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PLoS One. 2014 Jan 22;9(1):e85893. doi: 10.1371/journal.pone.0085893. eCollection 2014.

Smoking modifies the associated increased risk of future cardiovascular disease by genetic variation on chromosome 9p21.

Author information

  • 1Department of Clinical Sciences, Faculty of Medicine, Lund University, Malmö, Sweden ; Clinical Physiology and Nuclear Medicine Unit, Skåne University Hospital, Malmö, Sweden.
  • 2Department of Clinical Sciences, Faculty of Medicine, Lund University, Malmö, Sweden.
  • 3Department of Clinical Sciences, Faculty of Medicine, Lund University, Malmö, Sweden ; Department of Cardiology, Faculty of Medicine, Lund University, Lund, Sweden ; Department of Cardiology, Skåne University Hospital, Lund, Sweden ; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.
  • 4Department of Clinical Sciences, Faculty of Medicine, Lund University, Malmö, Sweden ; Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden.

Abstract

AIMS:

Genetic predisposition for cardiovascular disease (CVD) is likely to be modified by environmental exposures. We tested if the associated risk of CVD and CVD-mortality by the single nucleotide polymorphism rs4977574 on chromosome 9p21 is modified by life-style factors.

METHODS AND RESULTS:

A total of 24,944 middle-aged subjects (62% females) from the population-based Malmö-Diet-and-Cancer-Cohort were genotyped. Smoking, education and physical activity-levels were recorded. Subjects were followed for 15 years for incidence of coronary artery disease (CAD; N = 2309), ischemic stroke (N = 1253) and CVD-mortality (N = 1156). Multiplicative interactions between rs4977574 and life-style factors on endpoints were tested in Cox-regression-models. We observed an interaction between rs4977574 and smoking on incident CAD (P = 0.035) and CVD-mortality (P = 0.012). The hazard ratios (HR) per risk allele of rs4977574 were highest in never smokers (N = 9642) for CAD (HR = 1.26; 95% CI 1.13-1.40; P<0.001) and for CVD-mortality (HR = 1.40; 95% CI 1.20-1.63; P<0.001), whereas the risk increase by rs4977574 was attenuated in current smokers (N = 7000) for both CAD (HR = 1.05; 95%CI 0.95-1.16; P = 0.326) and CVD-mortality (HR = 1.08; 95%CI 0.94-1.23; P = 0.270). A meta-analysis supported the finding that the associated increased risk of CAD by the risk-allele was attenuated in smokers. Neither education nor physical activity-levels modified the associated risk of CAD, ischemic stroke and CVD mortality conferred by rs4977574.

CONCLUSION:

Smoking may modify the associated risk of CAD and CVD-mortality conferred by genetic variation on chromosome 9p21. Whether the observed attenuation of the genetic risk reflects a pathophysiological mechanism or is a result of smoking being such a strong risk-factor that it may eliminate the associated genetic effect, requires further investigation.

PMID:
24465769
[PubMed - in process]
PMCID:
PMC3899088
Free PMC Article

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