Sequence variation in telomerase reverse transcriptase (TERT) as a determinant of risk of cardiovascular disease: the Atherosclerosis Risk in Communities (ARIC) study.
Sequence variation in telomerase reverse transcriptase (TERT) as a determinant of risk of cardiovascular disease: the Atherosclerosis Risk in Communities (ARIC) study.
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DOI：
10.1186/s12881-015-0194-x
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发表时间：
2015-07-23
影响因子：
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通讯作者：
Boerwinkle E
中科院分区：
文献类型：
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作者：
Bressler J;Franceschini N;Demerath EW;Mosley TH;Folsom AR;Boerwinkle E
端粒酶逆转录酶（TERT）在DNA复制过程中通过催化短端粒重复序列的添加来维持端粒末端。端粒酶在体细胞中的表达通常受到抑制，导致端粒逐渐缩短，细胞随着年龄的增长而衰老。白细胞端粒长度的个体间变异先前与心血管疾病的易感性有关。本研究的目的是确定TERT基因的六种变异是否与基于双种族人群的社区动脉粥样硬化风险（ARIC）研究参与者的冠心病、缺血性卒中和死亡率发生风险相关，其中包括在全基因组分析中发现影响平均端粒长度的rs2736100。ARIC是一项前瞻性研究，研究了1987-1989年间15792名年龄在45 - 64岁的人的动脉粥样硬化的病因学和自然史。TERT中的单倍型标记snp使用定制阵列进行基因分型，该阵列包含2100个与心血管和代谢表型相关的基因中的近49,000个snp。在20年的随访期间，使用Cox比例风险模型评估了8,907名白人和3,022名非洲裔美国人的TERT多态性与心血管疾病和死亡率之间的关系，基线检查时没有疾病史，而患有流行心血管疾病的个体并未被排除在死亡率分析之外。在调整了年龄和性别，并假设一个加性遗传模型后，rs2736122和rs2853668在名义上分别与非裔美国人的冠心病（危险率比= 1.20,p = 0.02, 95%可信区间= 1.03 - 1.40）和中风（危险率比= 1.17,p = 0.05, 95%可信区间= 1.00 - 1.38）的发生相关。在白人研究参与者中，没有一种变异与心血管疾病或两种种族的死亡率显著相关。在其他基于群体的样本中进行复制，并结合其他参与端粒长度维持的基因多态性的基因分型，可能有助于确定与端粒稳态相关的遗传变异是否会影响中年人心血管疾病的风险。
Telomerase reverse transcriptase (TERT) maintains telomere ends during DNA replication by catalyzing the addition of short telomere repeats. The expression of telomerase is normally repressed in somatic cells leading to a gradual shortening of telomeres and cellular senescence with aging. Interindividual variation in leukocyte telomere length has been previously associated with susceptibility to cardiovascular disease. The aim of the present study was to determine whether six variants in the TERT gene are associated with risk of incident coronary heart disease, incident ischemic stroke, and mortality in participants in the biracial population-based Atherosclerosis Risk in Communities (ARIC) study, including rs2736100 that was found to influence mean telomere length in a genome-wide analysis. ARIC is a prospective study of the etiology and natural history of atherosclerosis in 15,792 individuals aged 45 to 64 years at baseline in 1987–1989. Haplotype tagging SNPs in TERT were genotyped using a custom array containing nearly 49,000 SNPs in 2,100 genes associated with cardiovascular and metabolic phenotypes. Cox proportional hazards models were used to assess the association between the TERT polymorphisms and incident cardiovascular disease and mortality over a 20-year follow-up period in 8,907 whites and 3,022 African-Americans with no history of disease at the baseline examination, while individuals with prevalent cardiovascular disease were not excluded from the analyses of mortality. After adjustment for age and gender, and assuming an additive genetic model, rs2736122 and rs2853668 were nominally associated with incident coronary heart disease (hazards rate ratio = 1.20, p = 0.02, 95 % confidence interval = 1.03– 1.40) and stroke (hazards rate ratio = 1.17, p = 0.05, 95 % confidence interval = 1.00 - 1.38), respectively, in African-Americans. None of the variants was significantly associated with cardiovascular disease in white study participants or with mortality in either racial group. Replication in additional population-based samples combined with genotyping of polymorphisms in other genes involved in maintenance of telomere length may help to determine whether genetic variants associated with telomere homeostasis influence the risk of cardiovascular disease in middle-aged adults.