Abstract 16182: Jay D. Coffman Early Career Investigator Award: Large-scale Targeted Sequencing of Genomic Regions Associated With Coronary Heart Disease Uncovers Evidence for Polygenic Overlap With Peripheral Arterial Disease
Introduction: Although both coronary heart disease (CHD) and peripheral arterial disease (PAD) result from atherosclerosis, relatively few genetic susceptibility variants for PAD have been discovered so far in contrast to CHD.
Hypothesis: We hypothesized that genes harboring variants conferring susceptibility to CHD in genome-wide association studies are also associated with PAD.
Methods: We performed targeted sequencing of 41 CHD susceptibility genomic regions (coding regions and 2/1 kb upstream/downstream) in 1826 PAD cases and 1725 controls. PAD cases (69±11 years, 61% men) had a resting/post-exercise ankle-brachial index (ABI) ≤0.9 or ≥1.4 and/or history of lower extremity revascularization, and no history of CHD at the time of recruitment. Controls (60±11 years, 55% men) had a normal ABI and no history of PAD or CHD. Sequencing was performed on an Illumina HiSeq 2000 (average read depth ≥30x). A gene-based global association analysis was done using the adaptive weighted sum of powered score test (aSPUw), followed by variant-level analyses using penalized regression models and fine mapping.
Results: Six genes, i.e. ABO, KCNK5, MRAS, PCSK9, SORT1, and CXCL12, met a gene-level based threshold of significance (P<0.005) for association with PAD after adjustment for age, sex, smoking, hypertension, diabetes, dyslipidemia, obesity, CHD, cerebrovascular disease and chronic kidney disease. The aSPU test for a total of 1511 variants passing quality control filters demonstrated the strongest association (P<4.8x106) of PAD with low-frequency variants (minor allele frequency 1-5%), followed by common and rare variants, respectively. A total of 352 genetic variants identified with penalized regression most parsimoniously explained the observed association with PAD for the 6 genomic regions, of which 18 were novel putatively impactful risk variants.
Conclusions: This large-scale targeted sequencing study of genomic regions associated with CHD uncovers evidence for polygenic overlap with PAD and provides insights into pleiotropy between these two subtypes of atherosclerotic vascular disease and the relevant biological pathways. Further functional studies are required to uncover the biological roles of identified genes and variants with PAD.
Author Disclosures: M.S. Safarova: None. E.E. Austin: None. D.J. Schaid: None. I.J. Kullo: None.
- © 2016 by American Heart Association, Inc.