Influence of Smoking Status and Intensity on Discovery of Blood Pressure Loci Through Gene-Smoking Interactions.
Influence of Smoking Status and Intensity on Discovery of Blood Pressure Loci Through Gene-Smoking Interactions.
复制标题
DOI：
10.1002/gepi.21904
复制
发表时间：
2015-09
影响因子：
2.1
通讯作者：
Rao DC
中科院分区：
文献类型：
--
作者：
Basson J;Sung YJ;Fuentes LL;Schwander K;Cupples LA;Rao DC
遗传变异约占血压（BP）变异的30%，但大多数变异并不归因于特定的变异。基因和BP相关因素之间的相互作用可以解释一些“缺失的遗传性”。吸烟在短期暴露后会增加血压，而在长期暴露后会降低血压。基因吸烟相互作用已经发现了新的BP位点，但吸烟状态和强度对基因发现的贡献尚不清楚。我们分析了基因吸烟强度相互作用与心脏收缩压（SBP）的关系，来自心脏研究的三个亚组：仅当前吸烟者（N = 1，057），当前和既往吸烟者（“曾经吸烟者”，N = 3，374）和所有受试者（N = 6，710）。我们使用了三个吸烟强度变量，定义为每天10支，15支和20支香烟（CPD）。我们评估了1度的自由度（DF）的相互作用和2DF联合测试使用广义估计方程。使用CPD截止值10分析当前吸烟者产生了两个与SBP相关的位点。rs 9399633次要等位基因与重度吸烟者（CPD>10）的SBP升高（5 mmHg）相关，但与轻度吸烟者（CPD≤10）的SBP降低（7 mmHg）相关。rs 11717948次要等位基因与轻度吸烟者SBP降低（8 mmHg）相关，但与重度吸烟者SBP降低（2 mmHg）相关。在所有9个分析中，19个额外的位点达到p < 1×10−6。尽管样本量减少，但对目前吸烟者的分析可能具有最高的检测基因吸烟相互作用的能力。SASH 1和KLHL 6/KLHL 24附近的位点与SBP的关联可能受到吸烟的调节。
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. 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. 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. 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.