Abstract
Objective:
Smoking is an established risk factor for atherosclerotic disease. However, the degree of the cigarette smoking-induced damage varies from individual to individual, partly due to the between-individual difference in genetic makeup. The aim of this study was to identify genetic loci influencing the effect of cigarette smoking on carotid intima-media thickness (IMT) by performing a genome-wide association smoking-by-SNP interaction analysis.
Methods and results:
Genome-wide genotyping was performed using the Affymetrix SNP array 6.0 among 1,010 individuals who underwent B-mode ultrasound examination of carotid IMT from the population-based Northern Manhattan Study. Cigarette pack-years was calculated as number of years smoked multiplied by number of cigarettes smoked per day, then divided by 20. After quality control, a total of 722,379 single nucleotide polymorphisms (SNPs) were included in the final analysis. Generalized linear modeling was conducted to look for smoking-by-SNP interaction on carotid IMT while controlling for age, sex, hypertension, diabetes, dyslipidemia, body mass index, waist-to-hip ratio, and the top 3 principal components estimated to capture ancestry by EIGENSTRAT. Ten SNPs near or within 5 genes showed an interactive effect with cigarette smoking on IMT with a p value <1.0E-5. Among them, 3 SNPs (including 1 exonic splice enhancer SNP rs3751283, P=8.3E-7) are near or within regulator of chromosome condensation and BTB domain containing protein 1 (RCBTB1) gene on 13q14. Specifically, for SNP rs3751283, the mean IMT was substantially increased among CC-carriers (0.70 mm, 0.76 mm, 0.81 mm for 0, <20, and ≥20 cigarette pack-years, respectively, P=2.6E-6), slightly increased with smoking pack-years among TC-carriers (0.72 mm, 0.74 mm, 0.75 mm for 0, <20, and ≥20 cigarette pack-years, respectively, P=0.03), but very similar (0.73 mm) among TT-carriers for the three smoking groups (P=0.84).
Conclusion:
Our genome-wide interaction analysis reveals multiple genes, especially RCBTB1, that may modify the effect of smoking on carotid IMT. These genes will be further evaluated in our full dataset with additional genotyping. Also, larger independent studies are needed to validate these findings.