Multiethnic Genome-Wide Association Study of Subclinical Atherosclerosis in Individuals With Type 2 Diabetes

Abstract

Background - Coronary artery calcification (CAC) and carotid artery intima-media thickness (cIMT) are measures of subclinical atherosclerosis in asymptomatic individuals and strong risk factors for cardiovascular disease (CVD). Type 2 diabetes (T2D) is an independent CVD risk factor that accelerates atherosclerosis. Methods - We performed meta-analyses of genome-wide association studies (GWAS) in up to 2,500 T2D individuals of European ancestry (EA) and 1,590 T2D individuals of African ancestry (AA) with or without exclusion of prevalent CVD, for CAC measured by cardiac computed tomography, and 3,608 EA and 838 AA with T2D for cIMT measured by ultrasonography within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Results - We replicated two loci (rs9369640 and rs9349379 near PHACTR1 and rs10757278 near CDKN2B ) for CAC and one locus for cIMT (rs7412 and rs445925 near APOE-APOC1 ) that were previously reported in the general EA populations. We identified one novel CAC locus (rs8000449 near CSNK1A1L/LINC00547/POSTN at 13q13.3) at P =2.0×10 -8 in EA. No additional loci were identified with the meta-analyses of EA and AA. The expression QTL analysis with nearby expressed genes derived from arterial wall and metabolic tissues from GTEx pinpoints POSTN , encoding a matricellular protein involved in bone formation and bone matrix organization, as the potential candidate gene at this locus. In addition, we found significant associations ( P <3.1×10 -4 ) for three previously reported coronary artery disease loci for these subclinical atherosclerotic phenotypes (rs2891168 near CDKN2B-AS1 and rs11170820 near FLJ12825 for CAC, and rs7412 near APOE for cIMT). Conclusions - Our results provide potential biological mechanisms that could link CAC and cIMT to increased CVD risk in individuals with T2D.

Type 2 Diabetes Modifies the Association of CAD Genomic Risk Variants With Subclinical Atherosclerosis

“…Second, for most of the variants, the direction of association with subclinical atherosclerosis in T2D cases mirrored the direction of association identified with CAD. This echoes the results from the Lu et al 26 study of subclinical atherosclerosis GWAS in T2D only, where they identified 3 significant associations (rs2891168 near CDKN2B-AS1 at 9p21, rs11170820 near FLJ12825 for CAC, and rs7412 near APOE for CIMT), concluding that some CAD loci act through subclinical atherosclerosis in individuals with T2D. Finally, while these associations were only nominally significant, the contributions from the interaction tests were the primary drivers of the nominally significant associations, suggesting that the overall fit of the model was improved by the inclusion of the T2D interaction term.…”

“…All CAD variants, except rs55730499 near LPA , have also previously been identified as associated with CAC in published CAC GWAS. 22,25,26…”

“…All CAD variants, except rs55730499 near LPA, have also previously been identified as associated with CAC in published CAC GWAS. 22,25,26 No SNVs met the Bonferroni-corrected threshold for significance in the interaction test, but 17 candidate variants were nominally significant (P int and P joint <0.05). Fifteen SNVs were in loci that had not previously been identified with CAC (Table 1).…”

“…Furthermore, many studies have not considered the role of T2D in their analyses, which may differentially influence the way loci impact the development of atherosclerosis. A study by Lu et al 26 conducted a GWAS of subclinical atherosclerosis limited to individuals with T2D and subsequently evaluated whether 161 known CAD loci were significantly associated with the development of subclinical atherosclerosis in individuals with T2D. While they successfully identified 3 CAD loci that were significantly associated with CAC and CIMT in those with T2D, the study did not formally evaluate the differential associations of CAD loci in T2D compared with normoglycemic controls.…”

Circulating MicroRNA Profiling Identifies Distinct MicroRNA Signatures in Acute Ischemic Stroke and Transient Ischemic Attack Patients

“…CTGF levels were higher in stroke than TIA and are associated with plaque stabilization following stroke [37]. Moreover, GWAS have associated CTGF with coronary artery calcification in type 2 diabetes patients [38]. Upregulation of miR-18a-5p in AIS patients indicates its potential roles in thrombotic or embolic ischemic strokes but needs further investigation.…”