SNPs and Extent of Atherosclerosis (SEA) Study

The SEA study is a genome-wide association study to identify genetic variants associated with premature atherosclerosis in subjects included in the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) repository - a unique NHLBI resource including data, DNA and arterial specimens from over 3000 multi-ethnic subjects 15-34 years of age who died of non-atherosclerotic causes (mostly trauma). All PDAY subjects had post-mortem quantitative assessment of raised atherosclerotic lesions in their aorta and coronary arteries - making this the largest and most carefully phenotyped cohort for premature atherosclerosis in the world. The goal of the current project was to use the quantitative measure of raised atherosclerotic lesions in the PDAY cohort as the target phenotype for a genome-wide association study and to use quantitative measures of subclinical atherosclerosis (coronary calcium and carotid IMT) in the Multi-Ethnic Study of Atherosclerosis (MESA) to confirm or refute candidate loci identified from the PDAY analysis. Identifying genetic factors that predispose individuals to premature atherosclerosis could lead to more effective screening and early treatment of high risk individuals and suggest novel molecular targets for treatment and prevention interventions.]]>
SEA Phase 2 MethodsPDAY Population and Atherosclerosis Phenotype: From 1987 to 1994 PDAY centers collected standardized autopsy specimens and selected risk factor data from black and white males and females, age 15-34 yrs, who died within 72 hours after injury. Using an unlinked anonymous coding system, the specimens and data were submitted to central pathology laboratories for detailed histopathologic analyses. The right coronary artery and left half of the aorta were stained with Sudan IV and the percent of intimal surface involved with raised atherosclerotic lesions in the distal and thoracic aorta and right coronary artery was independently estimated by three pathologists. This produced a pathologically specific and quantitatively precise description of atherosclerosis extent that was strongly correlated with blood lipids and other conventional risk factors in the PDAY cohort*. For the current project the percent surface involvement in the distal and thoracic aorta and right coronary artery was summed and then adjusted for age^2, race and gender to produce a total raised lesion score which was the primary phenotype for our genetic association analyses. Cases were defined as the PDAY subjects at >90th% for total raised lesion score. Controls were selected from among PDAY subjects with a total raised lesion score = 0 after matching to cases (2:1) on age, race and gender. In Phase I of the SEA Study quantitative genotyping was used to estimate allele frequency for >2.4 million SNPs in each of eight pools of DNA (3 case and 5 control pools). Pools were balanced for age, gender and genetic ancestry based on analysis of 311 ancestry informative markers typed on every sample before pool formation. Phase II and III of the SEA study involved individual level genotyping of promising SNPs in the PDAY subjects and subsequent replication in the MESA cohort. Phase II and III data are not included in the dbGap data set. *A more detailed description of the measurement of raised lesions in the PDAY cohort can be found in: Strong JP, Malcom GT, McMahan CA et al. Prevalence and extent of atherosclerosis in adolescents and young adults. Implications for prevention from the Pathobiological Determinants of Atherosclerosis in Youth study. JAMA 1999;281:727-35; PMID: 10052443.]]>
2005 - Grant funded 2006 - DNA extraction and preparation 2007 - Phase I genotyping completed 2008 - Phase II genotyping completed 2009 - Phase III genotyping completed 2010 - Phase III analyses completed ]]>