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Background: Left ventricular ejection fraction (EF) is an indicator of cardiac function, usually assessed in individuals with heart failure and other cardiac conditions. Although family studies indicate that EF has an important genetic component with heritability estimates up to 0.61, to date only 6 EF-associated loci have been reported. Methods: Here, we conducted a genome-wide association study (GWAS) of EF in 26 638 adults from the Genetic Epidemiology Research on Adult Health and Aging and the UK Biobank cohorts. Results: A meta-analysis combining results from Genetic Epidemiology Research on Adult Health and Aging and UK Biobank identified a novel locus: TMEM40 on chromosome 3p25 (rs11719526; β=0.47 and P =3.10×10 −8 ) that replicated in Biobank Japan and confirmed recent findings implicating the BAG3 locus on chromosome 10q26 in EF variation, with the strongest association observed for rs17617337 (β=−0.83 and P =8.24×10 −17 ). Although the minor allele frequencies of TMEM40 rs11719526 were generally common (between 0.13 and 0.44) in different ethnic groups, BAG3 rs17617337 was rare (minor allele frequenciesTMEM40 or BAG3 on EF are largely independent of these conditions. Conclusions: In this large and multiethnic study, we identified 2 loci, TMEM40 and BAG3 , associated with EF at a genome-wide significance level. Identifying and understanding the genetic determinants of EF is important to better understand the pathophysiology of this strong correlate of cardiac outcomes and to help target the development of future therapies.

Background A major expectation underlying the search for novel susceptibility genes for common diseases using genome-wide association studies (GWAS) is that these discoveries will lead to new drug targets. This claim has not been verified yet. Here, we tested the hypothesis that common single nucleotide polymorphisms (SNPs) within drug target genes are associated with the corresponding phenotypes, using a population-based GWAS dataset and lipid-lowering drugs as a test case. Methods We examined the association between 36 genotyped and 193 imputed SNPs within four lipid-lowering drug target genes (HMGCR, PPARA, HM74A/GPR109A and CETP) and four non-lipid drug target genes (ACE, AGTR1, P2RY12, and ATP4B) and lipid phenotypes, blood pressure, and coronary artery disease in 5635 adult participants of the Lausanne, Switzerland, CoLaus study, genotyped using the Affymetrix 500K SNP chip technology. Results The phenotypes associated with SNPs within drug target genes recapitulated to a certain extent the pharmacological effects of the drug. The amplitude of the SNP effect was about 10 times smaller than the pharmacological effect of the corresponding drug. In particular, several CETP SNPs were associated with an elevation in HDL-cholesterol levels, yet a lower diastolic blood pressure, providing evidence that the blood pressure elevation induced by the CETP inhibitor torcetrapib is more likely compound specific than class specific. Conclusion Pharmacological modulation of lipid-lowering drug targets recapitulates, and markedly amplifies, the phenotypic effects of common SNPs within these target genes. This data provides indirect evidence that, with certain limitations, large-scale GWAS represent a new tool for the discovery and the development of innovative drugs.

Association studies of gene variants and response to dietary challenges represent one way of investigating gene-nutrient interactions. Several studies reported in the present review concentrate on evaluating variation at the apolipoprotein AI-CIII-AIV and apolipoprotein E gene loci, as well as the fatty acid binding protein gene. In addition, the effect of nutrients can be directly evaluated at the level of gene expression, and reports of in-vitro studies of control of fatty acid and triglycerides synthesis are discussed in the present review.

Background —We investigated the relationship between variation in the apolipoprotein (apo) AI-CIII-AIV gene cluster and response to an oral glucose test (OGTT) and oral fat load test (OFTT) in the EARSII group of young, healthy male offspring whose fathers had had a myocardial infarction before the age of 55 years (cases, n=407) compared with age-matched controls (n=415). The apoCIII variations examined were C3238G ( Sst I) in the 3′-UTR, C1100T in exon 3, C-482T in the insulin response element (IRE), and T-2854G in the apoCIII-AIV intergenic region. Methods and Results —The postprandial response was regulated by variation at the T-2854G and C3238G sites. After the OFTT, carriers of the rare alleles had delayed clearance of triglyceride (Tg) levels; G-2854 carriers showed the largest effect on Tg (AUC, 24% greater, P P P P =0.03). However, after adjustment for fasting level of Tg, only the effect with the T-2854G remained significant. Variation at the C-482T (IRE) determined response to the OGTT, with carriers of the rare T-482 having significantly elevated glucose (28.7% AUC, P =0.013) and insulin (20.5% AUC, P Conclusions —These data suggest that specific genetic variants at the apoCIII gene locus differentially affect postprandial and response to OGTT and suggest a novel mechanism for the effects of variation at this locus on risk for atherosclerosis.