Diversity of Human Clock Genotypes and Consequences - Progress in Molecular Biology and Translational Science - page 56

Similar to BMAL1, CLOCK has also been suggested to play a role in
metabolic processes. A number of CLOCK polymorphisms are related to
body mass index (BMI). Two of these variants located in intron
12 (rs1554483) and the promoter region of the CLOCK gene
(rs4864548) form a haplotype associated with BMI, while two additional
variants, rs1801260 and rs3749474 (located in 3 0 -UTR), are individually
associated with BMI. 35,51,52 Both rs1801260 and rs3749474 are significantly
associated with weight, and the latter with waist circumference as well. 35
Under weight-reduction programs, rs1801260 G allele carriers display
greater difficulty losing weight, higher plasma ghrelin levels, altered eating
behavior, and dietary habits compared to the noncarriers. 32,35 Both
rs1801260 and rs3749474, along with an additional SNP in intron 9,
rs4580704, are significantly linked to changes in serum cholesterol at the
end of dietary treatment. 35 In contrast to overweight/obese individuals,
patients with anorexia nervosa or bulimia nervosa carrying the rs1801260
G allele have a lifetime body weight significantly lower than those carrying
the A/A genotype, implying a rather complex mechanism of how this
rs1801260 variant interacts with metabolism. 53 Notably, rs1801260
G carriers exhibit significantly less small dense low-density lipoprotein, an
abnormal lipid metabolite and one of the risk parameters for cardiometabolic
disorders, compared to individuals with rs1801260 A/A. 54 Several SNPs in
the CLOCK gene are significantly associated with energy intake, including
the aforementioned 3 0 -UTR SNP rs3749474, intron 9 SNP rs4580704,
promoter SNP rs4864548, and an SNP in intron 11. 35 Moreover,
rs3749474, rs4580704, and rs1801260 are related to plasma cytokine levels,
particularly those that highly correlated with energy intake. 35 These energy
intake-associated SNPs, including rs1801260, are also linked to the mono-
unsaturated fatty acid content of red blood cell membrane, which plays a
critical metabolic role. 55 rs4580704 and rs1801260 exhibit dietary fatty
acid-dependent associations with metabolic syndrome traits including glu-
cose and insulin resistance as well as waist circumference. 55 This suggests that
CLOCK polymorphisms interact with fatty acid to modulate metabolic pro-
cesses. In addition, rs4580704 is significantly associated with the risk of
hypertension. 55 A number of SNPs in the promoter and intronic regions
of CLOCK show significant associations with susceptibility to and severity
of nonalcoholic fatty liver disease, which is one of the most common abnor-
malities observed in obese people. 56 Two of these SNPs, promoter SNP
rs4864548 and intron 12 SNP rs1554483, have been reported to be linked
with BMI and energy intake as described earlier, adding further evidence