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CLOCK genetic variation and metabolic syndrome risk: modulation by monounsaturated fatty acids
Open accessAbstract
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.
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“However, when we investigated further the potential modulating effect of diet, we observed that the protective effect of the minor allele on insulin sensitivity was only present when MUFA intake was above the median (>13.2% of energy in this population).”
From Circadian rhythms, metabolism, and chrononutrition in rodents and humans (2016) · cites this paper as [53]
In the citing paper
“Finally, we also observed significant associations with markers of chronic inflammation (i.e., IL-6).”
From Circadian rhythms, metabolism, and chrononutrition in rodents and humans (2016) · cites this paper as [53]
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“Another finding came from the analysis of the MUFA content of red blood cell membranes, particularly oleic acid, which was significantly different according to CLOCK genetic variants.”
From Circadian rhythms, metabolism, and chrononutrition in rodents and humans (2016) · cites this paper as [53]
In the citing paper
“We investigated 5 selected CLOCK single-nucleotide polymorphisms (SNPs) (rs 4864548, rs4580704, rs1464490, rs1801260, and rs3749474), of which 3 (rs4580704, rs1801260, and rs3749474) yielded statistically significant associations with BMI (in kg/m 2 ), blood pressure, glycemic traits, and markers of dietary intake (red blood cell membrane fatty acids).”
From Circadian rhythms, metabolism, and chrononutrition in rodents and humans (2016) · cites this paper as [53]
In the citing paper
“Conversely, the detrimental effect of the minor allele at the rs1801260 SNP on waist circumference was only found with SFA intakes above the median (>11.8% of energy in GOLDN).”
From Circadian rhythms, metabolism, and chrononutrition in rodents and humans (2016) · cites this paper as [53]
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“One of these SNPs, rs4580704, appeared to be protective; minor allele carriers had a 46% lower risk of hypertension than did noncarriers.”
From Circadian rhythms, metabolism, and chrononutrition in rodents and humans (2016) · cites this paper as [53]
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Self-citation
Metadata
- Authors
- Garaulet, M., Lee, Y.-C., Shen, J., Parnell, L. D., Arnett, D. K., Tsai, M. Y., Lai, C.-Q., & Ordovas, J. M.
- Affiliations
- Tufts University (US)
- Corresponding author
- Garaulet, Marta
- ORCID
- Venue
- The American Journal of Clinical Nutrition
- Publisher
- Elsevier BV
- Published
- 2009-12
- Volume
- 90
- Issue
- 6
- Pages
- 1466-1475
- ISSN
- 0002-9165 (ISSN-L)
- PMC
- PMC2777463
- OpenAlex
- W2119294761
- Cited by
- 172
- References
- 59
- Citations by year
- 2026: 2 · 2025: 9 · 2024: 9 · 2023: 15 · 2022: 8 · 2021: 6 · 2020: 12 · 2019: 3 · 2018: 5 · 2017: 9 · 2016: 15 · 2015: 14 · 2014: 16 · 2013: 16 · 2012: 12
- FWCI
- 6.40
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- American Journal of Clinical Nutrition (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Seneca Foundation (02934/PI/05)
- NIH (1R21AR055228-01A1, U01 HL72524, HL54776, DK075030)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Nutrition, Genetics, and Disease
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- clock genes, circadian rhythm, metabolic syndrome, monounsaturated fatty acids, oleic acid, red blood cell membrane fatty acids, dietary fatty acid intake, saturated fatty acids, insulin resistance, hypertension, obesity, gene-diet interaction
- MeSH terms
- Adult, Aged, Erythrocyte Membrane, Fatty Acids, Monounsaturated, Female, Genotype, Haplotypes, Humans, Insulin Resistance, Male, Middle Aged, Risk, Body Mass Index, Polymorphism, Single Nucleotide, Metabolic Syndrome, CLOCK Proteins
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