Influence of Smoking Status and Intensity on Discovery of Blood Pressure Loci Through Gene-Smoking Interactions.
BACKGROUND
Genetic variation accounts for approximately 30% of blood pressure (BP) variability but most of that variability has not 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).


CONCLUSIONS
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.
Division of Biostatistics, Washington University School of Medicine, St. Louis, Missouri, USA.
Jacob
J
Basson
Division of Biostatistics, Washington University School of Medicine, St. Louis, Missouri, USA.
Yun Ju
YJ
Sung
Division of Biostatistics, Washington University School of Medicine, St. Louis, Missouri, USA.|Department of Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, Missouri, USA.
Lisa
L
de las Fuentes
Division of Biostatistics, Washington University School of Medicine, St. Louis, Missouri, USA.
Karen
K
Schwander
The Framingham Heart Study, Framingham, MA, 01702, USA.|Department of Biostatistics, Boston University School of Public Health, Boston, MA, 02118, USA.
L Adrienne
LA
Cupples
Division of Biostatistics, Washington University School of Medicine, St. Louis, Missouri, USA.
D C
DC
Rao
D000328:Adult; D000368:Aged; D000483:Alleles; D001794:Blood Pressure / Q000235:genetics* / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics; D005260:Female; D056426:Genetic Loci; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012097:Repressor Proteins; D012907:Smoking / Q000235:genetics*; D014029:Tobacco Use Disorder / Q000235:genetics / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics
D002352:Carrier Proteins; C584157:KLHL24 protein, human; C473356:KLHL6 protein, human; D012097:Repressor Proteins; C474743:SASH1 protein, human; D025521:Tumor Suppressor Proteins
blood pressure; cardiovascular genetics; gene interactions; smoking