Norrina B Allen1, Donald Lloyd-Jones2, Shih-Jen Hwang3, Laura Rasmussen-Torvik2, Myriam Fornage4, Alanna C Morrison4, Abigail S Baldridge2, Eric Boerwinkle4, Daniel Levy3, L Adrienne Cupples5, Caroline S Fox3, George Thanassoulis6, Line Dufresne7, Martha Daviglus8, Andrew D Johnson3, Jared Reis9, Jerome Rotter10, Walter Palmas11, Mathew Allison12, James S Pankow13, Christopher J O'Donnell14. 1. Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL. Electronic address: Norrina-allen@northwestern.edu. 2. Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL. 3. Division of Intramural Research, National Heart, Lung and Blood Institute (NHLBI), Framingham, MA; NHLBI's Framingham Heart Study, Framingham, MA. 4. Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX. 5. NHLBI's Framingham Heart Study, Framingham, MA. 6. Department of Medicine and the Research Institute, Preventive and Genomic Cardiology, McGill University Health Center, Montreal, QC, Canada; Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, QC, Canada. 7. Department of Medicine and the Research Institute, Preventive and Genomic Cardiology, McGill University Health Center, Montreal, QC, Canada. 8. University of Illinois, Chicago, IL. 9. National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health, Bethesda, MD. 10. Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA. 11. Department of Medicine, Columbia University, New York, NY. 12. Division of Preventive Medicine, University of California, San Diego, CA. 13. University of Minnesota, Minneapolis, MN. 14. Division of Intramural Research, National Heart, Lung and Blood Institute (NHLBI), Framingham, MA; NHLBI's Framingham Heart Study, Framingham, MA; Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Abstract
BACKGROUND: Multiple genetic loci are associated with clinical cardiovascular (CV) disease and individual CV risk factors. Individuals with ideal levels of all major CV risk factors have very low risk for CV disease morbidity or mortality. Ideal levels of risk factors can be attained by lifestyle modifications; however, little is known about gene variants associated with ideal CV health. Our objective was to carry out a genome-wide association study on the trait. METHODS AND RESULTS: We examined 2 dichotomous phenotypes of ideal CV health-clinical (untreated cholesterol <200 mg/dL, untreated blood pressure <120/<80, not diabetic) and clinical+behavioral (clinical plus: not a current smoker, body mass index <25 kg/m(2))-among white participants aged 50±5 years. We performed a meta-analysis of 4 genome-wide association studies (total n=11,708) from the MESA, CARDIA, ARIC, and Framingham Heart Study cohorts. We identified a single-nucleotide polymorphism (rs445925) in the APOC1/APOE region that was associated with clinical ideal CV health at genome-wide level of significance (P<2.0 × 10(-9)). The significance of this region was validated using exome chip genotyping. The association with ideal CV health was attenuated after adjusting for low-density lipoprotein cholesterol. CONCLUSION: A common single-nucleotide polymorphism in the APOC1/APOE region, previously found to be associated with protective levels of cholesterol and lower CV risk, may be associated with ideal health. In future replication studies, larger sample sizes may be needed to detect loci with more modest effects on ideal CV health. In addition to the important impact of lifestyle modifications, we have identified evidence for gene variation that plays a role in ideal CV health.
BACKGROUND: Multiple genetic loci are associated with clinical cardiovascular (CV) disease and individual CV risk factors. Individuals with ideal levels of all major CV risk factors have very low risk for CV disease morbidity or mortality. Ideal levels of risk factors can be attained by lifestyle modifications; however, little is known about gene variants associated with ideal CV health. Our objective was to carry out a genome-wide association study on the trait. METHODS AND RESULTS: We examined 2 dichotomous phenotypes of ideal CV health-clinical (untreated cholesterol <200 mg/dL, untreated blood pressure <120/<80, not diabetic) and clinical+behavioral (clinical plus: not a current smoker, body mass index <25 kg/m(2))-among white participants aged 50±5 years. We performed a meta-analysis of 4 genome-wide association studies (total n=11,708) from the MESA, CARDIA, ARIC, and Framingham Heart Study cohorts. We identified a single-nucleotide polymorphism (rs445925) in the APOC1/APOE region that was associated with clinical ideal CV health at genome-wide level of significance (P<2.0 × 10(-9)). The significance of this region was validated using exome chip genotyping. The association with ideal CV health was attenuated after adjusting for low-density lipoprotein cholesterol. CONCLUSION: A common single-nucleotide polymorphism in the APOC1/APOE region, previously found to be associated with protective levels of cholesterol and lower CV risk, may be associated with ideal health. In future replication studies, larger sample sizes may be needed to detect loci with more modest effects on ideal CV health. In addition to the important impact of lifestyle modifications, we have identified evidence for gene variation that plays a role in ideal CV health.
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