Gene–Smoking Interactions Identify Several Novel Blood Pressure Loci in the Framingham Heart Study

Cardiovascular diseases are among the most significant health problems in the United States. Genome-wide association studies (GWASs) have identified hundreds of common genetic variants associated with many common, complex disease traits (http://www.genome.gov). However, most identified variants confer relatively small increments in risk and explain only a small fraction of the heritability.1 For example, the 29 common variants identified through 3 recent GWASs consortia2–4 have shown to collectively explain <2.5% of systolic and diastolic blood pressure (BP) variance.4 It is increasingly recognized that the near-exclusive focus on main effects has become a barrier to the identification of additional genes underlying these complex traits. Greater emphasis is being placed in recent years on gene–environment interaction analyses.5 The identification of gene–environment interaction is important for many reasons. Gene–environment interaction or more complex pathways involving multiple genes and environments can explain part of the missing heritability.1,6 They can further elucidate the biological networks underlying complex disease risk and enable “profiling” of individuals at highest risk for disease.7 Many lifestyle factors, including physical activity, tobacco use, excessive alcohol consumption, and dietary factors, influence BP.8 These lifestyle factors may modulate the effect of genes on BP. This journal has recently published 3 articles that are related to environmental contribution to BP and hypertension. Dong et al. 9 presented the relationship between increasing trends in BP and body mass index among Chinese children and adolescents from 2005 to 2010. Xi et al. 10 presented a significant association of hypertension susceptibility loci in obese Chinese children, suggesting a likely influence of childhood obesity on the risk of hypertension. As nicely presented by Falkner,11 obesity and dietary sodium intake are potentially modifiable environmental factors. In this study, we focused on the role of smoking in the genetic and environmental architecture of BP. Cigarette smoking is a leading cause of preventable death, causing 5 million premature deaths worldwide each year, and current trends show that tobacco use will cause >8 million deaths annually by 2030, according to World Health Organization estimates. Smoking is a major risk factor for cancer, heart disease, stroke, and lung diseases. In the acute setting, cigarette smoking produces a rise in BP. Some epidemiologic studies have associated chronic smoking with lower BP, even after adjustment for other cardiovascular risk traits.12 Therefore, genome-wide studies incorporating interactions between genetic variants and smoking may enhance BP gene discovery efforts and provide novel insights into the biological mechanisms and pathways underlying BP regulation.7 We examined the contribution of interactions between genetic variants and 3moking measures on BP traits: (i) cigarettes per day, measuring a smoking rate (per day); (ii) pack-years of smoking, measuring a volume of smoking exposure during a person’s entire lifetime; and (iii) smoking status, a binary (yes/no) indicator of a current smoking status. We performed a genome-wide analysis of single nucleotide polymorphism (SNP)–smoking interactions on systolic BP (SBP) and diastolic BP (DBP) using 6,889 participants from the Framingham Heart Study (FHS). Our aim was to identify novel BP loci; discovery of such loci may facilitate smoking intervention strategies and achievement of BP goals in genetically susceptible individuals, thereby reducing the public health burden of hypertension.