MON-598 - Association Between Folate Cycle Gene Risk Alleles, Serotonin Alterations, and Biomarkers of Neuropsychiatric Risk in the Post-COVID Period

Background: Polymorphisms in folate cycle enzyme genes affect one-carbon methylation capacity, homocysteine (Hcy) metabolism, and monoamine neurotransmitter synthesis, potentially modulating neuropsychiatric vulnerability. Post-COVID syndrome represents a relevant model for evaluating gene–metabolite–neuropsychiatric interactions under persistent inflammation and coagulation dysregulation.

Objective: To assess the associations between risk alleles of MTHFR 677C>T, MTHFR 1298A>C, MTRR 66A>G, and MTR 2756A>G and serum Hcy, folate, coagulation markers, and neuropsychiatric outcomes in post-COVID patients.

Methods: A total of 69 post-COVID patients were genotyped for MTHFR 677C>T and MTHFR 1298A>C, and 65 patients for MTRR 66A>G and MTR 2756A>G. Genotype-based subgroups were formed. Serum Hcy, folate, D-dimer, CRP, and ESR levels were measured. Cognitive function, anxiety, and depression were assessed using validated questionnaires in a subset of 42–51 patients. Patients with T2DM were analyzed as a comorbidity subgroup. ANOVA and Pearson correlation were applied; a p-value < 0.05 was considered significant.

Results: MTHFR 1298 C/C homozygotes exhibited significantly elevated Hcy (19.56±1.89 µmol/L) compared with A/A (10.68±0.76; p=0.012) and A/C (11.63±1.25; p=0.013), higher BMI (33.83±0.72 kg/m²; p< 0.002), and a greater prevalence of hypertension (85%), heart failure (67%), and T2DM (66%). D-dimer was significantly higher in C/C carriers (747.2±45.2 ng FEU/mL) compared with A/A (402.6±75.6; p< 0.002) and A/C (290.8±39.7; p< 0.002), indicating increased coagulation activation.
MTRR 66 G/G homozygotes showed higher Hcy (16.56±1.64 µmol/L) compared with A/A (10.28±1.17; p=0.004) and A/G (11.32±1.17; p=0.013), longer hospitalization (17.15±1.65 vs 11.88±0.97 days; p=0.008), and higher rates of hypertension (67% vs 35%) and heart failure (67% vs 29%).
The MTHFR 677 T/T genotype was associated with elevated D-dimer (752.25±125 ng FEU/mL) and CRP (58.50±12.52 ng/mL) compared with C/C and C/T subgroups, reflecting thromboinflammatory activation.
In patients with T2DM, a significant inverse correlation between serum folate and Hcy was observed (r=–0.30; p< 0.05). No significant differences in cognitive function, anxiety, or depression scores were found across genotype subgroups for any polymorphism (all p>0.05).

Conclusions: Homozygous risk genotypes MTHFR 1298 C/C and MTRR 66 G/G are independently associated with hyperhomocysteinemia, prothrombotic activation, and increased cardiometabolic burden in post-COVID patients. Although no direct effects on psychometric outcomes were observed, the biomarker profile-elevated Hcy, D-dimer, and CRP-represents a plausible link between folate cycle dysfunction and neuropsychiatric risk. Larger studies with integrated assessment of serotonin pathways are warranted.

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