Trauma infantil y variantes en el gen MTHFR y su impacto en la susceptibilidad y el curso clínico de la depresión

Abstract

Introduction. Depression is a common, multifactorial disorder with a confluence of environmental and genetic factors. Environmental factors, such as adverse childhood experiences (ACEs), are recognized as robust risk factors for multiple mental health outcomes, including depression. Among the genetic factors, the folate pathway stands out: the MTHFR C677T variant (rs1801133) substitutes alanine for valine in the catalytic domain of methylenetetrahydrofolate reductase, generating a heat-labile enzyme whose activity decreases by approximately 35% for each T allele, thus altering folate metabolism and elevating homocysteine ​​levels. This dysfunction limits the synthesis of S-adenosylmethionine and monoaminergic neurotransmitters, offering a plausible biological substrate for depression; in fact, several meta-analyses have linked the 677T allele and the TT genotype with an increased risk of depression, although with heterogeneity among populations. A second variant, rs13306560, is located on a CpG island of the shared promoter region at the intergenic junction of MTHFR and CLCN6, and modulates MTHFR transcriptional activity. However, the combined contribution of autoimmune genetic associations (AIAs) and these variants to susceptibility to and clinical course of depression remains under-explored.

Objective. To evaluate the association of AIAs, the MTHFR variants rs1801133 and rs13306560, sex, and age with (i) case-control status for depression and (ii) time to first depressive episode among cases.

Methodology. Case-control genetic association study, reported according to STREGA criteria. Susceptibility was assessed in 428 participants using binomial logistic regression adjusted for age, sex (0=female, 1=male), AIE, MTHFR C677T (TT vs. non-TT), and rs13306560 (GG vs. AG). Prognosis was assessed in cases using multivariable Cox proportional hazards regression (30 events/200 patients), including AIE, MTHFR genotype, and sex as covariates. Adjusted odds ratios (OR) and hazard ratios (HR) with 95% confidence intervals (CI) are reported.

Results In the case-control analysis (N=428; R²McFadden=0.113), the following were independent predictors of depression: EAI (OR 2.68, p<0.001), older age (OR 1.028 per year, p<0.001), male sex as a protective factor against female sex (OR 0.36, p<0.001) and the MTHFR 677 TT genotype (OR 1.85, p=0.012); rs13306560 showed no association (OR 0.88, p=0.794). In the survival analysis, the overall model was significant (likelihood ratio test p=0.028; agreement 0.661): childhood adverse events more than doubled the risk of the event (adjusted HR 2.52; 95% CI 1.20–5.30; p=0.015), while neither the MTHFR genotype (HR 0.84 and 1.52; p>0.4) nor sex (HR 0.53, p=0.142) reached significance.

Conclusions. Childhood trauma was associated with both susceptibility to and a worse course of depression, reinforcing its role as an environmental adversity. The MTHFR 677 TT genotype was associated with susceptibility but not with prognosis, suggesting involvement in onset rather than progression; rs13306560 showed no association. The findings support the integration of psychosocial factors with folate pathway genotyping in risk stratification and should be confirmed in larger cohorts.