CRY1 circadian gene variant interacts with carbohydrate intake for insulin resistance in two independent populations: Mediterranean and North American

Abstract

Dysregulation in the circadian system induced by variants of clock genes has been associated with type 2 diabetes. Evidence for the role of cryptochromes, core components of the system, in regulating glucose homeostasis is not supported by CRY1 candidate gene association studies for diabetes and insulin resistance in human, suggesting possible dietary influences. The purpose of this study was to test for interactions between a CRY1 polymorphism, rs2287161, and carbohydrate intake on insulin resistance in two independent populations: a Mediterranean (n = 728) and an European origin North American population (n = 820). Linear regression interaction models were performed in two populations to test for gene-diet interactions on fasting insulin and glucose and two insulin-related traits, homeostasis model assessment of insulin resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI). In addition, fixed effects meta-analyses for these interactions were performed. Cohort-specific interaction analyses showed significant interactions between the CRY1 variant and dietary carbohydrates for insulin resistance in both populations (p < 0.05). Findings from the meta-analyses of carbohydrate-single nucleotide polymorphism interactions indicated that an increase in carbohydrate intake (% of energy intake) was associated with a significant increase in HOMA-IR (p = 0.011), fasting insulin (p = 0.007) and a decrease in QUICKI (p = 0.028), only among individuals homozygous for the minor C allele. This novel finding supports the link between the circadian system and glucose metabolism and suggests the importance this CRY1 locus in developing personalized nutrition programs aimed at reducing insulin resistance and diabetes risk.

Keywords: CRY1; Carbohydrate intake; diabetes; genetic epidemiology; gene–diet interaction.

Conflict of interest statement

DECLARATION OF INTEREST

The authors declare no conflict of interest. This study was supported by grants from Tomás Pascual and Pilar Gómez-Cuétara Foundations, Spanish Government of Science and Innovation (BFU2011-24720), Séneca Foundation from the Government of Murcia (15123/PI/10). National Heart, Lung, and Blood Institute grants HL-54776, National Institute of Diabetes and Digestive and Kidney Diseases, Grant Number DK075030 and by contracts 53-K06-5-10 and 58-1950-9-001 from the US Department of Agriculture Research. C. Smith is supported by K08 HL112845.

Figures

FIGURE 1

Gene–diet interaction for HOMA-IR in the Mediterranean population. Mean (± SE) HOMA-IR by CRY1 rs2287161 genotype according to total carbohydrate (% of total energy) intakes below and above the population median (41.65% of total energy). Allele was modeled recessively and estimated means were adjusted for age, sex, study number and clinic location. HOMA-IR, homeostasis model assessment-estimated insulin resistance.

FIGURE 2

Gene–diet interaction for HOMA-IR in the North American population. Predicted values of HOMA-IR according to CRY1 rs2287161 genotype plotted against carbohydrate intake (% of total energy) evaluated continuously. Predicted values for HOMA-IR (natural log) were calculated from the regression model after adjustment for age, sex, BMI, center location and family structure. p Values indicate the statistical significance of the interaction term in the adjusted regression model, the statistical significance of the adjusted regression coefficient in the regression line corresponding to CRY1 minor allele homozygotes and the statistical significance of the adjusted regression coefficient in the regression line to carriers of the CRY1 major allele. HOMA-IR, homeostasis model assessment- estimated insulin resistance.

FIGURE 3

Forest plot of the interaction between CRY1 variant (rs2287161) and carbohydrate intake (% of total energy) for HOMA-IR in two independent populations. Allele modeled recessively and carbohydrate intake (% of total energy) was evaluated dichotomously. Cohort-specific interaction analyses adjusted for age, sex, BMI and cohort-specific covariates. The estimate from each cohort study is indicated by a filled circle and the horizontal line represents the 95% CI. The overall summary estimate and its 95% CI are indicated by the open diamond.