CLOCK genetic variation and metabolic syndrome risk: modulation by monounsaturated fatty acids

Abstract

Background: Disruption of the circadian system may be causal for manifestations of the metabolic syndrome (MetS).

Objective: The objective was to study the associations of 5 CLOCK polymorphisms with MetS features by analyzing fatty acid (FA) composition from dietary and red blood cell (RBC) membrane sources.

Design: Participants (n = 1100) in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study were included. Dietary intake was estimated with a validated questionnaire. Anthropometric and biochemical measurements and genotypes were determined. Postprandial lipids and the FA composition of RBC membranes were analyzed.

Results: CLOCK single nucleotide polymorphisms were significantly associated with obesity and individual components of MetS. For single nucleotide polymorphism rs4580704, minor allele carriers had a 46% lower risk of hypertension than did noncarriers. The monounsaturated fatty acid (MUFA) content of RBC membranes, particularly oleic acid, changed according to CLOCK genetic variants (P < 0.05). We identified significant gene-diet interactions associated with MetS at the CLOCK locus. By dichotomizing MUFA intake, we found different effects across rs4580704 genotypes for glucose (P = 0.020) and insulin resistance (P = 0.026). The protective effect of the minor allele on insulin sensitivity was only present when MUFA intake was >13.2% of energy. We also found different effects across CLOCK 3111T-->C genotypes for saturated fatty acid intake (% of energy) (P = 0.017). The deleterious effect of gene variants on waist circumference was only found with high saturated fatty acid intakes (>11.8%).

Conclusions: CLOCK polymorphisms interact with FAs to modulate MetS traits. The dietary source and membrane content of MUFAs are implicated in the relations between alterations in the circadian system and MetS.

FIGURE 1

Linkage disequilibrium (LD) plot between the single nucleotide polymorphisms (SNPs) selected and the LD plot across the CLOCK gene. The horizontal white bar depicts the 113-kb DNA segment of chromosome 4q12 analyzed in the sample. The 5 tag SNP locations are indicated by hatch marks. In the LD plot depicted in the bottom part of the figure, each diamond represents the magnitude of LD for a single pair of markers. The dark tones indicate strong LD (r² = 1.0), the white tones indicate no LD (r² = 0), and the gray tones indicate intermediate LD. The numbers inside the diamonds indicate the r² (D′) value.

FIGURE 2

Mean (±SE) fasting plasma glucose concentrations by rs4580704 polymorphism at the CLOCK gene according to monounsaturated fatty acid (MUFA) intakes below and above the population median (13.2% of energy). Estimated means were adjusted for sex, age, and familial relationships. P values for the interaction (P = 0.020) terms between fat intake and the corresponding polymorphism were obtained in the hierarchical multivariate interaction model containing MUFA intake as a categorical variable with additional control for the other covariates.

FIGURE 3

Mean (±SE) waist circumference by rs1801260 (3111T→C) polymorphism at the CLOCK gene according to saturated fatty acid (SFA) intakes below and above the population median (11.8% of energy). Estimated means were adjusted for sex, age, and familial relationships. P values for the interaction (P = 0.017) terms between fat intake and the corresponding polymorphism were obtained in the hierarchical multivariate interaction model containing SFA intake as a categorical variable with additional control for the other covariates.