Dataset Information

Joint effects of common genetic variants from multiple genes and pathways on the risk of premature coronary artery disease.

ABSTRACT:

Objective

The aim of this study is to discover common variants in 6 lipid metabolic genes and construct and validate a genetic risk score (GRS) based on the joint effects of genetic variants in multiple genes from lipid and other pathobiologic pathways.

Background

Explaining the genetic basis of coronary artery disease (CAD) is incomplete. Discovery and aggregation of genetic variants from multiple pathways may advance this objective.

Methods

Premature CAD cases (n = 1,947) and CAD-free controls (n = 1,036) were selected from our angiographic registry. In a discovery phase, single nucleotide polymorphisms (SNPs) at 56 loci from internal discovery and external reports were tested for associations with biomarkers and CAD: 28 promising SNPs were then tested jointly for CAD associations, and a GRS consisting of SNPs contributing independently was constructed and validated in a replication set of familial cases and population-based controls (n = 1,320).

Results

Five variants contributed jointly to CAD prediction in a multigenic GRS model: odds ratio 1.24 (95% CI 1.16-1.33) per risk allele, P = 8.2 x 10(-11), adjusted OR 2.03 (1.53-2.70), fourth versus first quartile. 5-SNP genetic risk score had minor impact on area under the receiver operating characteristic curve (P > .05) but resulted in substantial net reclassification improvement: 0.16 overall, 0.28 in intermediate-risk patients (both P < .0001). GRS(5) predicted familial CAD with similar magnitude in the validation set.

Conclusions

The Intermountain Healthcare's Coronary Genetics study demonstrates the ability of a multigenic, multipathway GRS to improve discrimination of angiographic CAD. Genetic risk scores promise to increase understanding of the genetic basis of CAD and improve identification of individuals at increased CAD risk.

SUBMITTER: Anderson JL

PROVIDER: S-EPMC2919893 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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Publications

Joint effects of common genetic variants from multiple genes and pathways on the risk of premature coronary artery disease.

Anderson Jeffrey L JL Horne Benjamin D BD Camp Nicola J NJ Muhlestein Joseph B JB Hopkins Paul N PN Cannon-Albright Lisa A LA Mower Chrissa P CP Park James J JJ Clarke Jessica L JL Nicholas Zachary P ZP McKinney Jason T JT Carlquist John F JF

American heart journal 20100801 2

<h4>Objective</h4>The aim of this study is to discover common variants in 6 lipid metabolic genes and construct and validate a genetic risk score (GRS) based on the joint effects of genetic variants in multiple genes from lipid and other pathobiologic pathways.<h4>Background</h4>Explaining the genetic basis of coronary artery disease (CAD) is incomplete. Discovery and aggregation of genetic variants from multiple pathways may advance this objective.<h4>Methods</h4>Premature CAD cases (n = 1,947) ...[more]

PMID: 20691829

Similar Datasets

Project description:ObjectiveOnly a small fraction of coronary artery disease (CAD) heritability has been explained by common variants identified to date. Interactions between genes of importance to cardiovascular regulation may account for some of the missing heritability of CAD. This study aimed to investigate the role of gene-gene interactions in common variants in candidate cardiovascular genes in CAD.Approach and results2,101 patients with CAD from the British Heart Foundation Family Heart Study and 2,426 CAD-free controls were included in the discovery cohort. All subjects were genotyped with the Illumina HumanCVD BeadChip enriched for genes and pathways relevant to the cardiovascular system and disease. The primary analysis in the discovery cohort examined pairwise interactions among 913 common (minor allele frequency >0.1) independent single nucleotide polymorphisms (SNPs) with at least nominal association with CAD in single locus analysis. A secondary exploratory interaction analysis was performed among all 11,332 independent common SNPs surviving quality control criteria. Replication analyses were conducted in 2,967 patients and 3,075 controls from the Myocardial Infarction Genetics Consortium. None of the interactions amongst 913 SNPs analysed in the primary analysis was statistically significant after correction for multiple testing (required P<1.2x10-7). Similarly, none of the pairwise gene-gene interactions in the secondary analysis reached statistical significance after correction for multiple testing (required P = 7.8x10-10). None of 36 suggestive interactions from the primary analysis or 31 interactions from the secondary analysis was significant in the replication cohort. Our study had 80% power to detect odds ratios > 1.7 for common variants in the primary analysis.ConclusionsModerately large additive interactions between common SNPs in genes relevant to cardiovascular disease do not appear to play a major role in genetic predisposition to CAD. The role of genetic interactions amongst less common SNPs and with medium and small magnitude effects remain to be investigated.

Dataset Information

Joint effects of common genetic variants from multiple genes and pathways on the risk of premature coronary artery disease.

Objective

Background

Methods

Results

Conclusions

Publications

Joint effects of common genetic variants from multiple genes and pathways on the risk of premature coronary artery disease.

Similar Datasets

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