Abstract

BackgroundType 2 diabetes mellitus (T2DM) is a major cardiovascular disease (CVD) risk factor. Identification of genetic risk factors for CVD is important to understand disease risk. Two recent genome-wide association study (GWAS) meta-analyses in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium detected CVD-associated loci.MethodsVariants identified in CHARGE were tested for association with CVD phenotypes, including vascular calcification, and conventional CVD risk factors, in the Diabetes Heart Study (DHS) (n = 1208; >80% T2DM affected). This included 36 genotyped or imputed single nucleotide polymorphisms (SNPs) from DHS GWAS data. 28 coding SNPs from 14 top CHARGE genes were also identified from exome sequencing resources and genotyped, along with 209 coding variants from the Illumina HumanExome BeadChip genotype data in the DHS were also tested. Genetic risk scores (GRS) were calculated to evaluate the association of combinations of variants with CVD measures.ResultsAfter correction for multiple comparisons, none of the CHARGE SNPs were associated with vascular calcification (p < 0.0014). Multiple SNPs showed nominal significance with calcification, including rs599839 (PSRC1, p = 0.008), rs646776 (CELSR2, p = 0.01), and rs17398575 (PIK3CG, p = 0.009). Additional COL4A2 and CXCL12 SNPs were nominally associated with all-cause or CVD-cause mortality. Three SNPs were significantly or nominally associated with serum lipids: rs3135506 (Ser19Trp, APOA5) with triglycerides (TG) (p = 5×10−5), LDL (p = 0.00070), and nominally with high density lipoprotein (HDL) (p = 0.0054); rs651821 (5′UTR, APOA5) with increased TGs (p = 0.0008); rs13832449 (splice donor, APOC3) associated with decreased TGs (p = 0.0015). Rs45456595 (CDKN2A, Gly63Arg), rs5128 (APOC3, 3′UTR), and rs72650673 (SH2B3, Glu400Lys) were nominally associated with history of CVD, subclinical CVD, or CVD risk factors (p < 0.010). From the exome chip, rs3750103 (CHN2, His204Arg/His68Arg) with carotid intima-medial thickness (IMT) (p = 3.9×10−5), and rs61937878 (HAL, Val549Met) with infra-renal abdominal aorta CP (AACP) (p = 7.1×10−5). The unweighted GRS containing coronary artery calcified plaque (CAC) SNPs was nominally associated with history of prior CVD (p = 0.033; OR = 1.09). The weighted GRS containing SNPs was associated with CAC and myocardial infarction (MI) was associated with history of MI (p = 0.026; OR = 1.15).ConclusionsGenetic risk factors for subclinical CVD in the general population (CHARGE) were modestly associated with T2DM-related risk factors and CVD outcomes in the DHS.

Highlights

  • Type 2 diabetes mellitus (T2DM) is a major public health concern throughout the world

  • We found that Genetic risk scores (GRS) containing calcified plaque (CAC) risk single nucleotide polymorphism (SNP) or SNPs associated with increased CAC and myocardial infarction (MI) were associated with cardiovascular disease (CVD) events in the Diabetes Heart Study (DHS) (Table 5)

  • Taken together, these results provide evidence that the variants and genes implicated by the earlier CHARGE association studies affect clinical and subclinical CVD risk as well as CVD risk factors in European American individuals with T2DM

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Summary

Introduction

Type 2 diabetes mellitus (T2DM) is a major public health concern throughout the world. T2DM is associated with several comorbidities, including retinopathy, nephropathy, and especially cardiovascular disease (CVD) [2]. CVD is a major complication of T2DM. An individual’s risk for CVD is two to four times greater if they have T2DM relative to an individual not affected by T2DM [3,4]. Diabetes is an independent CVD risk factor, with relative risk for CVD-associated mortality 2.1 for men and 4.9 for women compared to those not affected by T2DM [3,4]. Type 2 diabetes mellitus (T2DM) is a major cardiovascular disease (CVD) risk factor. Identification of genetic risk factors for CVD is important to understand disease risk. Two recent genome-wide association study (GWAS) meta-analyses in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium detected CVD-associated loci

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