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Protein interaction-based genome-wide analysis of incident coronary heart disease.

ABSTRACT: Network-based approaches may leverage genome-wide association (GWA) analysis by testing for the aggregate association across several pathway members. We aimed to examine if networks of genes that represent experimentally determined protein-protein interactions (PPIs) are enriched in genes associated with risk of coronary heart disease (CHD).Genome-wide association analyses of approximately ?700,000 single-nucleotide polymorphisms in 899 incident CHD cases and 1823 age- and sex-matched controls within the Nurses' Health and the Health Professionals Follow-up Studies were used to assign genewise P values. A large database of PPIs was used to assemble 8351 unbiased protein complexes and corresponding gene sets. Superimposed genewise P values were used to rank gene sets based on their enrichment in genes associated with CHD. After correcting for the number of complexes tested, 1 gene set was overrepresented in CHD-associated genes (P=0.002). Centered on the ?1-adrenergic receptor gene (ADRB1), this complex included 18 protein interaction partners that have not been identified as candidate loci for CHD. Of the 19 genes in the top complex, 5 are involved in abnormal cardiovascular system physiological features based on knockout mice (4-fold enrichment; Fisher exact test, P=0.006). Ingenuity pathway analysis revealed that canonical pathways, especially related to blood pressure regulation, were significantly enriched in the genes from the top complex.The integration of a GWA study with PPI data successfully identifies a set of candidate susceptibility genes for incident CHD that would have been missed in single-marker GWA analysis.

SUBMITTER: Jensen MK

PROVIDER: S-EPMC3197770 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Protein interaction-based genome-wide analysis of incident coronary heart disease.

Jensen Majken K MK Pers Tune H TH Dworzynski Piotr P Girman Cynthia J CJ Brunak Søren S Rimm Eric B EB

Circulation. Cardiovascular genetics 20110831 5

<h4>Background</h4>Network-based approaches may leverage genome-wide association (GWA) analysis by testing for the aggregate association across several pathway members. We aimed to examine if networks of genes that represent experimentally determined protein-protein interactions (PPIs) are enriched in genes associated with risk of coronary heart disease (CHD).<h4>Methods and results</h4>Genome-wide association analyses of approximately ≈700,000 single-nucleotide polymorphisms in 899 incident CHD ...[more]

PMID: 21880673

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Project description:BackgroundA high body mass index (BMI) is associated with an increased risk of mortality from coronary heart disease (CHD); however, a low BMI may also be associated with an increased mortality risk. There is limited information on the relation of incident CHD risk across a wide range of BMI, particularly in women. We examined the relation between BMI and incident CHD overall and across different risk factors of the disease in the Million Women Study.Methods1.2 million women (mean age=56 years) participants without heart disease, stroke, or cancer (except non-melanoma skin cancer) at baseline (1996 to 2001) were followed prospectively for 9 years on average. Adjusted relative risks and 20-year cumulative incidence from age 55 to 74 years were calculated for CHD using Cox regression.ResultsAfter excluding the first 4 years of follow-up, we found that 32,465 women had a first coronary event (hospitalization or death) during follow-up. The adjusted relative risk for incident CHD per 5 kg/m2 increase in BMI was 1.23 (95% confidence interval (CI) 1.22 to 1.25). The cumulative incidence of CHD from age 55 to 74 years increased progressively with BMI, from 1 in 11 (95% CI 1 in 10 to 12) for BMI of 20 kg/m2, to 1 in 6(95% CI 1 in 5 to 7) for BMI of 34 kg/m2. A 10 kg/m2 increase in BMI conferred a similar risk to a 5-year increment in chronological age. The 20 year cumulative incidence increased with BMI in smokers and non-smokers, alcohol drinkers and non-drinkers, physically active and inactive, and in the upper and lower socioeconomic classes. In contrast to incident disease, the relation between BMI and CHD mortality (n=2,431) was J-shaped. For the less than 20 kg/m2 and ≥35 kg/m2 BMI categories, the respective relative risks were 1.27 (95% CI 1.06 to 1.53) and 2.84 (95% CI 2.51 to 3.21) for CHD deaths, and 0.89 (95% CI 0.83 to 0.94) and 1.85 (95% CI 1.78 to 1.92) for incident CHD.ConclusionsCHD incidence in women increases progressively with BMI, an association consistently seen in different subgroups. The shape of the relation with BMI differs for incident and fatal disease.

Dataset Information

Protein interaction-based genome-wide analysis of incident coronary heart disease.

Publications

Protein interaction-based genome-wide analysis of incident coronary heart disease.

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