Gene-environment interactions of circadian-related genes for cardiometabolic traits

Authors: DASHTI, HASSAN - Tufts University; FOLLIS, JACK - University Of St Thomas; SMITH, CAREN - Tufts University; TANAKA, TOSHIKO - National Institute On Aging (NIA, NIH); GARAULET, MARTA - University Of Spain; GOTTLIEB, DANIEL - Harvard Medical School; HRUBY, ADELA - Harvard School Of Public Health; JACQUES, PAUL - Tufts University; KIEFTER-DE JONG, JESSICA - Leiden University; LAMON-FAVA, STEFANIA - Tufts University; SCHEER, FRANK - Harvard Medical School; BARTZ, TRACI - University Of Washington; KOVANEN, LEENA - Helsinki Hospital; WOJCZYNSKI, MARY - Washington University School Of Medicine; FRAZIER-WOOD, ALEXIS - Children'S Nutrition Research Center (CNRC); AHULWALIA, TARUNVEER - University Of Copenhagen; PERALA, MIA - Helsinki Hospital; JONSSON, ANNA - University Of Copenhagen; MUKA, TAULANT - Erasmus Medical Center; KALAFATI, IOANNA - Harokopio University Of Athens; MIKKILA, VERA - University Of Helsinki; ORDOVAS, JOSE - Tufts University

Submitted to: Diabetes Care
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/15/2015
Publication Date: 8/1/2015
Citation: Dashti, H.S., Follis, J.L., Smith, C.E., Tanaka, T., Garaulet, M., Gottlieb, D.J., Hruby, A., Jacques, P.F., Kiefter-De Jong, J.C., Lamon-Fava, S., Scheer, F.A., Bartz, T.M., Kovanen, L., Wojczynski, M.K., Frazier-Wood, A.C., Ahulwalia, T.S., Perala, M.M., Jonsson, A., Muka, T., Kalafati, I.P., Mikkila, V., Ordovas, J.M. 2015. Gene-environment interactions of circadian-related genes for cardiometabolic traits. Diabetes Care. 38(8):1456-1466.

Interpretive Summary: Genes that are related to how our body clock functions (are you a "lark" or a "night owl") associate with increased risk for conditions such as type 2 diabetes. Sleep quality and diet also associate with type 2 diabetes. We wanted to know if there was an interaction between body clock genes and either sleep or diet on type 2 diabetes risk. To address this, we analyzed data from up to 28,190 participants and examined the interactions between circadian SNPs, diet and sleep on fasting glucose [FG], HOMA-insulin resistance, BMI, waist circumference, and HDL-cholesterol. No interactions were evident after accounting for multiple comparisons. However, we observed nominally significant interactions between carbohydrate intake and one variant on glucose, and between sleep duration and another variant on HDL-cholesterol. These results suggest that lower carbohydrate intake and normal sleep duration may ameliorate cardiometabolic abnormalities conferred by common circadian-related genetic variants. This information may contribute towards the development of personalized recommendations for reducing cardiometabolic risk in the future.

Technical Abstract: Common circadian-related gene variants associate with increased risk for metabolic alterations including type 2 diabetes. However, little is known about whether diet and sleep could modify associations between circadian-related variants (CLOCK-rs1801260, CRY2-rs11605924, MTNR1B-rs1387153, MTNR1B-rs10830963, NR1D1-rs2314339) and cardiometabolic traits (fasting glucose [FG], HOMA-insulin resistance, BMI, waist circumference, and HDL-cholesterol) to facilitate personalized recommendations. We conducted inverse-variance weighted, fixed-effect meta-analyses of results of adjusted associations and interactions between dietary intake/sleep duration and selected variants on cardiometabolic traits from 15 cohort studies including up to 28,190 participants of European descent from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We observed significant associations between relative macronutrient intakes and glycemic traits and short sleep duration (<7 h) and higher FG and replicated known MTNR1B associations with glycemic traits. No interactions were evident after accounting for multiple comparisons. However, we observed nominally significant interactions (all P < 0.01) between carbohydrate intake and MTNR1B-rs1387153 for FG with a 0.003 mmol/L higher FG with each additional 1% carbohydrate intake in the presence of the T allele, between sleep duration and CRY2-rs11605924 for HDL-cholesterol with a 0.010 mmol/L higher HDL-cholesterol with each additional hour of sleep in the presence of the A allele, and between long sleep duration (>=9 h) and MTNR1B-rs1387153 for BMI with a 0.60 kg/m(2) higher BMI with long sleep duration in the presence of the T allele relative to normal sleep duration (>=7 to <9 h).Our results suggest that lower carbohydrate intake and normal sleep duration may ameliorate cardiometabolic abnormalities conferred by common circadian-related genetic variants. Until further mechanistic examination of the nominally significant interactions is conducted, recommendations applicable to the general population regarding diet-specifically higher carbohydrate and lower fat composition-and normal sleep duration should continue to be emphasized among individuals with the investigated circadian-related gene variants.