The Impacts of MTHFR C677T Variant (rs1801133) on Cardiometabolic Profiles and Early Onset Coronary Artery Disease: A Case–Control Study

Background: The MTHFR C677T polymorphism (rs1801133) is a well-documented genetic variant in cardiovascular research, yet its mechanistic role in early onset coronary artery disease (EOCAD) remains poorly characterized in East Asian populations. This study aimed to explore whether rs1801133 modulates EOCAD risk by altering proatherogenic cardiometabolic traits in the Chinese Han population. Methods: This rigorous case–control study enrolled 128 patients with angiographically confirmed EOCAD and 100 age- and sex-matched controls with nonobstructive coronary arteries. Standard enzymatic assays were used to detect blood lipid profiles and one-carbon metabolic markers. We constructed prediction models integrating conventional cardiometabolic risk factors with rs1801133. Model incremental performance was evaluated via integrated discrimination improvement (IDI) and net reclassification improvement (NRI), with 1000 bootstrap replicates for internal validation. Results: The rs1801133 T allele was significantly associated with higher EOCAD susceptibility. Compared with CC carriers, TT genotype individuals exhibited adverse cardiometabolic profiles, including elevated low-density lipoprotein cholesterol (LDL-C) (3.22 ± 0.48 vs. 2.83 ± 0.85 mmol/L, p < 0.05), systolic blood pressure (145.25 ± 25.28 vs. 133.03 ± 19.89 mmHg, p = 0.01), diastolic blood pressure (90.31 ± 15.56 vs. 85.68 ± 13.19 mmHg, p = 0.04), and homocysteine (16.98 ± 9.48 vs. 12.67 ± 4.47 μmol/L, p < 0.05). Receiver operating characteristic (ROC) analysis identified LDL-C as the dominant EOCAD predictor, and logistic regression confirmed rs1801133 as an independent risk factor. Adding rs1801133 to the base model significantly improved IDI (0.022, p = 0.012) and NRI (0.291, p = 0.040). Bootstrap validation with minimal model optimism (0.034–0.036) verified favorable internal stability. Conclusions: rs1801133 is a functional genetic determinant of EOCAD in the Chinese Han population. The TT genotype defines a high-risk subgroup aggravated by combined dyslipidemia and hyperhomocysteinemia. rs1801133 yielded significant incremental discrimination and reclassification value over traditional risk factors. These findings support personalized EOCAD risk stratification, highlighting intensive LDL-C management for T allele carriers as a promising early intervention strategy.