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.

[1]  J. Rowley,et al.  AML1 and the 8;21 and 3;21 translocations in acute and chronic myeloid leukemia. , 1995, Blood.

[2]  Jason H. Moore,et al.  Missing heritability and strategies for finding the underlying causes of complex disease , 2010, Nature Reviews Genetics.

[3]  M. Daly,et al.  Estimation of the multiple testing burden for genomewide association studies of nearly all common variants , 2008, Genetic epidemiology.

[4]  B. Falkner.  What childhood blood pressure studies reveal about genetics and environment. , 2013, American journal of hypertension.

[5]  D. Levy,et al.  Discovery and replication of novel blood pressure genetic loci in the Women's Genome Health Study , 2011, Journal of hypertension.

[6]  Andrew D. Johnson,et al.  Genome-wide association study of blood pressure and hypertension , 2009, Nature Genetics.

[8]  N. Benowitz,et al.  Inverse relation between serum cotinine concentration and blood pressure in cigarette smokers. , 1989, Circulation.

[9]  Jian-Min Yuan,et al.  A prospective study of tobacco and alcohol use as risk factors for pharyngeal carcinomas in Singapore Chinese , 2007, Cancer.

[10]  D. Pinto,et al.  Rare deletions at the neurexin 3 locus in autism spectrum disorder. , 2012, American journal of human genetics.

[11]  E Jucha,et al.  Blood pressure in smokers and nonsmokers: epidemiologic findings. , 1986, American heart journal.

[12]  D. Mozaffarian,et al.  Heart disease and stroke statistics--2014 update: a report from the American Heart Association. , 2014, Circulation.

[13]  Judy H. Cho,et al.  Finding the missing heritability of complex diseases , 2009, Nature.

[14]  Charles Rotimi,et al.  A Genome-Wide Association Study of Hypertension and Blood Pressure in African Americans , 2009, PLoS genetics.

[15]  Peter Kraft,et al.  Challenges and opportunities in genome-wide environmental interaction (GWEI) studies , 2012, Human Genetics.

[16]  Chuan-Yun Li,et al.  Molecular Genetics of Addiction and Related Heritable Phenotypes , 2008, Annals of the New York Academy of Sciences.

[17]  Mary K. Wojczynski,et al.  Genome-Wide Association of Body Fat Distribution in African Ancestry Populations Suggests New Loci , 2013, PLoS genetics.

[18]  L. Mascia,et al.  The synaptic proteins neurexins and neuroligins are widely expressed in the vascular system and contribute to its functions , 2009, Proceedings of the National Academy of Sciences.

[19]  G. Uhl,et al.  Neurexin 3 polymorphisms are associated with alcohol dependence and altered expression of specific isoforms. , 2007, Human molecular genetics.

[20]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[21]  P. O’Reilly,et al.  Genome-wide association study identifies eight loci associated with blood pressure , 2009, Nature Genetics.

[22]  J. Mi,et al.  Influence of obesity on association between genetic variants identified by genome-wide association studies and hypertension risk in Chinese children. , 2013, American journal of hypertension.

[23]  L Adrienne Cupples,et al.  Genetics Analysis Workshop 16 Problem 2: the Framingham Heart Study data , 2009, BMC proceedings.

[24]  Y. Miki,et al.  Identification of Evi-1 as a novel effector of PKCδ in the apoptotic response to DNA damage. , 2011, Biochimica et biophysica acta.

[25]  S. Krishnaswami,et al.  Non-replication study of a genome-wide association study for hypertension and blood pressure in African Americans , 2012, BMC Medical Genetics.

[26]  Jun Yu,et al.  OPCML Is a Broad Tumor Suppressor for Multiple Carcinomas and Lymphomas with Frequently Epigenetic Inactivation , 2008, PloS one.

[27]  P. Brennan,et al.  Tobacco consumption and genetic susceptibility to nasopharyngeal carcinoma (NPC) in Thailand , 2012, Cancer Causes & Control.

[28]  I. Fleming,et al.  Cytochrome P450 Enzymes in Vascular Homeostasis , 2001 .

[29]  R. Bergman,et al.  Identification of Quantitative Trait Loci for Glucose Homeostasis The Insulin Resistance Atherosclerosis Study (IRAS) Family Study , 2022 .

[30]  P. Riegman,et al.  Translocation (12;22) (p13;q11) in myeloproliferative disorders results in fusion of the ETS-like TEL gene on 12p13 to the MN1 gene on 22q11. , 1995, Oncogene.

[31]  Hyun-Seok Jin,et al.  Replication of an African-American GWAS on blood pressure and hypertension in the Korean population , 2011, Genes & Genomics.

[32]  Y. Funae,et al.  Role of human cytochrome P4502A6 in C-oxidation of nicotine. , 1996, Drug metabolism and disposition: the biological fate of chemicals.

[33]  P H Riegman,et al.  Cloning and characterization of MN1, a gene from chromosome 22q11, which is disrupted by a balanced translocation in a meningioma. , 1995, Oncogene.

[34]  Leena Peltonen,et al.  Genome-wide association study of smoking initiation and current smoking. , 2009, American journal of human genetics.

[35]  D. Thomas,et al.  Gene–environment-wide association studies: emerging approaches , 2010, Nature Reviews Genetics.

[36]  Peter Kraft,et al.  Exploiting Gene-Environment Interaction to Detect Genetic Associations , 2007, Human Heredity.

[37]  M. Gratacós,et al.  Association of Neurexin 3 polymorphisms with smoking behavior , 2012, Genes, brain, and behavior.

[38]  Claude Bouchard,et al.  A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance , 2012, Nature Genetics.

[39]  S. Cockcroft.  Phosphatidylinositol transfer proteins: a requirement in signal transduction and vesicle traffic , 1998, BioEssays : news and reviews in molecular, cellular and developmental biology.

[40]  Christian Gieger,et al.  Genetic Variants in Novel Pathways Influence Blood Pressure and Cardiovascular Disease Risk , 2011, Nature.

[41]  Jun Ma,et al.  Trends in blood pressure and body mass index among Chinese children and adolescents from 2005 to 2010. , 2013, American journal of hypertension.

[42]  Nicholas J Schork,et al.  Common genetic mechanisms of blood pressure elevation in two independent rodent models of human essential hypertension. , 2005, American journal of hypertension.

[43]  E. Liu,et al.  A genome-wide association study of nasopharyngeal carcinoma identifies three new susceptibility loci , 2010, Nature Genetics.

[44]  Christian Gieger,et al.  Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium , 2009, Nature Genetics.

[45]  Yurii S. Aulchenko,et al.  BIOINFORMATICS APPLICATIONS NOTE doi:10.1093/bioinformatics/btm108 Genetics and population analysis GenABEL: an R library for genome-wide association analysis , 2022 .