Unraveling the genetic basis of subclinical atherosclerosis: Early genetic detection can improve cardiovascular prevention

Decoding the genetic basis of coronary artery disease (CAD) through an intermediate phenotype - coronary calcification - can help us to better understand this deadly disease and enable the creation of better therapeutic strategies. This work aims to assess the relationship between a set of single nucleotide polymorphisms (SNPs) previously associated with CAD and coronary artery calcium (CAC) score in a Portuguese asymptomatic population. A prospective study was conducted in a cohort of 1284 subjects (aged 59.3±8.9 years, 73.6% males) without CAD. CAC score was performed using cardiac computed tomography. Thirty-three SNPs were genotyped using TaqMan real-time PCR. Anthropometric, conventional, and biochemical risk factors were evaluated. Bivariate and multivariate regression analysis estimated variables associated with the CAC score. PHACTR1 rs1332844 C>T, a downstream regulator of the endothelin-1 gene, showed a significant association with CAC score (p=0.015), together with CDKN2B-AS1 variants rs4977574 A>G (p=0.002) and rs1333049 G>C (p=0.010) in the 9p21.3 locus. MTHFD1L rs6922269 G>A variant encoding a mitochondrial enzyme responsible for homocysteine remethylating showed protection against artery calcification (p=0.013). After multivariate logistic regression, PHACTR1 rs1332844 (CT+TT) (OR=1.478;p=0.009) and CDKN2B-AS1 rs4977574 (GG) (OR=1.479;p=0.002) remained in the equation as independently associated with arterial calcification. MTHFD1L rs6922269 (AA) also remained associated with a lower CAC score (OR=0.558;p=0.027). This study showed that three genetic variants previously linked with CAD are associated with CAC in asymptomatic populations. Understanding these genetic factors, combined with conventional risk factors, could guide lifestyle changes or pharmacologic interventions to mitigate CAD risk before the disease becomes clinical.