Influence of Smoking Status and Intensity on Discovery of Blood Pressure Loci Through Gene‐Smoking Interactions

Abstract

Background Genetic variation accounts for approximately 30% of blood pressure (BP) variability but most of that variability hasn't been attributed to specific variants. Interactions between genes and BP-associated factors may explain some ‘missing heritability.’ Cigarette smoking increases BP after short-term exposure and decreases BP with longer exposure. Gene-smoking interactions have discovered novel BP loci, but the contribution of smoking status and intensity to gene discovery is unknown. Methods We analyzed gene-smoking intensity interactions for association with systolic BP (SBP) in three subgroups from the Framingham Heart Study: current smokers only (N = 1,057), current and former smokers (‘ever smokers’, N = 3,374), and all subjects (N = 6,710). We used three smoking intensity variables defined at cutoffs of 10, 15, and 20 cigarettes per day (CPD). We evaluated the 1 degree-of-freedom (df) interaction and 2df joint test using generalized estimating equations. Results Analysis of current smokers using a CPD cutoff of 10 produced two loci associated with SBP. The rs9399633 minor allele was associated with increased SBP (5 mmHg) in heavy smokers (CPD>10) but decreased SBP (7 mmHg) in light smokers (CPD≤10). The rs11717948 minor allele was associated with decreased SBP (8 mmHg) in light smokers but decreased SBP (2 mmHg) in heavy smokers. Across all nine analyses, 19 additional loci reached p < 1×10−6. Discussion Analysis of current smokers may have the highest power to detect gene-smoking interactions, despite the reduced sample size. Associations of loci near SASH1 and KLHL6/KLHL24 with SBP may be modulated by tobacco smoking.

Genome-Wide Gene–Sodium Interaction Analyses on Blood Pressure

“…For example, the SASH1 gene has been associated with thyroid function 26 and suggestively associated with responses to rate control therapy among patients with atrial fibrillation 27 . A more recent study indicated that the SASH1 gene may interact with smoking on SBP 28 . While the role of LOC105369882 in BP is unclear, another gene at this locus, CEP290 , is potentially relevant to BP regulation 29 , with mutations of this gene shown to associate with many disease phenotypes characterized by renal impairment 30, 31 .…”

A Review of the Genetics of Hypertension with a Focus on Gene-Environment Interactions

“…BP is known to be modulated by a variety of lifestyle factors, such as diet [21], exercise [22], and smoking [23], as well as other factors such as age [24, 25] and obesity [26]. In GWAS for HTN-related phenotypes, significant GxE interactions have been identified with alcohol consumption [27], body mass index (BMI) [28], smoking [29, 30], education levels [31], and sodium intake [46] which are all modifiable through lifestyle changes. These findings suggest that further investigation into GxE interaction may identify causal genetic loci that contribute to missing heritability [33].…”

Novel and Known Gene-Smoking Interactions With cIMT Identified as Potential Drivers for Atherosclerosis Risk in West-African Populations of the AWI-Gen Study

“…A previous study using a systems biology approach revealed that cigarette smoke induced a concentration-dependent (direct and indirect) biological mechanism that promotes monocyte-endothelial cell adhesion (Poussin et al, 2015). Hence, the influence of smoking intensity on the detection of gene-smoking interaction was previously reported in a study of gene-smoking interaction for blood pressure in the Framingham Heart Study (Basson et al, 2015). They found different associated loci in the light smoker and the heavy smoker groups (>10 cigarettes per day).…”