CLOCK gene is implicated in weight reduction in obese patients participating in a dietary programme based on the Mediterranean diet

Abstract

Introduction: The success of obesity therapy is dependent on the genetic background of the patient. Circadian Locomotor Output Cycles Kaput (CLOCK), one of the transcription factors from the positive limb of the molecular clock, is involved in metabolic alterations.

Objective: To investigate whether five candidate polymorphisms from CLOCK were associated with anthropometric, metabolic measures and weight loss in response to a behavioural weight reduction programme based on the Mediterranean diet.

Methods: Five hundred overweight/obese subjects, aged 20-65 years, who attended outpatient clinics specializing in obesity, were studied. Anthropometric, biochemical and dietary intake variables were analysed. Effectiveness of the programme and weight loss progression during 28 weeks of treatment was assessed.

Results: Four of five CLOCK SNPs selected were significantly associated with obesity variables (P<0.05). The genetic variation in the rs1801260 CLOCK was associated with obesity at baseline and also affected weight loss. Patients with the variant allele (G) lost significantly less weight i(P=0.008) compared with wild type. Repeated measures analysis showed that weight loss over time was significantly different between rs1801260 CLOCK variations (P=0.038). Carriers of the G allele displayed greater difficulty in losing weight than non-carriers. In this particular polymorphism, the frequency of short-time sleepers (< or =6 h per day) was greater in minor allele carriers than in non-carriers (59% vs 41%; P<0.05). CLOCK polymorphisms were also associated with significant differences in total plasma cholesterol at the completion of dietary treatment (P<0.05).

Conclusions: We have replicated previous studies showing a relationship between CLOCK gene polymorphisms and obesity. CLOCK rs1801260 SNP may predict the outcome of body weight reduction strategies based on low-energy diets.

Figures

Figure 1

Linkage disequilibrium (LD) plot across the CLOCK gene. The horizontal white bar depicts the 113 kb DNA segment of chromosome 4q12 analysed in the sample. The 5 tagSNP locations are indicated by hatch marks. An LD plot is depicted in the bottom part of the figure: each diamond represents the magnitude of LD for a single pair of markers. Black indicates strong LD (r2 = 1.0); white indicates no LD (r2 = 0) and the grey tones indicate intermediate LD. The numbers inside the diamonds indicate the r2 (D’) value.

Figure 2

Significant associations between CLOCK SNPs and obesity parameters. (a) CLOCK rs3749474 and BMI; (b) CLOCK rs3749474 and waist circumference; (c) CLOCK rs180126 (3111T>C) and BMI.

Figure 3

CLOCK variants and weight loss evolution during 28 weeks of treatment: (a) CLOCK rs3749474; (b) CLOCK rs4580704; (c) CLOCK rs180126 (3111T>C).