Interaction of Genetics and Dietary Patterns Scored by the High Healthy Eating Index in Hyperhomocysteinaemia Influencing Cardiovascular Disease Risk

Hyperhomocysteinaemia has been associated with increased cardiovascular disease (CVD) risk, but the complex interplay between genetic determinants and modifiable lifestyle factors in modulating homocysteine (HC) levels remains incompletely understood. We aimed to investigate the aetiology of hyperhomocysteinaemia by examining the interactions between genetic predisposition, dietary patterns and other lifestyle factors and their potential associations with metabolic syndrome (MetS) and CVD risk. Cross-sectional analysis from the Korean Genome and Epidemiology Study, a hospital-based cohort conducted by the Korean Centers for Disease Control and Prevention from 2012 to 2016. Korean adults (n = 62 743, aged 40-79 years) were categorised into Low-HC (n = 53 450) and High-HC (n = 9293) groups based on a 15 μM serum homocysteine cutoff. Demographic, anthropometric and biochemical data were analysed. Genome-wide association and gene-environment interaction models explored genetic variants influencing hyperhomocysteinaemia and their interplay with lifestyle factors, including nutrient intake. Multivariable logistic regression assessed associations between hyperhomocysteinaemia and metabolic/CVD risks, adjusting for covariates. Genetic variant-environment interaction analyses identified genetic determinants and their interactions with diet/lifestyle. The High-HC group exhibited an elevated MetS risk. Hyperhomocysteinaemia was correlated with liver damage, inflammation and CVD risks. Low vitamin B12 intake (< 5.4 μg/day) showed a stronger association with hyperhomocysteinaemia than low folate intake (< 350 μg/day), with combined deficiencies exacerbating hyperhomocysteinaemia. An inverse relationship was observed between hyperhomocysteinaemia and healthy eating indices like Asian balanced and plant-based diets. Variants in MTHFR, NOX4, PLOD1, MIIP, PAX6 and CBS genes, involved in methionine/cysteine metabolism, exhibited differential expression in skeletal muscle, liver and adipose tissues. High polygenic risk scores interacted with poor diet quality, excess energy intake, a high glycemic index, smoking and heavy alcohol consumption to contribute to hyperhomocysteinaemia. In conclusion, these findings elucidate the complex interplay between genetics, diet and lifestyle in modulating homocysteine levels, providing insights for personalised nutrition strategies to mitigate CVD risk.