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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Cardiovascular Diseases / etiology
  • Cardiovascular Diseases / genetics*
  • Cardiovascular Diseases / mortality
  • Chromosomes, Human, Pair 9 / genetics*
  • Educational Status
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease / etiology
  • Genetic Predisposition to Disease / genetics*
  • Genotype
  • Humans
  • Incidence
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide*
  • Proportional Hazards Models
  • Prospective Studies
  • Registries / statistics & numerical data
  • Risk Factors
  • Smoking / adverse effects*
  • Surveys and Questionnaires
  • Survival Rate
  • Sweden / epidemiology

Grants and funding

This work was supported by grants from the European Research Council (StG-282255), the Swedish Medical Research Council, the Swedish Heart and Lung Foundation, the Medical Faculty of Lund University, LUA/ALF from the Sahlgrenska Academy at Göteborg University, MalmöUniversity Hospital, the Albert Påhlsson Research Foundation, the Crafoord Foundation, the Ernhold Lundströms Research Foundation, Novo Nordic Foundation, the Region Skane, Hulda and Conrad Mossfelt Foundation and King Gustaf V and Queen Victoria Foundation, the Lennart Hanssons Memorial Fund and the Marianne and Marcus Wallenberg Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.