Coronary artery calcification (CAC) is a marker of atherosclerosis and is associated with increased risk of coronary heart disease (CHD) mortality, especially in individuals with type 2 diabetes (T2D). While numerous studies have identified genetic loci involved in CAC, CHD, and T2D, the shared genetic architecture between these highly associated traits is still being understood. We compared the effects of 388 genetic variants significantly associated with CHD in the literature in 2,971 individuals with T2D and 13,022 normoglycemic controls utilizing whole genome sequencing generated by the National Heart, Lung, and Blood Institute’s Trans-Omics for Precision Medicine (TOPMed) program. Participants were from four race/ethnic groups, including European American, African American, Hispanic/Latinx, and East Asian. CAC was first log transformed, then further transformed through inverse rank-based normalization of the residuals accounting for age and sex. Linear mixed models accounting for relatedness, implemented in GENESIS, were used to test for interaction between each variant and T2D status. Analyses were adjusted for age, sex, study and the first eleven principal components. The genetic main and interaction effects were assessed in a joint test using a two degree of freedom model to determine if a CHD variant was associated with CAC, then further evaluated to determine if these variants had a significantly different effect in T2D cases versus controls. Using Bonferroni corrected significance threshold of P<1.3x10-4 (0.05/388), we identified 20 CHD variants associated with CAC according to the joint test, of which 11 had a statistically significant different effect in T2D cases and controls (rs1807214 near ABHD2, rs668948 near APOB, rs11655024 in BCAS3, rs840616 near CALCRL, rs1321309 near CDNK1A, rs6883598 near FBN2, rs249760 near FGF1, rs12897 near FNDC3B, rs12691049 near MYH11, rs6494488 near RBPMS2, rs7118294 near WT1). While rs668948 has not previously been implicated in previous CAC GWAS, it lies nearest to APOB, which is a known driver of plaque development and subsequent atherosclerosis. Similarly, rs840616 lies near CALCRL, which is involved in the maintenance of calcium homeostasis. Overall, 159 of the CHD variants were nominally significant (P<0.05) for CAC according to the joint test, including 96 variants with nominally significant T2D interactions. These results highlight T2D as an important moderator of the association of CHD loci with subclinical atherosclerosis.

Coronary artery calcification (CAC) is a marker of atherosclerosis and is associated with increased risk of coronary heart disease (CHD) mortality, especially in individuals with type 2 diabetes (T2D). While numerous studies have identified genetic loci involved in CAC, CHD, and T2D, the shared genetic architecture between these highly associated traits is still being understood. We compared the effects of 388 genetic variants significantly associated with CHD in the literature in 2,971 individuals with T2D and 13,022 normoglycemic controls utilizing whole genome sequencing generated by the National Heart, Lung, and Blood Institute’s Trans-Omics for Precision Medicine (TOPMed) program. Participants were from four race/ethnic groups, including European American, African American, Hispanic/Latinx, and East Asian. CAC was first log transformed, then further transformed through inverse rank-based normalization of the residuals accounting for age and sex. Linear mixed models accounting for relatedness, implemented in GENESIS, were used to test for interaction between each variant and T2D status. Analyses were adjusted for age, sex, study and the first eleven principal components. The genetic main and interaction effects were assessed in a joint test using a two degree of freedom model to determine if a CHD variant was associated with CAC, then further evaluated to determine if these variants had a significantly different effect in T2D cases versus controls. Using Bonferroni corrected significance threshold of P<1.3x10-4 (0.05/388), we identified 20 CHD variants associated with CAC according to the joint test, of which 11 had a statistically significant different effect in T2D cases and controls (rs1807214 near ABHD2, rs668948 near APOB, rs11655024 in BCAS3, rs840616 near CALCRL, rs1321309 near CDNK1A, rs6883598 near FBN2, rs249760 near FGF1, rs12897 near FNDC3B, rs12691049 near MYH11, rs6494488 near RBPMS2, rs7118294 near WT1). While rs668948 has not previously been implicated in previous CAC GWAS, it lies nearest to APOB, which is a known driver of plaque development and subsequent atherosclerosis. Similarly, rs840616 lies near CALCRL, which is involved in the maintenance of calcium homeostasis. Overall, 159 of the CHD variants were nominally significant (P<0.05) for CAC according to the joint test, including 96 variants with nominally significant T2D interactions. These results highlight T2D as an important moderator of the association of CHD loci with subclinical atherosclerosis.

Coronary artery calcification (CAC) is a marker of atherosclerosis and is associated with increased risk of coronary heart disease (CHD) mortality, especially in individuals with type 2 diabetes (T2D). While numerous studies have identified genetic loci involved in CAC, CHD, and T2D, the shared genetic architecture between these highly associated traits is still being understood. We compared the effects of 207 genetic variants that were previously identified as associated with CHD and/or CAC in 2,971 individuals with T2D and 13,022 non-diabetic controls utilizing whole genome sequencing generated by the National Heart, Lung, and Blood Institute’s Trans-Omics for Precision Medicine (TOPMed) program. Participants were from four race/ethnic groups, including European American, African American, Hispanic/Latinx, and East Asian. CAC was first log transformed, then further transformed through inverse rank-based normalization of the residuals accounting for age and sex. Linear mixed models accounting for relatedness, implemented in GENESIS, were used to test for interaction between each variant and T2D status. Analyses were adjusted for age, sex, study and the first eleven principal components. The genetic main and interaction effects were assessed in a joint test using a two degree of freedom model to determine if a CHD variant was associated with CAC, then further evaluated to determine if these variants had a significantly different effect in T2D cases versus controls. Using a significance threshold of P<2x10-4, we identified eighteen CHD variants associated with CAC according to the joint test, of which six had a statistically significant different effect in T2D cases and controls (rs6494488 near RBPMS2, rs7212798 in BCAS3, rs1321309 near PI16, rs668948 near APOB, rs840616 near CALCRL, rs12897 near FNDC3B). The association of five of these variants was stronger in cases than in controls, while for rs7212798 it was stronger in controls. While rs668948 has not previously been implicated in previous CAC GWAS, it lies nearest to APOB, which is a known driver of plaque development and subsequent atherosclerosis. Similarly, rs840616 lies near CALCRL, which is a part of a group of calcitonin receptors involved in the maintenance of calcium homeostasis. Overall, 85 of the CHD variants were nominally significant (p<0.05) for CAC according to the joint test, including 55 variants with nominally significant T2D interactions. These results highlight T2D as an important moderator of the association of CHD loci with subclinical atherosclerosis. Through our analysis, we identified potential new loci involved in the development of CAC in individuals with T2D.