Sequencing of 2 Subclinical Atherosclerosis Candidate Regions in 3669 Individuals
Year: 2014
Type: article
Study design: Observational Study
Abstract: BACKGROUND: Atherosclerosis, the precursor to coronary heart disease and stroke, is characterized by an accumulation of fatty cells in the arterial intimal-medial layers. Common carotid intima media thickness (cIMT) and plaque are subclinical atherosclerosis measures that predict cardiovascular disease events. Previously, genome-wide association studies demonstrated evidence for association with cIMT (SLC17A4) and plaque (PIK3CG). METHODS AND RESULTS: We sequenced 120 kb around SLC17A4 (6p22.2) and 251 kb around PIK3CG (7q22.3) among 3669 European ancestry participants from the Atherosclerosis Risk in Communities (ARIC) study, Cardiovascular Health Study (CHS), and Framingham Heart Study (FHS) in Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Primary analyses focused on 438 common variants (minor allele frequency ≥1%), which were independently meta-analyzed. A 3' untranslated region CCDC71L variant (rs2286149), upstream from PIK3CG, was the most significant finding in cIMT (P=0.00033) and plaque (P=0.0004) analyses. A SLC17A4 intronic variant was also associated with cIMT (P=0.008). Both were in low linkage disequilibrium with the genome-wide association study single nucleotide polymorphisms. Gene-based tests including T1 count and sequence kernel association test for rare variants (minor allele frequency <1%) did not yield statistically significant associations. However, we observed nominal associations for rare variants in CCDC71L and SLC17A3 with cIMT and of the entire 7q22 region with plaque (P=0.05). CONCLUSIONS: Common and rare variants in PIK3CG and SLC17A4 regions demonstrated modest association with subclinical atherosclerosis traits. Although not conclusive, these findings may help to understand the genetic architecture of regions previously implicated by genome-wide association studies and identify variants within these regions for further investigation in larger samples.
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Awards: G10717269, G1220223050, CORONARY HEART DISEASE AND STROKE, CORONARY HEART DISEASE &STROKE IN PEOPLE AGED 65-84, G1462415530, CHS-ULTRASOUND READING, CORONARY HEART DISEASE AND STROKE, Rare variants and NHLBI traits in deeply phenotyped cohorts, G2193588257, G2194386449, CORONARY HEART DISEASE AND STROKE IN PEOPLE AGED 65-84, CORONARY HEART DISEASE &STROKE IN PEOPLE AGED 65-84, G2273349799, G232264632, G2391884931, G250621538, Exceptional Survival: Trajectories to Functional Aging (CHS All Stars), G2555954497, CORONARY HEART DISEASE &STROKE IN THE ELDERLY, G2818913090, G3045517347, WGA Study to Identify Genetic Variants Associated with CV Events in CHS, Prospective meta-analyses of drug-gene interactions: CHARGE GWAS consortium, G3220743633, UCLA Clinical and Translational Science Institute, Genomic Epidemiology of Cardiovascular Disease, G36937976, CENTRAL BLOOD ANALYSIS LABORATORY FOR CHS, Predictors of Alheimers Disease in Mild Cognitive Impairment, The Human Genome Sequencing Center, G4617276643, G4705346009, G4987078009, G503914490, G5164707915, Genome-Wide Association for Loci Influencing CHD and Other Heart, Lung and Blood, Epidemiology of Venous Thrombosis and Pulmonary Embolism, G573134505, G581887176, CHARGE consortium: omics discovery for CVD and aging phenotypes, CHS Events Follow-up Study, G6226795708, Predictors of Alzheimers Disease in Mild Cognitive Impairment, The Framingham Heart Study, G6705035318, CHS-Transition Phase, G7176672723, CHS RETINAL READING CENTER, Exceptional Survival: Trajectories to Functional Aging (CHS All Stars), G777822606, CHS Events Follow-up Study, G7999488110, COGNITIVE TESTS, APOE, BRAIN MRI AND RISKS OF DEMENTIA, Hormonal trajectories in aging, Building on GWAS for NHLBI-disease: the CHARGE consortium, Diabetes Research Center (DRC), From GWAS loci to blood pressure genes, variants & mechanisms - Renewal
OpenAlex ID: W2125780305