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

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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.

Project description:Approximately 10% of patients undergoing cardiac surgery have perioperative myocardial injury. A recent genome-wide association study identified an association between myocardial infarction in nonsurgical populations and common genetic variants on chromosome 9p21. We hypothesized that these variants are also associated with perioperative myocardial injury after isolated primary coronary artery bypass graft surgery.In a prospective observational study of 846 Caucasian patients undergoing primary coronary bypass surgery at 2 US centers, we genotyped 61 linkage-disequilibrium tagging single nucleotide polymorphisms, encompassing 436 kbp of the 9p21 region. A multivariable logistic model was used to adjust for previously identified clinical covariates of perioperative myocardial injury. Perioperative myocardial injury was defined as a postoperative day 1 cardiac troponin I in the top 10th percentile (>9.13 microg/L) of the cohort. Multiple testing of single nucleotide polymorphisms was corrected for with family-wise errors.Prior myocardial infarction and longer cardiopulmonary bypass time were significant independent predictors of perioperative myocardial injury. Levels of postoperative cardiac troponin I were incrementally increased for each additional copy of the risk alleles of 3 single nucleotide polymorphisms: rs10116277, rs6475606, and rs2383207. Adjusted additive odds ratios ranged between 1.64 and 1.79 (asymptotic P value between 3.7 x 10(-3) and 6 x 10(-4)) and remained significantly associated with perioperative myocardial injury even after accounting for clinical covariates including severity of coronary disease, and multiple comparisons.We have now demonstrated that common genetic variants in the same 9p21 locus, previously known to be associated with myocardial infarction in nonsurgical populations, are also associated with perioperative myocardial injury after coronary artery bypass grafting. Further investigation is warranted to elucidate functional mechanisms.

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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