Progress in understanding the genetic underpinning of coronary artery disease: from genotype to phenotype

Abstract Background The functional dissection of genetic risk opens the door to strategies for pharmacological manipulation of molecular and cellular processes implicated in human diseases, including coronary artery disease (CAD). Aim To assess the relationship between a set of single nucleotide polymorphisms previously associated with CAD and coronary artery calcium (CAC) score in an asymptomatic population from Portugal. Methods Prospective study in a cohort of 1,284 subjects aged 59.3±8.9 years, 73.6% males without apparent CAD. The CAC score was performed by cardiac computed tomography and reported as Agatston units according to the Hoff nomogram. Anthropometric, conventional, and biochemical risk factors were evaluated. Thirty-three single nucleotide polymorphisms were genotyped by TaqMan real-time PCR. Bivariate and multivariate logistic regression analysis estimated variables associated with the CAC score. Results After bivariate analysis, 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 in the locus 9p21.3 (p=0.002) and rs1333049 G>C (p=0.010). MTHFD1L gene encodes a mitochondrial enzyme responsible for homocysteine remethylating in methionine, and rs6922269 G>A showed protection against artery calcification (p=0.013). After multivariate logistic regression, PHACTR1 rs1332844 (CT+TT) (p=0.009) and CDKN2B-AS1 rs4977574 A>G (GG) (p=0.002) remained in the equation as independently associated with arterial calcification, together with male sex (p=0.039), age (p<0.0001), hypertension (p=0.001), diabetes (p<0.0001), smoking status (p<0.0001) and obesity (p=0.020). MTHFD1L rs6922269 AA also remained as significant protection from arterial calcification (p=0.027). Conclusion The present work showed two genetic variants, PHACTR1 and CDKN2B-AS1, linked to arterial wall calcification, herewith clinical and environmental risk factors. MTHFD1L showed protection. Understanding the genetic basis of vessel calcification can enable lifestyle changes or pharmacologic therapy to attenuate risk before the disease becomes clinic. More research in this field is critical to understanding the genetic basis of CAD through an intermediate phenotype, coronary arterial wall calcification.