Abstract 18767: Association of Protein-Coding Genetic Variants with Coronary Arterial Calcification in 21,000 Individuals of European and African Ancestries

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Introduction: Coronary arterial calcification (CAC) is a marker of subclinical atherosclerosis in asymptomatic individuals, and is a heritable risk factor that correlates with the risk of coronary artery disease (CAD) development. Genotyping protein-coding regions of the genome with an array is a scalable approach to potentially discover causal low-frequency and rare protein-coding mutations with large phenotypic effects. Methods: Using the Illumina HumanExome BeadChip, we genotyped 247,870 variants (of which 231,539 are in exons) in each of 17,953 participants of European ancestry and 3,078 participants of African ancestry without clinical CAD from the Diabetes Heart Study, Framingham Heart Study, Family Heart Study, Cardiovascular Health Study, Rotterdam Study, Age Gene/Environment Susceptibility Study, Multi-Ethnic Study of Atherosclerosis, Dutch & Belgian Lung Cancer Screening Trial, Young Finns Study, Gene Study of Atherosclerosis Risk in Families, High Risk Plaque Bioimage Study, Old Order Amish Study, and Jackson Heart Study. We tested whether protein-coding variants, individually or aggregated within a gene, were associated with CAC, both as a continuous and binary variable. Results: We first robustly replicated prior CAC genomic non-coding association signals at 9p21 (p=9.85 x 10-29) and PHACTR1 (p=4.10 x 10-23) identified in GWAS based on HapMap imputation. A rare nonsynonymous variant in APOB (rs5742904) was associated with increased CAC (p=1.01 x 10-10) although this signal was driven by the Old Order Amish where it is a known founder mutation. The nonsynonymous APOE rs7412 variant (maf=0.078), the APOE epsilon2 allele, was associated with reduced CAC (p=2.61 x 10-9). Additionally, there was evidence of association for the nonsynonymous SSTR3 rs4988466 variant (maf=0.046) (p=7.77 x 10-8). SSTR3 is involved in cell proliferation, among other functions. Gene-based burden approaches did not yield statistically significant associations. Conclusions: We discovered nonsynonymous coding variants in APOB, APOE, and SSTR3 associated with CAC in a meta-analysis approach of 21,000 individuals using an exon-enriched genotyping array.