We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 cases and 64,762 controls of European descent, followed by genotyping of top association signals in 60,738 additional individuals. This genomic analysis identified 13 novel loci harboring one or more SNPs that were associated with CAD at P<5×10−8 and confirmed the association of 10 of 12 previously reported CAD loci. The 13 novel loci displayed risk allele frequencies ranging from 0.13 to 0.91 and were associated with a 6 to 17 percent increase in the risk of CAD per allele. Notably, only three of the novel loci displayed significant association with traditional CAD risk factors, while the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the novel CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits.

SummaryBackgroundHigh plasma HDL cholesterol is associated with reduced risk of myocardial infarction, but whether this association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent of non-genetic confounding, and are unmodified by disease processes, mendelian randomisation can be used to test the hypothesis that the association of a plasma biomarker with disease is causal.MethodsWe performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20 913 myocardial infarction cases, 95 407 controls). Second, we used as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12 482 cases of myocardial infarction and 41 331 controls. As a positive control, we also tested a genetic score of 13 common SNPs exclusively associated with LDL cholesterol.FindingsCarriers of the LIPG 396Ser allele (2·6% frequency) had higher HDL cholesterol (0·14 mmol/L higher, p=8×10−13) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with non-carriers. This difference in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio [OR] 0·87, 95% CI 0·84–0·91). However, we noted that the 396Ser allele was not associated with risk of myocardial infarction (OR 0·99, 95% CI 0·88–1·11, p=0·85). From observational epidemiology, an increase of 1 SD in HDL cholesterol was associated with reduced risk of myocardial infarction (OR 0·62, 95% CI 0·58–0·66). However, a 1 SD increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0·93, 95% CI 0·68–1·26, p=0·63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in LDL cholesterol associated with OR 1·54, 95% CI 1·45–1·63) was concordant with that from genetic score (OR 2·13, 95% CI 1·69–2·69, p=2×10−10).InterpretationSome genetic mechanisms that raise plasma HDL cholesterol do not seem to lower risk of myocardial infarction. These data challenge the concept that raising of plasma HDL cholesterol will uniformly translate into reductions in risk of myocardial infarction.FundingUS National Institutes of Health, The Wellcome Trust, European Union, British Heart Foundation, and the German Federal Ministry of Education and Research.

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IntroductionAngiotensin II (ANG II) is known to be a potent growth promoting factor for vascular smooth muscle cells and fibroblasts but little is known about its influence on growth in endothelial cells. We studied the effects of ANG II Angiotensin II (ANG II),' the main effector peptide of the renin-angiotensin system, has long been known to play an important role in the regulation of blood pressure and body fluid homeostasis. More recently, ANG II has been reported to induce hyperplasia or hypertrophy in cultured vascular smooth muscle cells derived from the aorta ( 1-4), in small resistance arteries (5) and in cardiomyocytes (6).We have previously observed that chronic oral treatment of spontaneously hypertensive rats (SHR) with an angiotensin converting enzyme inhibitor induced myocardial capillary growth independently of the antihypertensive and antihypertrophic actions of the drug (7). Theoretically, this effect could be due to a potentiation of endogenous kinins or to a reduced generation of ANG II. In the latter case, one would have to expect an antiproliferative effect of ANG II on myocardial endothelial cells which gives rise to cardiac capillaries. This hypothesis is at variance with the widely accepted idea of ANG II being a growth promoting factor in cardiovascular tissues. However, using coronary endothelial cells (CEC) from SHR and normotensive Wistar Kyoto rats in primary culture, we recently found that ANG II significantly attenuated proliferation when growth was stimulated by fetal calf serum (8, 9). Thus, in contrast to its proliferating effects on vascular smooth muscle cells (VSMC), ANG II may indeed exert antiproliferative actions on vascular endothelial cells.VSMC in culture, a common cell line to study the trophic effects of ANG II, exclusively express ATI-and no AT2-receptors (10). Therefore, ANG 11-induced growth shown in VSMC in vitro has been attributed to the ATl-receptor. The obvious discrepancy between the effects of ANG II on VSMC and on microvascular endothelial cells could be explained twofold. First, angiotensin receptors on endothelial cells could be identical to those on VSMC (i.e., ATI) but coupled to intracellular pathways different from those present in VSMC. Second, the antiproliferative response to treatment with ANG II, as observed in endothelial cells, could be due to the stimulation of an angiotensin receptor subtype different from AT1, for instance the AT2-receptor. In addition, the antiproliferative effect of ANG II could be a phenomenon occurring in serum-stimulated rat cardiac microvascular endothelial cells but not a general feature of CEC under stimulation with defined growth factors.In the present study we investigated, first, whether ANG II is antimitogenic for CEC stimulated to proliferate by the administration of a defined growth factor and second, by which angiotensin receptor subtype, ATl or AT2, the antimitogenic

Crohn disease and ulcerative colitis are two subphenotypes of inflammatory bowel disease (IBD), a complex disorder resulting from gene-environment interaction. We refined our previously defined linkage region for IBD on chromosome 10q23 and used positional cloning to identify genetic variants in DLG5 associated with IBD. DLG5 encodes a scaffolding protein involved in the maintenance of epithelial integrity. We identified two distinct haplotypes with a replicable distortion in transmission (P = 0.000023 and P = 0.004 for association with IBD, P = 0.00012 and P = 0.04 for association with Crohn disease). One of the riskassociated DLG5 haplotypes is distinguished from the common haplotype by a nonsynonymous single-nucleotide polymorphism 113G→A, resulting in the amino acid substitution R30Q in the DUF622 domain of DLG5. This mutation probably impedes scaffolding of DLG5. We stratified the study sample according to the presence of risk-associated CARD15 variants to study potential gene-gene interaction. We found a significant difference in association of the 113A DLG5 variant with Crohn disease in affected individuals carrying the risk-associated CARD15 alleles versus those carrying non-risk-associated CARD15 alleles. This is suggestive of a complex pattern of genegene interaction between DLG5 and CARD15, reflecting the complex nature of polygenic diseases. Further functional studies will evaluate the biological significance of DLG5 variants. D10S201 D10S213 cM