Hamrefors Viktor, Hedblad Bo, Hindy George, Smith J Gustav, Almgren Peter, Engström Gunnar, Sjögren Marketa, Gränsbo Klas, Orho-Melander Marju, Melander Olle
Department of Clinical Sciences, Faculty of Medicine, Lund University, Malmö, Sweden ; Clinical Physiology and Nuclear Medicine Unit, Skåne University Hospital, Malmö, Sweden.
Department of Clinical Sciences, Faculty of Medicine, Lund University, Malmö, Sweden.
PLoS One. 2014 Jan 22;9(1):e85893. doi: 10.1371/journal.pone.0085893. eCollection 2014.
Genetic predisposition for cardiovascular disease (CVD) is likely to be modified by environmental exposures. We tested if the associated risk of CVD and CVD-mortality by the single nucleotide polymorphism rs4977574 on chromosome 9p21 is modified by life-style factors.
A total of 24,944 middle-aged subjects (62% females) from the population-based Malmö-Diet-and-Cancer-Cohort were genotyped. Smoking, education and physical activity-levels were recorded. Subjects were followed for 15 years for incidence of coronary artery disease (CAD; N = 2309), ischemic stroke (N = 1253) and CVD-mortality (N = 1156). Multiplicative interactions between rs4977574 and life-style factors on endpoints were tested in Cox-regression-models. We observed an interaction between rs4977574 and smoking on incident CAD (P = 0.035) and CVD-mortality (P = 0.012). The hazard ratios (HR) per risk allele of rs4977574 were highest in never smokers (N = 9642) for CAD (HR = 1.26; 95% CI 1.13-1.40; P<0.001) and for CVD-mortality (HR = 1.40; 95% CI 1.20-1.63; P<0.001), whereas the risk increase by rs4977574 was attenuated in current smokers (N = 7000) for both CAD (HR = 1.05; 95%CI 0.95-1.16; P = 0.326) and CVD-mortality (HR = 1.08; 95%CI 0.94-1.23; P = 0.270). A meta-analysis supported the finding that the associated increased risk of CAD by the risk-allele was attenuated in smokers. Neither education nor physical activity-levels modified the associated risk of CAD, ischemic stroke and CVD mortality conferred by rs4977574.
Smoking may modify the associated risk of CAD and CVD-mortality conferred by genetic variation on chromosome 9p21. Whether the observed attenuation of the genetic risk reflects a pathophysiological mechanism or is a result of smoking being such a strong risk-factor that it may eliminate the associated genetic effect, requires further investigation.
心血管疾病（CVD）的遗传易感性可能会受到环境暴露的影响。我们测试了9号染色体p21区域的单核苷酸多态性rs4977574与心血管疾病及心血管疾病死亡率的相关风险是否会受到生活方式因素的影响。
对基于人群的马尔默饮食与癌症队列中的24944名中年受试者（62%为女性）进行基因分型。记录吸烟、教育程度和身体活动水平。对受试者进行了15年的随访，以观察冠心病（CAD；n = 2309）、缺血性中风（n = 1253）和心血管疾病死亡率（n = 1156）的发生情况。在Cox回归模型中测试rs4977574与生活方式因素在终点事件上的乘法相互作用。我们观察到rs4977574与吸烟在CAD发病（P = 0.035）和心血管疾病死亡率（P = 0.012）方面存在相互作用。rs4977574每个风险等位基因的风险比（HR）在从不吸烟者（n = 9642）中对于CAD（HR = 1.26；95%CI 1.13 - 1.40；P<0.001）和心血管疾病死亡率（HR = 1.40；95%CI 1.20 - 1.63；P<0.001）最高，而在当前吸烟者（n = 7000）中，rs4977574对CAD（HR = 1.05；95%CI 0.95 - 1.16；P = 0.326）和心血管疾病死亡率（HR = 1.08；95%CI 0.94 - 1.23；P = 0.270）的风险增加作用减弱。一项荟萃分析支持了吸烟者中风险等位基因与CAD相关风险增加减弱的这一发现。教育程度和身体活动水平均未改变rs4977574所赋予的CAD、缺血性中风和心血管疾病死亡率的相关风险。
吸烟可能会改变9号染色体p21区域基因变异所赋予的CAD和心血管疾病死亡率的相关风险。观察到的遗传风险减弱是反映了一种病理生理机制，还是由于吸烟是一个如此强大的风险因素以至于可能消除相关遗传效应的结果，尚需进一步研究。
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