Exploring the impact of the GJA4 rs618675 variant on cardiovascular prevention

The gap junction alpha-4 (GJA4) gene, which encodes connexin37, regulates endothelial function and influences inflammation, platelet adhesion, and thrombus formation in vascular endothelial cells, which may favour atherosclerosis and cardiovascular (CV) events. The main objective was to assess whether the GJA4 rs618675 T>C variant is a risk factor for the onset of CV events in an asymptomatic Portuguese population.

One thousand four hundred twenty-one individuals without CV disease (52.2±8.3 years, 73.6% male) were followed up during a mean of 7.3±6.0 years, and CV events were recorded. GJA4 rs618675 T>C was genotyped by real-time PCR (TaqMan), and four genetic models were created. We analyzed traditional, biochemical and clinical risk factors. We performed bivariate analysis and adjusted logistic regression with respective OR. Kaplan-Meier estimated event-free survival and Cox regression, adjusted for confounding, evaluated the association between four genetic models and CV events (HR).

Wild TT genotype, TC, and CC were 50.6%, 39.2%, and 10.1% in the CV events group and 66.2%, 30.4% and 3.4% in the non-events group (p=0.001). After logistic regression, the codominant model (CCvsTT and CTvsTT) showed an OR of 3.9 (p=0.002). Kaplan-Meier showed 87.6% event-free time for TT and 64.8% for CC (p=0.005). Adjusted Cox regression identified the codominant model as the best predictor (HR=2.8; p=0.008), together with male gender (HR=2.1; p=0.020), age (HR=1.1; p=0.001), hypertension (HR=1.9; p=0.014), smoking (HR=1.9; p=0.010), and leukocytosis (HR=1.2; p=0.003).

We have demonstrated that the CC variant of GJA4 is significantly associated with CV events. Further investigations into this biomarker may improve CV risk prediction, leading to better primary prevention.