title: Analysis of gene-gene interactions among common variants in candidate cardiovascular genes in coronary artery disease.
abstract: OBJECTIVE
  Only 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.
  
  
  RESULTS
  2,101 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.
  
  
  CONCLUSIONS
  Moderately 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.
authors: Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, United Kingdom; NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom.
authors: Muntaser D
authors: MD
authors: Musameh
authors: School of Medicine, University of Queensland, Brisbane, Queensland, Australia.
authors: William Y S
authors: WY
authors: Wang
authors: Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, United Kingdom; NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom.
authors: Christopher P
authors: CP
authors: Nelson
authors: Cardiovascular Epidemiology and Genetics, IMIM, Barcelona, Spain.
authors: Carla
authors: C
authors: Lluís-Ganella
authors: Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, United Kingdom; NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom.
authors: Radoslaw
authors: R
authors: Debiec
authors: Cardiovascular Epidemiology and Genetics, IMIM, Barcelona, Spain; Epidemiology and Public Health Network (CIBERESP), Barcelona, Spain.
authors: Isaac
authors: I
authors: Subirana
authors: Cardiovascular Epidemiology and Genetics, IMIM, Barcelona, Spain.
authors: Roberto
authors: R
authors: Elosua
authors: Division of Epidemiology, LIGHT, School of Medicine, University of Leeds, Leeds, United Kingdom.
authors: Anthony J
authors: AJ
authors: Balmforth
authors: University of Leeds, MCRC, Leeds Institute of Genetics, Health and Therapeutics, Leeds, United Kingdom.
authors: Stephen G
authors: SG
authors: Ball
authors: Division of Epidemiology, LIGHT, School of Medicine, University of Leeds, Leeds, United Kingdom.
authors: Alistair S
authors: AS
authors: Hall
authors: The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors: Sekar
authors: S
authors: Kathiresan
authors: Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, United Kingdom.
authors: John R
authors: JR
authors: Thompson
authors: Cardiovascular Epidemiology and Genetics, IMIM, Barcelona, Spain.
authors: Gavin
authors: G
authors: Lucas
authors: Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, United Kingdom; NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom.
authors: Nilesh J
authors: NJ
authors: Samani
authors: Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, United Kingdom; NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom.
authors: Maciej
authors: M
authors: Tomaszewski
mesh_terms: D000328:Adult; D015331:Cohort Studies; D003324:Coronary Artery Disease / Q000235:genetics*; D004843:Epistasis, Genetic; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D006113:United Kingdom