Gene-smoking interactions identify several novel blood pressure loci in the Framingham Heart Study

Background: Cardiovascular diseases are among the most significant health problems in the United States. Blood pressure (BP) variability has a genetic component, and most of the genetic variance remains to be identified. One promising strategy for gene discovery is genome-wide analysis of interactions between single nucleotide polymorphisms (SNPs) and environmental factors related to cardiovascular diseases.

Methods: We investigated SNP-smoking interaction effects on BP in genome-wide data in 6,889 participants from the Framingham Heart Study. We performed the standard 1 degree of freedom (df) test of the interaction effect and the joint 2 df test of main and interaction effects. Three smoking measures were used: cigarettes per day (CPD), pack years of smoking, and smoking status.

Results: We identified 7 significant and 21 suggestive BP loci. Identified through the joint 2 df test, significant SBP loci include: rs12149862 (P = 3.65×10(-9)) in CYB5B, rs2268365 (P = 4.85×10(-8)) in LRP2, rs133980 (P = 1.71×10(-8) with CPD and P = 1.07×10(-8) with pack-years) near MN1, and rs12634933 (P = 4.05×10(-8)) in MECOM. Through 1 df interaction analysis, 1 suggestive SBP locus at SNP rs8010717 near NRXN3 was identified using all 3 smoking measures (P = 3.27×10(-7) with CPD, P = 1.03×10(-7) with pack-years, and P = 1.19×10(-7) with smoking status).

Conclusions: Several of these BP loci are biologically plausible, providing physiological connection to BP regulation. Our study demonstrates that SNP-smoking interactions can enhance gene discovery and provide insight into novel pathways and mechanisms regulating BP.