Validating coronary artery disease genetic findings using coronary artery calcification measures in Clinseq® cohorts

Authors

• Z Liu
• H Sung
• AF Wilson
• LG Biesecker
• NF Hansen
• JC Mullikin

Abstract

Coronary artery disease (CAD) is the leading cause of death world-wide, with a heritability of 40-60%. Advanced CAD usually includes plaque calcification, which can be quantified by coronary artery calcification (CAC) scoring. High CAC scores (>300) are strong predictors of future cardiac events. The Miami Cardiovascular Registry (MCR) study had previously identified genes associated with angiographic stenosis of CAD in a Hispanic-majority population. We suggest that these genes may also play a role in CAC. To further validate MCR and previously published CAD candidate genes, we will verify their associations with CAC in the ClinSeq® cohort, which includes male and female participants between 45 and 65 years of age when they enrolled into the study at the NIH Clinical Center. The first ClinSeq® cohort included 1,014 participants of predominantly European ancestry. Exome sequencing was performed on gDNA samples from all individuals. The CAC score for each participant was calculated based on the Agatston method. Due to a considerable proportion of participants with a CAC score of zero, the value of one was added to all CAC scores and log10 transformed, before adjusting for appropriate covariates, such as age, sex, BMI, and cholesterol medication usage. 48 candidate genes, which included 46 from a previous meta-analysis study and two from MCR top associated genes (p-value = 0.001), were tested with CAC score residuals using the Sequence Kernel Association Test (SKAT). Both common and rare variants in the ClinSeq® dataset that passed QC were collapsed into genes for combined gene-based tests. Two previously published genes SLC22A4 and PDGFD from a meta-analysis study, were significantly associated with CAC score residuals in the dataset (p-value = 0.00027 and 0.020, respectively). The p-value of SLC22A4 remained significant after Bonferroni correction. In addition, recruitment of a second ClinSeq® cohort of 500 African Americans is well underway and gDNA samples from these individuals will be exome sequenced. Admixture mapping analysis on candidate gene regions will be performed in the second cohort to further validate previous findings. Our validation study used exome sequencing data to corroborate previous genome-wide association study findings, and verified that SLC22A4 and PDGFD were significantly associated with CAC. Going forward, studying under-represented populations, such as African Americans, may also help us to identify ancestry-specific genetic effects, which may further explain the missing heritability of CAD.

Scientific Focus Area: Genetics and Genomics

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