PO74 Association between TCF21 rs12190287 polymorphism and Coronary Heart Disease. Could it be regarded as a promising treatment for heart disease?

Background TCF21 gene is a transcription factor controlling cell fate decisions in the developing epicardium. SNP rs12190287 (C allele) tends to reduce TCF21 expression in vascular smooth-muscle cells (SMCs), leading to fewer SMCs undergoing a phenotypic switch to fibromyocytes, with diminished fibrous and thinner caps, making them more prone to rupture. So, it is linked to an increased risk of coronary heart disease (CHD). However, the molecular mechanisms of TCF21 in CHD remain fundamentally problematic. Aim Evaluate the association between the TCF21 rs12190287 G>C polymorphism and CHD in a Southern European population. Methods We performed a case-control study with 3209 participants, 1722 coronary patients with more than 75% coronary obstruction (mean age 53.3±7.9;78.8% male). Controls were selected from electoral rolls to be similar according to age and gender. Genotype and allele distribution between groups with and without coronary obstruction were determined. The dominant genetic model (heterozygous GC plus homozygous CC) and the recessive and allelic model were constructed and compared to wild-type GG to assess CHD. Bivariate and multivariate analyses were performed. Finally, the Cox regression model, adjusted for significant risk factors and the best genetic model, assessed which variables were independently associated with CHD events. Kaplan Meier estimated events survival. Results In the bivariate analysis, coronary patients presented a higher percentage of risk factors compared to controls, namely physical inactivity 62.5% vs. 42.2%; current smoker 47.4% vs. 24.2%; obesity 34.3% vs. 28.2%; hypertension 70.8% vs 50.6%; dyslipidemia 94.4% vs. 69.9% and diabetes 35.3% vs. 14.1% (all p<0.0001). Regarding genetic models, the dominant model was observed in 90.5% of patients and 88.1% of controls, while the recessive model was observed in 47.3% of patients and 41.7% of controls. The dominant model was considered the best for further analysis. Logistic regression analysis disclosed physical inactivity (OR=1.77;p<0.0001), current smoker (OR=3.03;p<0.0001), hypertension (OR=1.91;p<0.0001), dyslipidemia (OR=5.42;p<0.0001), diabetes (OR=2.68;p<0.0001) and TCF21 dominant model (OR=1.38;p=0.013). After Cox regression, physical inactivity (HR=1.38;p<0.0001), diabetes (HR=1.19;p=0.029) and TCF21 (dominant model) (HR=1.44;p=0.012) remained as independently associated to CHD. Kaplan-Meier showed that risk allele carriers had worse survival-free event time. Conclusions Our findings show that TCF21 rs12190287 G>C was associated with CHD risk in our population. This work suggests that TCF21 (G wild-type) functions as a protective factor by promoting VSMC transition to fibroblast-like cells in the lesion and fibrous cap. Modulation of TCF21 expression or its downstream targets could provide novel therapeutic options for ischemic and fibrotic heart diseases. Though regenerative medicine could be regarded as a promising treatment for heart disease.