multicenter, NIH-funded Genetic Risk Assessment of Defibrillator Events (GRADE) study. CFTR ΔF508 alleles were discriminated by real time fluorescence PCR. GRADE subjects were followed for up to 5 years to the primary endpoint of freedom from appropriate ICD shocks and the secondary endpoints of death and death/heart transplant/VAD placement. The results were compared by genotype using Kaplan-Meier analysis and Log Rank testing. Results: Genotyping revealed 33 CFTR ΔF508 heterozygotes (allele frequency 2.4%). ΔF508 carriers were older (68 vs 64 yrs, p=0.03); more likely to be diabetic (55 vs 34%, p=0.02), to have had an MI (77 vs 57%, p=0.02), and to have a RBBB on ECG (18 vs 7%, p=0.03); and had lower EFs (19 vs 21%, p=0.01). CFTR ΔF508 carriers had markedly higher rates of death (HR>2; p Conclusion: We have confirmed that carrying one CFTR ΔF508 allele is associated with an increased mortality in cardiomyopathy patients, and that this is likely not due to increased arrhythmic death. These findings may have implications for the treatment of this high risk heart failure subgroup. Future studies are needed to determine whether the increased mortality stems from a cardiac and/or pulmonary etiology.

Background: Heart failure patients are at increased risk of ventricular arrhythmias and all-cause mortality. However, existing clinical and serum markers only modestly predict these adverse events. Objective: We sought to use metabolic profiling to identify novel biomarkers in two independent prospective cohorts of patients with implantable cardioverter defibrillators (ICDs) for primary prevention of sudden cardiac death (SCD). Methods and Results: Baseline serum was quantitatively profiled for 42 known biologically-relevant amine-based metabolites among 402 patients from the PROSE-ICD Study (derivation group) and 240 patients from the GRADE Study (validation group) for ventricular arrhythmia-induced ICD shocks and all-cause mortality. In multivariate Cox models adjusted for traditional cardiovascular risk factors, 3 amines (N-methyl-L-histidine, symmetric dimethylarginine [SDMA], and L-kynurenine) were associated with all-cause mortality in both derivation and validation cohorts (Figure 1). Additionally, L-histidine, SDMA, L-kynurenine, L-4-hydroxyproline, and L-glutamine were associated with ventricular arrhythmia-induced ICD shocks in one of the cohorts, suggesting their potential to be novel markers of ventricular arrhythmia (Figure 2). Conclusions: Utilizing metabolic profiling, we identified several novel amine markers that were associated with appropriate shock and mortality in primary prevention ICD patients. These findings shed insight into the potential biologic pathways leading to adverse events in these patients, which will in turn aid the development of newer therapeutics for reducing SCD and mortality.

Introduction: Genetic background can influence heart failure survival and the impact of therapeutics. A polymorphism of a G protein beta subunit, GNB3 C825T, has been investigated extensively for its impact on the genomic risk of hypertension. The T allele is associated with low renin hypertension and increased alpha adrenergic tone. The T allele is more prevalant in African Americans and in the AHeFT trial was associated with a greater impact of therapy with a fixed dose combination of hydralazine and isosorbide dinitrates. We investigated the impact of GNB3 C825T on transplant free survival in systolic heart failure in GRACE (Genetic Risk Assessment of Cardiac Events), a singe center study based in an outpatient heart failure clinic. Methods: 944 subjects with systolic heart failure were enrolled from the Heart Failure Clinic at the University of Pittsburgh and followed for up to 5 years to an endpoint of death or cardiac transplantation. Demographic information was recorded at the time of enrollment and medical therapy reassessed annually. Blood was obtained at entry for DNA banking, and the GNB3 C825T genotype was determined. Transplant free survival was compared by Kaplan Meier log rank assessment. Results: The cohort was 28% female, 13% black, 48% ischemic, mean age 56 + 9, mean LVEF 0.25 + 0.09, and was NYHA class % 1/2/3/4=4%/52%/40%/4%. In terms of the GNB3 genotype the %TT/TC/CC were 16.5%/41.8%/41.7% and the frequency of the T allele differed significantly by race and was more common in Blacks (p Conclusions: The GNB3 825T allele was associated with poorer survival in a cohort with chronic heart failure. Its role in racial differences in heart failure outcomes warrants futher investigation.