Abstract 15300: Genetic Determinants of Plasma Glycine Levels Are Associated With Coronary Artery Disease: Meta-Analysis of Genome-Wide Association Studies in ~105,000 Subjects of European Ancestry
We recently identified a variant (rs715) in carbamoyl phosphatase 1 (CPS1) on chr2q34 that was strongly associated with plasma betaine and glycine levels, and showed a striking female-specific association with risk of coronary artery disease (CAD). To follow up these findings we combined GWAS summary statistics with 2,208,551 SNPs and 7,723 subjects of European descent from the GeneBank, TwinsUK, and KORA cohorts. The most significant locus for glycine was with rs715 (p=6.2x10-146), confirming our previous findings. To identify other independent signals throughout the genome, we used a stepwise model selection procedure. This approach identified a second SNP independently associated with glycine at the CPS1 locus (rs4673553; p=1.2x10-115). We next combined the results in the GeneBank, TwinsUK and KORA with another publicly available meta-analysis, MAGNETIC NMR. This analysis included 24,229 subjects of European descent and yielded a p-value 1.4x10-257, providing further evidence for association of rs467355 with glycine. In GeneBank, rs4673553 was also associated with betaine levels (p=4.0x10-4) and exhibited an interaction with sex (p-int<0.05), with stronger effect in females (log(beta)=-0.0755, p=1.8x10-3) compared to males (log(beta)=-0.0262, p=3.9x10-2). To determine the relationship between rs4673553 and CAD risk, we used the results of a meta-analysis of GWAS data with 19,955 cases and 60,712 controls from the CARDIoGRAM Consortium. The minor allele of rs4673553 was associated with decreased risk of CAD (OR=0.97, 95% CI 0.94-0.99, p=0.01), and a sex-stratified analysis revealed that risk of CAD was significant in women (OR 0.94, 95% CI 0.89-0.98, p=8.8x10-3), but not in men (OR 0.98, 95% CI 0.95-1.02, p=0.42). These results are consistent with our previous findings for rs715 and provide further evidence that CPS1 harbors independent variants that appear to be cardioprotective specifically in women. While it is not entirely clear why glycine-raising variants are associated with decreased risk of CAD in only women, previous studies have implicated glycine in reducing inflammation in macrophages and coronary endothelial cells. A better understanding of the role of glycine in atherogenesis will require additional follow-up studies.
Author Disclosures: J.A. Hartiala: None. W. Tang: None. Z. Wang: None. J. Erdmann: None. S.L. Hazen: Research Grant; Modest; S.L.H. reports he has received research funds from Abbott, Astra Zeneca, Cleveland Heart Lab, Esperion, Procter & Gamble and Takeda. Speakers Bureau; Modest; S.L.H. reports he has been paid as a consultant or speaker for the following companies: Cleveland Heart Lab, Inc., Esperion and Procter & Gamble. Ownership Interest; Modest; S.L.H. is named as co-inventor on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics and therapeutics. Other; Modest; S.L.H. has the right to receive royalty payments for inventions or discoveries related to cardiovascular diagnostics and therapeutics from Cleveland Heart Lab, Inc., Frantz Biomarkers, LLC, Procter &. H. Allayee: None.
- © 2016 by American Heart Association, Inc.