Associations between a Genetic Risk Score for Clinical CAD and Early Stage Lesions in the Coronary Artery and the Aorta

<div><p>Objective</p><p>The correlation between the extent of fatty streaks, more advanced atherosclerotic lesions, and community rates of coronary artery disease (CAD) is substantially higher for the coronary artery compared to the aorta. We sought to determine whether a genetic basis contributes to these differences.</p><p>Approach and Results</p><p>We conducted a cluster analysis of 6 subclinical atherosclerosis phenotypes documented in 564 white participants of the Pathobiological Determinants of Atherosclerosis in Youth study including the extent of fatty streaks and raised lesions in the coronary artery (CF and CR), thoracic aorta (TF and TR), and abdominal aorta (AF and AR) followed by a genetic association analysis of the same phenotypes. Our cluster analysis grouped all raised lesions and fatty streaks in the coronary into one cluster (CF, CR, TR, and AR) and the fatty streaks in the aorta into a second cluster (TF and AF). We found a genetic risk score of high-risk alleles at 57 susceptibility loci for CAD to be variably associated with the phenotypes in the first cluster (OR: 1.30 p = 0.009 for being in top quartile of degree of involvement of CF, 1.34 p = 0.005 for CR, 1.25: p = 0.11 for TR, and 1.19 p = 0.08 for AR) but not at all with the phenotypes in the second cluster (OR: 1.01, p = 0.95 for TF and 0.98, p = 0.82 for AF).</p><p>Conclusions</p><p>The genetic determinants of fatty streaks in the aorta do not appear to overlap substantially with the genetic determinants of fatty streaks in the coronary as well as raised lesions in both the coronary and the aorta. These findings may explain why a larger fraction of fatty streaks in the aorta are less likely to progress to raised lesions compared to the coronary artery.</p></div

Cluster analysis of six phenotypes in 564 white participants of the Pathobiological Determinants of the Youth (PDAY) study including percent surface area of involvement by raised lesions and fatty streaks in the coronary (CR and TF), thoracic aorta (TR and TF), and abdominal aorta (AR and TF).

<p>Both clustering algorithms identified 2 clusters. The first cluster includes CF, CR, TR, and AR and the second cluster includes TF and AF.</p

Summary statistics for the six phenotypes of interest in 564 white/European genotyped participants of the Pathobiological Determinants of Youth study.

<p>Summary statistics for the six phenotypes of interest in 564 white/European genotyped participants of the Pathobiological Determinants of Youth study.</p

Forest plot of Odds Ratio per standard deviation increases in the weighted GRS (wGRS) for being in the top quartile of percent surface area of involvement (case) of early arterial lesions compared to the bottom three quartiles (controls).

<p>Odds Ratios are adjusted for age and sex at time of autopsy. Results for all 3 vascular beds are grouped by lesion type (raised lesions vs. fatty streak) and shown for wGRS that includes all 57 SNPs associated with clinical CAD (A) and for the subset of 38 SNPs not associated with traditional risk factors (B).</p

Association of the Lipoprotein Receptor <i>SCARB1</i> Common Missense Variant rs4238001 with Incident Coronary Heart Disease

<div><p>Background</p><p>Previous studies in mice and humans have implicated the lipoprotein receptor <i>SCARB1</i> in association with atherosclerosis and lipid levels. In the current study, we sought to examine association of <i>SCARB1</i> missense single nucleotide polymorphism (SNP) rs4238001 with incident coronary heart disease (CHD).</p><p>Methods and Results</p><p>Genotypes for rs4238001 were imputed for 2,319 White, 1,570 African American, and 1,292 Hispanic-American MESA participants using the 1,000 Genomes reference set. Cox proportional hazards models were used to determine association of rs4238001 with incident CHD, with adjustments for age, sex, study site, principal components of ancestry, body mass index, diabetes status, serum creatinine, lipid levels, hypertension status, education and smoking exposure. Meta-analysis across race/ethnic groups within MESA showed statistically significant association of the T allele with higher risk of CHD under a consistent and formally adjudicated definition of CHD events in this contemporary cohort study (hazard ratio [HR]=1.49, 95% CI [1.04, 2.14], <i>P</i> = 0.028). Analyses combining MESA with additional population-based cohorts expanded our samples in Whites (total n = 11,957 with 871 CHD events) and African Americans (total n = 5,962 with 355 CHD events) and confirmed an increased risk of CHD overall (HR of 1.19 with 95% CI [1.04, 1.37], <i>P</i> = 0.013), in African Americans (HR of 1.49 with 95% CI [1.07, 2.06], <i>P</i> = 0.019), in males (HR of 1.29 with 95% CI [1.08, 1.54], <i>P</i> = 4.91x10^-3) and in White males (HR of 1.24 with 95% CI [1.03, 1.51], <i>P</i> = 0.026).</p><p>Conclusion</p><p><i>SCARB1</i> missense rs4238001 is statistically significantly associated with incident CHD across a large population of multiple race/ethnic groups.</p></div

Effect estimates (log hazard ratio of CHD for rs4238001 effect allele T) and corresponding 95% confidence intervals shown for Model 1 (basic), Model 2 (extended), Model 3 (Model 2 + lipid medication) and Model 4 (NMR lipids).

<p>Analyses were conducted stratified by race/ethnic group and combined by meta- analysis, for all participants as well as stratified by sex (males or female).</p

Characteristics of MESA participants across three ethnic groups.

<p>Data are presented as N (%) for binary measures or median [IQR] for continuous measure.</p><p>*Summary statistics are reported for the subset of individuals with data available for at least one of the clinical events.</p><p>†P-values are presented for statistical significance of the difference in values across race/ethnic groups according to a likelihood ratio test with 2 degrees of freedom.</p><p>Characteristics of MESA participants across three ethnic groups.</p

Summary of genetic additive effects of rs4238001 allele T on HDL-C (log mg/dL), HDL particle number (nmol/L) and HDL particle size (log nm) under a basic model (Model 1).

<p>Analyses were conducted stratified by race/ethnic group and combined by meta-analysis, for all participants as well as stratified by sex (males or female).</p

Summary of estimated genetic additive effects of rs4238001 allele T on LDL-C (mg/dL), LDL particle number (nmol/L) and LDL particle size (log nm) under a basic regression model (Model 1).

<p>Analyses were conducted stratified by race/ethnic group and combined by meta-analysis, for all participants as well as stratified by sex (males or female).</p

DNA methylation ratio and AA/DGLA (<i>FADS1</i> efficiency) and GLA/LA (<i>FADS2</i> efficiency) of cg27386326 stratified by rs174537 genotype.

<p>Markers for each ethnic group, by genotype, are indicated in the legend.</p