When Genetics Meets the Mediterranean Diet Across Metabolic Diseases

Metabolic diseases and related cardiometabolic conditions, including type 2 diabetes (T2D), obesity, metabolic syndrome (MetS), and metabolic dysfunction-associated steatotic liver disease (MASLD), arise from complex interactions between genetic predisposition and environmental factors. Among dietary patterns, the Mediterranean diet (MedDiet) has consistently been associated with improved metabolic health and a reduced risk of cardiometabolic diseases. However, substantial interindividual variability in metabolic responses to dietary exposures suggests that genetic susceptibility may contribute to differences in response to the MedDiet. Over the past two decades, nutrigenetic research has investigated whether adherence to the MedDiet can modify the effects of genetic variants associated with metabolic risk. Initial studies focused primarily on candidate genes involved in glucose metabolism, adiposity regulation, circadian rhythms, and hepatic lipid metabolism, including variants in genes such as TCF7L2, FTO, CLOCK, ADIPOQ, and PNPLA3. More recently, research has expanded to genetic risk score and polygenic risk score approaches, providing a broader assessment of inherited susceptibility. This literature review summarizes current evidence on MedDiet-gene interactions in T2D, obesity, MetS, MASLD, and related cardiometabolic traits, highlighting the transition from candidate-gene approaches to aggregate genetic risk models. Overall, the available literature suggests that the beneficial effects of the MedDiet are observed across different levels of genetic susceptibility, whereas evidence supporting clinically relevant gene-diet interactions remains heterogeneous and limited. Further large-scale, multi-ancestry, and well-designed prospective studies are needed before genetically tailored MedDiet recommendations can be routinely implemented in clinical practice.