Short Telomere Length and Ischemic Heart Disease: Observational and Genetic Studies in 290 022 Individuals
Short Telomere Length and Ischemic Heart Disease: Observational and Genetic Studies in 290 022 Individuals
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DOI：
10.1373/clinchem.2016.258566
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发表时间：
2016-08-01
影响因子：
9.3
通讯作者：
Bojesen, Stig E.
中科院分区：
文献类型：
--
作者：
Madrid, Alexander Scheller;Rode, Line;Bojesen, Stig E.
背景技术背景：短端粒与衰老相关，并且在观察性研究中与缺血性心脏病的高风险相关;然而，后一种相关性可能是由于残留混杂和/或反向因果关系。我们想用孟德尔随机化方法来检验短端粒与缺血性心脏病高风险相关的假设，该方法没有反向因果关系和大多数混杂因素。我们对OBFC 1中的3种遗传变异进行了基因分型。（寡核苷酸/寡糖结合倍数含1），TERT端粒酶逆转录酶（telomerase reverse transcriptase，TERC）和端粒酶RNA组分（telomerase RNA component，TERC），它们编码参与端粒维持的蛋白质和RNA。我们研究了来自哥本哈根的105055人;其中17235人在1977年至2013年期间被诊断患有缺血性心脏病，66618人测量了端粒长度。对于遗传学研究，我们进一步纳入了冠状动脉疾病全基因组复制和荟萃分析（CARDIoanalysis）联盟数据集，其中包括多达184 967名参与者和60 837例缺血性心脏病病例。我们进行了多变量调整后的考克斯比例风险模型的观察estimates，使用逻辑和工具变量分析遗传estimate.RESULTS：观察，200 bp短端粒长度与缺血性心脏病的多变量调整后的风险比为1.02（95%CI，1.01-1.03）。每个等位基因，端粒短67 bp（73-60）。在所有4项研究的荟萃分析中，OBCF 1、TERT和TERC的缺血性心脏病的比值比分别为1.05（1.03-1.08）、1.04（1.02-1.06）和1.01（0.99 - 1.03）。基因决定的端粒长度短200 bp与缺血性心脏病的优势比为1.10（1.06 - 1.14）。结论：从观察和遗传角度来看，端粒短与缺血性心脏病的风险较高相关。(C)2016年美国临床化学协会
BACKGROUND: Short telomeres are associated with aging and have been associated with a high risk of ischemic heart disease in observational studies; however, the latter association could be due to residual confounding and/or reverse causation. We wanted to test the hypothesis that short telomeres are associated with high risk of ischemic heart disease using a Mendelian randomization approach free of reverse causation and of most confounding.METHODS: We genotyped 3 genetic variants in OBFC1 (oligonucleotide/oligosaccharide binding fold containing 1), TERT (telomerase reverse transcriptase), and TERC (telomerase RNA component), which code for proteins and RNA involved in telomere maintenance. We studied 105 055 individuals from Copenhagen; 17 235 of these individuals were diagnosed with ischemic heart disease between 1977 and 2013, and 66 618 had telomere length measured. For genetic studies, we further included the Coronary ARtery DIsease Genome wide Replication and Meta-analysis (CARDIoGRAM) consortium dataset, which included up to 184 967 participants and 60 837 cases of ischemic heart disease. We conducted multivariable adjusted Cox proportional hazard models for observational estimates, using logistic and instrumental variable analysis for genetic estimates.RESULTS: Observationally, a 200-bp-shorter telomere length was associated with a multivariable adjusted hazard ratio for ischemic heart disease of 1.02 (95% CI, 1.01-1.03). Per allele, telomeres were shorter by 67 bp (73-60). In meta-analyses of all 4 studies combined, odds ratios for ischemic heart disease were 1.05 (1.03-1.08) for OBCF1, 1.04 (1.02-1.06) for TERT, and 1.01 (0.99 -1.03) for TERC. A genetically determined 200-bp-shorter telomere length was associated with an odds ratio for ischemic heart disease of 1.10 (1.06 -1.14).CONCLUSIONS: Shorter telomeres were associated with a higher risk of ischemic heart disease, both observationally and genetically. (C) 2016 American Association for Clinical Chemistry