Researchers suggest mechanisms acting on vessel walls may interplay with plaque-promoting processes.

Three research groups have separately reported the discovery of new cardiovascular disease (CAD) risk genes in the latest issue of Nature Genetics. A meta-analysis of 14 prior genome-wide association studies involving some 87,000 individuals of European ancestry, was carried out by the international Coronary Artery Disease Genome-Wide Replication and Meta-Aanalysis (CARDIoGRAM) consortium. This identified 13 new genetic loci, 10 of which reside in gene regions not previously implicated in pathogenesis of the disease. The CARDiOGRAM study in addition confirmed 10 of 12 gene loci previously associated with CAD.

The second reported study, by the Coronary Artery Disease (C4D) Genetics Consortium, involved a meta-analysis of four GWAS involving 71,075 Europeans and South Asians. The analysis identified five loci newly associated with CAD. The third study, carried out as a new GWAS involving 7,593 individuals of Han Chinese ancestry, linked one locus on chromosome 6q24.1 with CAD. The Chinese research team claims prior to their research no GWAS had yet been reported specifically in a Chinese population.

Heritable factors have been estimated to account for 30–60% of the inter-individual variation in the risk of CAD, but genetic variants identified to date can only account for a small fraction of such heritability, according to the CARDiOGRAM team, led by Heribert Schunkert, M.D., at the University of Lübeck in Germany. The consortium’s new meta-analysis of 14 previous GWAS identified 13 new loci with risk allele frequencies ranging from 0.13 to 0.91 that were associated with a 6-17% increased risk of CAD per allele. Interestingly, 17 of the 23 new and existing loci linked with CAD risk appear to act through mechanisms that are independent of traditional risk factors, they point out. Eight of the 23 CAD loci were also associated with multiple other diseases and traits. The team’s findings from the 14-GWAS meta-analysis were verified by genotyping the most strongly implicated gene regions in another 56,000 CAD patients and healthy controls.

“The lack of apparent association with the risk factors we know so well is the source of a lot of excitement concerning these results,” notes lead co-author, Sekar Kathiresan, M.D., director of preventive cardiology at Massachusetts General Hospital. “It suggests there are new mechanisms we don’t yet understand.”

Such mechanisms may be impacting directly on biological processes in the vessel wall that are reacting to the plaque–promoting effects of traditional risk factors, suggests another of the 10 CARDiOGRAM co-lead authors, Themistocles Assimes, M.D., assistant professor of medicine at Stanford University Medical Center. “We’ve been slow in understanding the molecular pathways associated with the disease process in the walls of blood vessels”.

He believes studying the function of the genes in these regions could provide new insights into how the process of plaque development in the vessel wall could be blocked. “Currently there are not drugs that directly target the vessel wall. Heart disease drugs such as statins, beta blockers, or blood pressure medications target bad cholesterol or hypertension and other risk factors but not necessarily the molecular mechanisms that are directly responsible for forming plaque.” The CARDiOGRAM study is titled, “Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease.”

The C4D study also implicated new pathways in CAD susceptibility. The consortium analyzed data from 4 GWAS: the Precocious Coronary Artery Disease (PROCARDIS) study and Heart Protection Study (HPS) in people of European descent; and the Pakistan Risk of Myocardial Infarction Study (PROMIS) and London Life Sciences Prospective Population (LOLIPOP) study, which involved CAD cases of South Asian ancestry (chiefly from Pakistan and India). None of the five new loci identified by C4D have had any previously reported associations with established CAD risk factors, such as lipids, blood pressure, glucometabolic traits or body mass index, they report. Interestingly, all of the known and new variants were significantly associated with CAD risk in both the European and South Asian populations, which they suggest indicates that “the importance of the genes associated with CAD beyond the European ancestry groups in which they were first defined.”

Moreover, as both the CARDiOGRAM and C4D groups stress, it is becoming apparent as increasing numbers of CAD-associated genes are identified, that any heritable risk for CAD is likely to be the result of multiple alleles.  “The effect sizes of previously uni­dentified CAD-associated genes discovered by GWAS have become progressively smaller, suggesting that there may not be large-effect common variants remaining to be discovered, but rather that a large number of common variants of small effect may contribute to CAD risk,” the C4D researchers conclude.

C4D was chaired by Hugh Watkins M.D., at the department of cardiovascular medicine, The Wellcome Trust Centre for Human Genetics, University of Oxford, U.K. The resulting Nature Genetics paper is titled, “A genome-wide association study in Europeans and South Asians identifies five new loci for coronary artery disease.”

The third study published in Nature Genetics is claimed to be the first GWAS for CAD specifically in the Chinese Han population. The study was led by Xin Tu and Qing K. Wang, at the Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Institute, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China. The published paper is titled “Genome-wide association identifies a susceptibility locus for coronary artery disease in the Chinese Han population.”

The researchers’ three-stage GWAS identified a new association between CAD risk and a SNP designated rs6903956 in a putative gene denoted as C6orf105 on chromosome 6p24.1. They note that although the two discovery populations used for the first stage of their GWAS were small compared with most recent GWAS for CAD in populations of European ancestry, the study did encompass independent discovery populations from two geographically differ­ent regions of China. The selected SNPs from the discovery populations were then validated in a central China population of 572 cases and 436 controls, and positive SNPs from this validation study were subsequently replicated in three independent populations.

rs6903956 was found to demonstrate a significant association with CAD in all three of these populations. This association was still significant after adjustment for other known statistically significant covariates, the authors note. Significantly, the locus has not previously identified rs6903956 as a suscepti­bility locus in earlier GWAS in populations of European ancestry, they add. “Thus, the association between rs6903956 and CAD may be limited to the Chinese population and might not be able to be extrapolated to other ethnic populations.”

The Chinese researchers suggest that although the function of C6orf105 is unknown, expression studies also indicate that decreased expression of C6orf105 may be a possible pathogenic cause of CAD. C6orf105 was found to share 33% identity and 51% homology with human androgen-inducible gene 1 product (AIG-1). However, as they admit, “AIG1 expression can be induced by androgen, but little is known about the function of AIG1 … Further studies may be needed to identify the true causative variant(s) for CAD at this new 6p24.1 CAD locus.”

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