Carbohydrate-dependent interaction between AMY1A/AMY2B copy number variation and APOA5 rs651821 associated with hypertriglyceridemia in Korean middle-aged adults

BACKGROUND: Hypertriglyceridemia arises from complex interactions between genetic and dietary factors. AMY1A/AMY2B copy number variation (CNV) and APOA5 rs651821 have been associated with triglyceride metabolism, and their effects may be modified by carbohydrate intake. This study investigated the combined influence of AMY1A/AMY2B CNV, APOA5 rs651821, and dietary carbohydrate intake on the odds of hypertriglyceridemia in middle-aged Korean adults. METHODS: This cross-sectional study of 595 Korean adults from the Korean Genome and Epidemiology Study (KoGES) 2001-2002 evaluated amylase gene CNV and the APOA5 rs651821 single-nucleotide polymorphism (SNP) in relation to hypertriglyceridemia (triglyceride ≥ 150 mg/dL). A CNV segment encompassing AMY1A/AMY2B (chr1:104,144,265-104,220,453) and the APOA5 rs651821 SNP, which has previously been linked to hypertriglyceridemia, was selected for analysis. Participants were categorized into diploid and duplication CNV groups, as well as into TT and C-carrier SNP groups. Multivariable logistic regression was performed to assess the associations of CNV and SNP status with hypertriglyceridemia, adjusting for covariates. CNV-SNP interactions were examined using multiplicative and additive models to estimate odds ratios, confidence intervals (CI), and attributable proportions. Subgroup analyses, stratified by the median carbohydrate intake, were performed to evaluate the potential three-way interaction effects. RESULTS: In the fully adjusted model, the independent association of AMY1A/AMY2B duplication with hypertriglyceridemia was attenuated to a marginal trend, whereas APOA5 rs651821 C-carrier showed a significant independent association (OR = 2.00; 95% CI: 1.39-2.88). Compared with diploid × TT, the duplication × C-carrier group showed higher odds of hypertriglyceridemia (OR = 3.11; 95% CI: 1.69-5.72); however, multiplicative and additive two-way interaction metrics were not significant. In carbohydrate-stratified analyses, the duplication × C-carrier group showed the highest odds in the low-carbohydrate group (< median, 73.2% of energy: OR = 4.33; 95% CI: 1.78-10.56), whereas the corresponding association in the high-carbohydrate group (≥ median, 73.2% of energy) did not remain significant after FDR correction. The three-way interaction was nominally significant but did not remain significant after FDR correction. CONCLUSIONS: Although the independent effect of AMY1A/AMY2B CNV was attenuated by clinical covariates, its synergistic interaction with the APOA5 C allele remains a robust predictor of hypertriglyceridemia. AMY1A/AMY2B duplication may increase starch digestion and hepatic de novo lipogenesis, whereas the APOA5 C allele may be associated with reduced triglyceride clearance via impaired lipoprotein lipase activation.