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. Issue 1 (December 2016)

• Record Type: Journal Article
• Authors: Corella, Dolores; Asensio, Eva.; Coltell, Oscar; Sorlí, José; Estruch, Ramón; Martínez-González, Miguel; Salas-Salvadó, Jordi; Castañer, Olga; Arós, Fernando; Lapetra, José; Serra-Majem, Lluís; Gómez-Gracia, Enrique; Ortega-Azorín, Carolina; Fiol, Miquel; Espino, Javier; Díaz-López, Andrés; Fitó, Montserrat; Ros, Emilio; Ordovás, José
• Is Part Of: Cardiovascular diabetology. Volume 15:Issue 1(2016)
• Page Start: 1
• Page End: 12
• Publication Date: 2016-12
• Subjects: CLOCK gene -- Diabetes -- Cardiovascular diseases -- Stroke -- Mediterranean diet; Diabetes -- Complications -- Periodicals; Cardiovascular system -- Diseases -- Complications -- Periodicals; Cardiovascular system -- Diseases -- Prevention -- Periodicals; 616.462
• DOI: 10.1186/s12933-015-0327-8
• Languages: English
• ISSNs: 1475-2840

Abstract

Abstract Background 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 betweenCLOCK gene variation and T2D or CVD incidence. Moreover, although in a previous work we detected a gene-diet interaction between theCLOCK -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. Methods We analyzed the association between theCLOCK -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. Results We observed a significant association between theCLOCK -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) betweenCLOCK -rs4580704 SNP and T2D status on stroke. Thus, only in T2D subjects wasCLOCK -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. Conclusions 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 aCLOCK polymorphism and stroke in T2D subjects, suggesting that core clock genes may significantly contribute to increased CVD risk in T2D.