CC genotype at TCF7L2 diabetes risk locus rs7903146 directs a coordinated fatty acid response to a Mediterranean diet intervention: a randomized controlled trial

Authors: Parnell, Laurence; Lai, Chao Qiang; HOLZAPFEL, CHRISTINA - Technical University Of Munich; CHRISTENSEN, JACOB - University Of Oslo; ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Lifestyle Genomics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/28/2024
Publication Date: 1/28/2025
Citation: Parnell, L.D., Lai, C., Holzapfel, C., Christensen, J.J., Ordovas, J.M. 2025. CC genotype at TCF7L2 diabetes risk locus rs7903146 directs a coordinated fatty acid response to a Mediterranean diet intervention: a randomized controlled trial. Lifestyle Genomics. https://doi.org/10.1159/000542468.
DOI: https://doi.org/10.1159/000542468

Interpretive Summary: A short-term feeding study was conducted with volunteers carrying a specific genetic variant known to affect type 2 diabetes risk. The volunteers were first put on a low-fat or Mediterranean diet for one week and then after about 10 days, switched to the alternate diet. Specific fat molecules in the blood were analyzed to identify differences based on the diet and the genetic variant. The analyses showed that individuals with a higher genetic risk for diabetes showed less coordinated regulation of fat molecules on either diet. However, individuals carrying the variant that offers some genetic protection against diabetes displayed a stronger coordination of these fats on the Mediterranean diet. These findings highlight that diet-genetic interactions can influence the body’s response to blood fat levels, potentially affecting risk of developing type 2 diabetes.

Technical Abstract: Background: Previous studies have identified genetic links between the TCF7L2 C/T variant rs7903146, type 2 diabetes (T2D), and obesity. We wished to deepen our understanding of how specific diets interact with this gene variant to affect blood metabolites, an aspect not previously investigated. To do this, we conducted a study where individuals with different genotypes followed a Mediterranean or low-fat diet for one week. Methods: The cohort was recruited from the Boston, MA (USA) area. Anthropometric and clinical measures were taken, and genotypes at rs7903146 were ascertained. Those homozygous carriers of the more common and protective CC or risk TT genotype were invited to participate. Each participant followed one of the diets (low-fat or Mediterranean) for one week, then swapped to the other diet after approximately 10 days of washout. Blood samples were taken before and after each diet for metabolomics analysis using nuclear magnetic resonance spectroscopy. We evaluated how the diet affected different metabolites based on genetic profile. Results: The cohort of 35 individuals was 43% female, aged 18 to 70 y, with body mass indices between 26.4 to 33.9 kg/m2. Focusing on fatty acids and other lipid metabolic factors (n = 23), we observed a greater number and stronger correlations among these factors in the CC genotype-Med diet group than the other three genotype-diet combinations. An aggregate of 11 factors, each negatively correlating with delta saturated fat (SFA), showed a significant genotype interaction on delta-SFA in CC individuals on the Med diet (P = 0.0046). A similar genotype interaction was observed for delta-monounsaturated fats (MUFA) (P = 0.0078). These interactions were not significant with the low-fat intervention. Conclusion: Our findings suggest that the Mediterranean diet has a stronger influence on the regulation of lipid factors in individuals with the CC genotype at rs7903146. This diet-genotype interaction may have significant implications for understanding and managing the risk of T2D.