CLOCK gene variation is associated with incidence of type-2 diabetes and cardiovascular diseases in type-2 diabetic subjects: dietary modulation in the PREDIMED randomized trial.
CLOCK gene variation is associated with incidence of type-2 diabetes and cardiovascular diseases in type-2 diabetic subjects: dietary modulation in the PREDIMED randomized trial.
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CLOCK 基因变异与 2 型糖尿病受试者中 2 型糖尿病和心血管疾病的发病率相关：PREDIMED 随机试验中的饮食调节。
DOI：
10.1186/s12933-015-0327-8
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发表时间：
2016-01-07
影响因子：
9.3
通讯作者：
Ordovás JM
中科院分区：
文献类型：
--
作者：
Corella D;Asensio EM;Coltell O;Sorlí JV;Estruch R;Martínez-González MÁ;Salas-Salvadó J;Castañer O;Arós F;Lapetra J;Serra-Majem L;Gómez-Gracia E;Ortega-Azorín C;Fiol M;Espino JD;Díaz-López A;Fitó M;Ros E;Ordovás JM
昼夜节律调节影响代谢途径的关键生物过程。失调与2型糖尿病（T2D）和心血管疾病（CVD）有关。昼夜节律是由涉及核心时钟基因的转录自动调节反馈环产生的。CLOCK（昼夜运动输出周期蛋白kaput）是这些核心基因之一，已知在啮齿动物模型中调节葡萄糖代谢。人类横断面研究报告了该位点与肥胖、血糖、高血压和T2D患病率之间的关联，支持其在心血管风险中的作用。然而，没有纵向研究调查CLOCK基因变异与T2D或CVD发病率之间的关联。此外，尽管在先前的工作中，我们检测到了CLOCK-rs4580704（C> G）单核苷酸多态性（SNP）和单不饱和脂肪酸（MUFA）摄入对胰岛素抵抗的基因-饮食相互作用，但没有干预性研究分析了基因-饮食相互作用对T2D或CVD结局的影响。 我们在中位4.8年随访后，在7098名PREDIMED试验（ISRCTN35739639）参与者中纵向分析了CLOCK-rs4580704 SNP与T2D和CVD发病率之间的关联。我们还研究了地中海饮食（MedDiet）干预（高MUFA）对这些关联的调节。我们在n = 3671名非T2D PREDIMED参与者中观察到CLOCK-rs4580704 SNP与T2D发病率之间的显著相关性，与CC纯合子相比，变异等位基因（G）携带者显示发病率降低（显性模型）（HR：0.69; 95%CI 0.54 - 0.87; P = 0.002）。这种保护作用在MedDiet干预组（HR：0.58; 95% CI 0.43 - 0.78; P <0.001）中比在对照组（HR：0.95; 95% CI 0.63 - 1.44; P = 0.818）中更显著。此外，我们检测到CLOCK-rs4580704 SNP与中风的T2D状态之间存在统计学显著的相互作用（P = 0.018）。因此，在多变量校正模型中，仅在T2D受试者中CLOCK-rs4580704 SNP与中风风险相关，G携带者具有降低的风险（HR：0.61; 95%CI 0.40 - 0.94; P = 0.024相对于CC）。与我们先前的结果一致，显示G等位基因对高血糖症的保护作用，我们通过报告与较低的T2D发病率的新关联并提出饮食调节来扩展我们的研究结果。此外，我们首次报告了CLOCK多态性与T2D受试者中风之间的关联，表明核心时钟基因可能显著增加T2D患者的CVD风险。本文的在线版本（doi：10.1186/s12933 - 015 - 0327 - 8）包含补充材料，可供授权用户使用。
Circadian rhythms regulate key biological processes influencing metabolic pathways. Disregulation is associated with type 2 diabetes (T2D) and cardiovascular diseases (CVD). Circadian rhythms are generated by a transcriptional autoregulatory feedback loop involving core clock genes. CLOCK (circadian locomotor output cycles protein kaput), one of those core genes, is known to regulate glucose metabolism in rodent models. Cross-sectional studies in humans have reported associations between this locus and obesity, plasma glucose, hypertension and T2D prevalence, supporting its role in cardiovascular risk. However, no longitudinal study has investigated the association between CLOCK gene variation and T2D or CVD incidence. Moreover, although in a previous work we detected a gene-diet interaction between the CLOCK-rs4580704 (C > G) single nucleotide polymorphism (SNP) and monounsaturated (MUFA) intake on insulin resistance, no interventional study has analyzed gene-diet interactions on T2D or CVD outcomes. We analyzed the association between the CLOCK-rs4580704 SNP and incidence of T2D and CVD longitudinally in 7098 PREDIMED trial (ISRCTN35739639) participants after a median 4.8-year follow-up. We also examined modulation by Mediterranean diet (MedDiet) intervention (high in MUFA) on these associations. We observed a significant association between the CLOCK-rs4580704 SNP and T2D incidence in n = 3671 non-T2D PREDIMED participants, with variant allele (G) carriers showing decreased incidence (dominant model) compared with CC homozygotes (HR: 0.69; 95 % CI 0.54–0.87; P = 0.002). This protection was more significant in the MedDiet intervention group (HR: 0.58; 95 % CI 0.43–0.78; P < 0.001) than in the control group (HR: 0.95; 95 % CI 0.63–1.44; P = 0.818). Moreover, we detected a statistically significant interaction (P = 0.018) between CLOCK-rs4580704 SNP and T2D status on stroke. Thus, only in T2D subjects was CLOCK-rs4580704 SNP associated with stroke risk, G-carriers having decreased risk (HR: 0.61; 95 % CI 0.40–0.94; P = 0.024 versus CC) in the multivariable-adjusted model. In agreement with our previous results showing a protective effect of the G-allele against hyperglycemia, we extended our findings by reporting a novel association with lower T2D incidence and also suggesting a dietary modulation. Moreover, we report for the first time an association between a CLOCK polymorphism and stroke in T2D subjects, suggesting that core clock genes may significantly contribute to increased CVD risk in T2D. The online version of this article (doi:10.1186/s12933-015-0327-8) contains supplementary material, which is available to authorized users.