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Heterogeneity of the phenotypic definition of coronary artery disease and its impact on genetic association studies.

ABSTRACT: Variability in phenotypic characterization of coronary artery disease (CAD) may contribute to the heterogeneity of genetic association studies, and more consistency in phenotype definitions might improve replication of genetic associations. We assessed the extent of phenotypic heterogeneity and quantified its impact in a large literature sample of association studies.We searched for large (?15 studies) meta-analyses of genetic associations and reviewed all studies included therein. From each primary study, we extracted phenotypic definitions, demographics, study design characteristics, and genotypic data. For each association, we assessed the magnitude and heterogeneity of genetic effects within and across CAD phenotypes, using meta-analytic methodologies. A total of 965 individual studies investigating 32 distinct variants in 22 genes were included, from which we grouped CAD phenotypes into 3 categories: acute coronary syndromes (ACS) (426 [44%] studies); angiographically documented disease (323 [34%] studies); and broad, not otherwise specified CAD (216 [22%] studies). These clinical phenotypes were overlapping. Subgroup meta-analyses by phenotype showed discordant results, but phenotypic classification generally explained small proportions of between-study heterogeneity. Differences between phenotypic groups were minimized for associations with robust statistical support. No CAD phenotype was consistently associated with larger or more homogeneous genetic effects in meta-analyses.Substantial phenotypic heterogeneity exists in CAD genetic associations, but differences in phenotype definition make a small contribution to between-study heterogeneity. We did not find a consistent effect in terms of the magnitude or homogeneity of summary effects for a specific phenotype to support its preferential use in genetic studies or meta-analyses for CAD.

SUBMITTER: Kitsios GD

PROVIDER: S-EPMC3048058 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Heterogeneity of the phenotypic definition of coronary artery disease and its impact on genetic association studies.

Kitsios Georgios D GD Dahabreh Issa J IJ Trikalinos Thomas A TA Schmid Christopher H CH Huggins Gordon S GS Kent David M DM

Circulation. Cardiovascular genetics 20101213 1

<h4>Background</h4>Variability in phenotypic characterization of coronary artery disease (CAD) may contribute to the heterogeneity of genetic association studies, and more consistency in phenotype definitions might improve replication of genetic associations. We assessed the extent of phenotypic heterogeneity and quantified its impact in a large literature sample of association studies.<h4>Methods and results</h4>We searched for large (≥15 studies) meta-analyses of genetic associations and revie ...[more]

PMID: 21149552

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Project description:BACKGROUND:The relation between burden of risk factors, familial coronary artery disease (CAD), and known genetic variants underlying CAD and low-density lipoprotein cholesterol (LDL-C) levels is not well-explored in clinical samples. We aimed to investigate the association of these measures with age at onset of CAD requiring revascularizations in a clinical sample of patients undergoing first-time coronary angiography. METHODS:1599 individuals (mean age 64 years [min-max 29-96 years], 28% women) were genotyped (from blood drawn as part of usual clinical care) in the Copenhagen area (2010-2014). The burden of common genetic variants was measured as aggregated genetic risk scores (GRS) of single nucleotide polymorphisms (SNPs) discovered in genome-wide association studies. RESULTS:Self-reported familial CAD (prevalent in 41% of the sample) was associated with -3.2 years (95% confidence interval -4.5, -2.2, p<0.0001) earlier need of revascularization in sex-adjusted models. Patients with and without familial CAD had similar mean values of CAD-GRS (unweighted scores 68.4 vs. 68.0, p = 0.10, weighted scores 67.7 vs. 67.5, p = 0.49) and LDL-C-GRS (unweighted scores 58.5 vs. 58.3, p = 0.34, weighted scores 63.3 vs. 61.1, p = 0.41). The correlation between the CAD-GRS and LDL-C-GRS was low (r = 0.14, p<0.001). In multivariable adjusted regression models, each 1 standard deviation higher values of LDL-C-GRS and CAD-GRS were associated with -0.70 years (95% confidence interval -1.25, -0.14, p = 0.014) and -0.51 years (-1.07, 0.04, p = 0.07) earlier need for revascularization, respectively. CONCLUSIONS:Young individuals presenting with CAD requiring surgical interventions had a higher genetic burden of SNPs relating to LDL-C and CAD (although the latter was statistically non-significant), compared with older individuals. However, the absolute difference was modest, suggesting that genetic screening can currently not be used as an effective prediction tool of when in life a person will develop CAD. Whether undiscovered genetic variants can still explain a "missing heritability" in early-onset CAD warrants more research.

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Heterogeneity of the phenotypic definition of coronary artery disease and its impact on genetic association studies.

Publications

Heterogeneity of the phenotypic definition of coronary artery disease and its impact on genetic association studies.

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