Abstract 11049: Rare Genetic Variants in Individuals with Low ASCVD Risk and Hard Chd or High Coronary Artery Disease: Multi-Ethnic Study of Atherosclerosis

Abstract

Introduction: Even though various risk estimators are widely used to predict atherosclerosis from subclinical levels to hard CHD, there is a remarkable proportion of low-risk individuals with inordinately high coronary artery calcification (CAC) or with hard CHD events. Rare pathogenic variants (<0.1%) in the atherosclerosis gene panel with larger effect sizes may predispose low-risk individuals to develop atherosclerosis. Hypothesis: There are rare pathogenic variants in the atherosclerosis gene panel in low-ASCVD-risk individuals with high CAC scores or hard CHD events than low-risk individuals with a CAC score of zero or no events. Methods: The MESA whole-genome sequencing data (2000-02) was evaluated to capture variants in 224 atherosclerosis-related genes. Coding variants with a frequency of <0.1% in each racial/ethnic group and damaging effects were assessed by the ClinVar and ACMG-AMP guidelines for pathogenicity. Participants with an ASCVD score of <7.5% were defined as low risk. Two different case groups were defined based on (1) hard CHD events and (2) CAC scores higher than the 90 th percentile of age, sex, and race-adjusted reference scores. Associated control groups were age-, sex-, and race-matched participants with no CHD events or zero CAC score. Results: A total of 159 cases with high CAC and 1256 matched controls were evaluated within the low-risk group. In the case group, there were three rare, likely pathogenic variants ( LDLR c.681C>G, p.D227E and c.2026G>A, p.G676S; and AHI1 c.2168G>A, p.R723Q ) . None of these variants were observed in the control group. A total of 86 cases had a hard CHD event, among whom two had rare, likely pathogenic variants ( KCNQ1 c.517G>A, p.A173T and LDLR c.1201C>G, p.L401V). None of the 1546 controls had these variants. The LDLR c.1201C>G variant is currently a variant of uncertain significance that would be likely pathogenic with the assumption of genotype-phenotype specificity [pathogenicity supporting criterion 4]. Conclusions: We observed five likely pathogenic variants in atherosclerosis-related genes in low-risk individuals for ASCVD who had high CAC scores or hard CHD events. Rare variants with large effect sizes may unravel the missed risk prediction of a common trait like atherosclerosis.