Abstract
Background and aimsCardiometabolic disorders (CMD) arise from a constellation of features such as increased adiposity, hyperlipidemia, hypertension and compromised glucose control. Many genetic loci have shown associations with individual CMD-related traits, but no investigations have focused on simultaneously identifying loci showing associations across all domains. We therefore sought to identify loci associated with risk across seven continuous CMD-related traits. Methods and resultsWe conducted separate genome-wide association studies (GWAS) for systolic and diastolic blood pressure (SBP/DBP), hemoglobin A1c (HbA1c), low- and high- density lipoprotein cholesterol (LDL-C/HDL-C), waist-to-hip-ratio (WHR), and triglycerides (TGs) in the UK Biobank (N = 356,574–456,823). Multiple loci reached genome-wide levels of significance (N = 145–333) for each trait, but only four loci (in/near VEGFA, GRB14-COBLL1, KLF14, and RGS19-OPRL1) were associated with risk across all seven traits (P < 5 × 10−8). We sought replication of these four loci in an independent set of seven trait-specific GWAS meta-analyses. GRB14-COBLL1 showed the most consistent replication, revealing nominally significant associations (P < 0.05) with all traits except DBP. ConclusionsOur analyses suggest that very few loci are associated in the same direction of risk with traits representing the full spectrum of CMD features. We identified four such loci, and an understanding of the pathways between these loci and CMD risk may eventually identify factors that can be used to identify pathologic disturbances that represent broadly beneficial therapeutic targets.
Highlights
Cardiometabolic risk, the chance of developing type 2 diabetes (T2D), cardiovascular disease (CVD) and/or stroke, is typically assessed through measures of adiposity, glucose control, lipid metabolism, and blood pressure [1]
We first examined seven continuous cardiometabolic traits in the United Kingdom (UK) Biobank: hemoglobin A1c (HbA1c), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), TGs, waist-to-hip ratio adjusted for body mass index (BMI) (WHRadjBMI), and systolic blood pressure (SBP) and diastolic blood pressure (DBP) adjusted for BMI
We examined the association of the four identified SNPs with coronary artery disease (CAD), T2D, and stroke, some of the major outcomes arising from Cardiometabolic disorders (CMD), using genome-wide association studies (GWAS) meta-analysis results published by the Coronary Artery Disease Genome-wide Replication And Metaanalysis (CARDIOGRAM; n Z up to 185,000) [33], Diabetes Genetics Replication And Meta-analysis (DIAGRAM; n Z 898,130) [33], and MEGASTROKE (n Z 521,612) [34] consortia
Summary
Cardiometabolic risk, the chance of developing type 2 diabetes (T2D), cardiovascular disease (CVD) and/or stroke, is typically assessed through measures of adiposity, glucose control, lipid metabolism, and blood pressure [1]. Only two loci have previously been identified as being implicated across T2D and cardiovascular disease: CDKN2A/B and IRS1 [9,10] Identifying those genetic factors that convey risk across multiple CMD traits may increase our understanding of why risk factor clustering is not uniform across individuals, and further help identify those whose overall CMD profile suggests a greater risk of T2D and CVD and whom may especially benefit from behavioral interventions [11]. We identified four such loci, and an understanding of the pathways between these loci and CMD risk may eventually identify factors
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