ADAM33 Gene Polymorphisms and Mortality. A Prospective Cohort Study

The ADAM33 gene is associated with the pathophysiology of Chronic Obstructive Pulmonary Disease (COPD) and atherosclerosis. In this study we investigated all-cause, COPD and cardiovascular mortality, in relation to single nucleotide polymorphisms (SNPs) in ADAM33 (Q_1, S_1, S_2, T_1 and T_2) that were genotyped in 1,390 subjects from the Vlagtwedde/Vlaardingen cohort. Participants were examined at entry in 1989/1990 and followed up till evaluation of the vital status on December 31st, 2008. Using Cox proportional hazards regression we estimated the risk of the SNPs in relation to mortality, adjusting for gender, age, FEV1, height, place of residence and packyears of smoking. Additionally, we performed stratified analyses according to gender and smoking habits. After 18 years, 284 (20.4%) subjects had died (107 due to cardiovascular disease and 20 due to COPD). Individuals homozygous for the minor allele of SNP T_2 had an increased risk of all-cause and cardiovascular mortality compared to wild types: hazard ratio 3.6 (95% confidence interval 2.0 to 6.7) and 3.4 (1.2 to 9.5) respectively. Individuals homozygous for the minor allele of S_1, S_2, T_2 or Q_1 had a significantly increased risk of COPD mortality. In stratified analyses the risk of all-cause mortality associated with SNP T_2 did not change: females 3.5 (1.5 to 8.3), males 3.1 (1.2 to 7.6), never smokers 3.8 (0.9 to 16.3), ever smokers 3.6 (1.8 to 7.2). This study shows for the first time that ADAM33 is a pleiotropic gene that is associated with all-cause, COPD and cardiovascular mortality, independent of potential confounders.

ADAM33基因与慢性阻塞性肺疾病（Chronic Obstructive Pulmonary Disease, COPD）及动脉粥样硬化的病理生理学密切相关。本研究以Vlagtwedde/Vlaardingen队列的1390名受试者为研究对象，对其ADAM33基因的单核苷酸多态性（single nucleotide polymorphisms, SNPs，包括Q_1、S_1、S_2、T_1及T_2）进行基因分型，探究上述多态性与全因死亡率、COPD相关死亡率及心血管相关死亡率的关联。受试者于1989/1990年入组时接受基线检查，随访至2008年12月31日以评估其生存状态，总随访时长达18年。本研究采用Cox比例风险回归模型，在校正性别、年龄、第一秒用力呼气容积（FEV1）、身高、居住地及吸烟包年数等混杂因素后，估算了各SNPs与死亡风险的关联；此外，还依据性别与吸烟习惯开展了分层分析。随访结束后，共计284名（20.4%）受试者死亡，其中107例死于心血管疾病，20例死于COPD。携带T_2次要等位基因纯合子的个体，其全因死亡率及心血管死亡率均显著高于野生型个体：风险比（hazard ratio, HR）分别为3.6（95%置信区间：2.0~6.7）与3.4（95%置信区间：1.2~9.5）。携带S_1、S_2、T_2或Q_1次要等位基因纯合子的个体，其COPD相关死亡率均显著升高。分层分析结果显示，与T_2 SNP相关的全因死亡率风险未发生明显改变：女性HR=3.5（95%置信区间：1.5~8.3），男性HR=3.1（95%置信区间：1.2~7.6），从不吸烟者HR=3.8（95%置信区间：0.9~16.3），曾吸烟者HR=3.6（95%置信区间：1.8~7.2）。本研究首次证实，ADAM33是一种多效性基因，其与全因死亡率、COPD相关死亡率及心血管相关死亡率均存在独立于潜在混杂因素的关联。