Defining a Contemporary Ischemic Heart Disease Genetic Risk Profile Using Historical Data

Abstract

Background Continued reductions in morbidity and mortality attributable to ischemic heart disease (IHD) require an understanding of the changing epidemiology of this disease. We hypothesized that we could use genetic correlations, which quantitate the shared genetic architectures of phenotype pairs, and extant risk factors from a historical prospective study to define the risk profile of a contemporary IHD phenotype. Methods and Results We used 37 phenotypes measured in the Atherosclerosis Risk in Communities (ARIC) study (n=7,716 European ancestry subjects) and clinical diagnoses from an electronic health record (EHR) data set (n=19,093). All subjects had genome-wide SNP genotyping. We measured pairwise genetic correlations (rG) between the ARIC and EHR phenotypes using linear mixed models. The genetic correlation estimates between the ARIC risk factors and the EHR IHD were modestly linearly correlated with hazards ratio estimates for incident IHD in ARIC (Pearson’s correlation [r]=0.62), indicating that the two IHD phenotypes had differing risk profiles. For comparison, this correlation was 0.80 when comparing EHR and ARIC type 2 diabetes (T2D) phenotypes. The EHR IHD phenotype was most strongly correlated with ARIC metabolic phenotypes including total-to-HDL cholesterol ratio (rG=−0.44, p=0.005), HDL (rG=−0.48, p=0.005), systolic blood pressure (rG=0.44, p=0.02) and triglycerides (rG=0.38, p=0.02). EHR phenotypes related to T2D, atherosclerotic and hypertensive diseases were also genetically correlated with these ARIC risk factors. Conclusions The EHR IHD risk profile differed from ARIC, and indicates that treatment and prevention efforts in this population should target hypertensive and metabolic disease.

Predictive Accuracy of a Polygenic Risk Score Compared With a Clinical Risk Score for Incident Coronary Heart Disease

“…Because the existing polygenic risk score was derived from a majority of persons (77%) with white European ancestry via genome-wide association study analysis and calibrated for use in this population, analyses were restricted to participants with European ancestry. In the ARIC cohort, genetic ancestry was determined using the STRUCTURE program . In the MESA cohort, individuals of European ancestry were those whose race was reported as white and confirmed by principal components analyses.…”

The polygenic architecture of left ventricular mass mirrors the clinical epidemiology

“…eMERGE subjects were genotyped on multiple platforms and underwent QC analyses and imputation as previously described 17,18 . Quality control (QC) analyses used PLINK v 1.90β3 19 and included reconciling strand flips, verifying that allele frequencies were concordant among data sets, and identifying duplicate and related individuals (one of each pair of subjects with a pi-hat >0.05 was excluded) 17,20 . Data sets were standardized using the HRC-1000G-check tool v4.2.5 (http://www.well.ox.ac.uk/~wrayner/tools/) and pre-phased using SHAPEIT 21 .…”

Association of Thyroid Function Genetic Predictors With Atrial Fibrillation

“…In the BioVU eMERGE EHR cohort, SNVs genotype data were acquired on the Illumina Human660W-Quadv1_A, HumanOmni1-Quad, HumanOmni5-Quad, MEGA-EX, Human610, Human550, HumanOmniExpressExome-8v1.2A, and Affymetrix 6.0 SNV array platforms. Quality control steps for the EHR data sets were performed per previously published protocols . For each data set, SNVs were prephased using SHAPEIT, version 2.r837 (Oliver Delaneau), and imputed using IMPUTE2, version 2.3.0 (University of Oxford), in conjunction with the October 2014 release of the 1000 Genomes cosmopolitan reference haplotypes.…”