Cardiovascular disease remains the main cause of death in Portugal 1, and risk stratification, with identification of individuals at risk, is still an unfinished challenge of contemporary medicine.

The Gap Junction Alpha-4 (GJA4) gene and its encoded protein, connexin 37 (Cx37), were associated with adverse outcomes in the Framingham Heart Study 3, and later in other cohorts 4. Cx37 is a gap junction protein expressed in endothelial cells, macrophages, and platelets. It helps protect against atherosclerosis by preventing monocyte adhesion and regulating endothelial cell growth, controlling endothelial permeability, and limiting inappropriate blood clot formation by downregulating platelet reactivity 5. The GJA4 rs618675 T>C single-nucleotide polymorphism has previously been identified as significantly associated with an increased risk of cardiovascular events.

In this cohort of 1421 randomly selected adults from Madeira with no apparent cardiovascular disease, followed for an average of 7.3±6.0 years, Mendonça et al. report higher rates of cardiovascular events ̶ including a composite of nonfatal myocardial infarction, unstable angina, percutaneous coronary intervention or coronary artery bypass grafting, nonfatal stroke, transient ischemic attack, peripheral arterial disease, hospitalization due to heart failure, and cardiovascular death ̶ among carriers of the CC genotype (adjusted hazard ratio=2.81, 95%CI 1.31-6.04, p=0.008; adjusted for sex, age, hypertension, diabetes, smoking status, homocysteine, hs-CRP, and leucocytes) and the TC genotype (adjusted hazard ratio=1.57, 95%CI 0.98-2.51, p=0.064) 6.

This finding is noteworthy because GJA4 rs617586 appears to enhance the predictive value when combined with traditional predictors and biomarkers associated with diverse atherosclerotic plaque-related phenomena. The authors postulate that adding the GJA4 rs617586 variant to SCORE2 could potentially enhance conventional cardiovascular risk prediction by capturing lifelong genetic susceptibility and vascular dysfunction, among other mechanisms not represented in classical risk factors 1,2,7.

This is an interesting study that takes advantage of Madeira's ideal genetic laboratory features: settled in the 15th century, its population includes a unique mix of European (mostly Portuguese) settlers, Sephardic Jews, North Africans, and Sub-Saharan Africans, along with a degree of geographic isolation over the last 500 years. Despite including no patients with prior cardiovascular events and a relatively low mean age (52.2±8.3 years), the prevalence of classical risk factors was high: dyslipidaemia in 69.7%, hypertension in 50.7%, diabetes in 13.7%, physical inactivity in 41.9%, alcohol consumption of>300g per week (27 standard drinks per week) in 13.0%, and BMI ≥ 30kg/m2 in 28.5%. Interestingly, despite the considerable follow-up duration, the broad composite endpoint, and high baseline clinical risk, the event rate was low: 5.6%, with 79 patients sustaining events.

Future studies utilizing larger samples and more comprehensive genotyping chips could possibly explore other genetic variants of interest related to cardiovascular disease. Extending the follow-up duration to obtain higher event rates—thereby allowing analysis and development of risk predictors for the individual components of the utilized composite endpoint—focusing on other forms of cardiovascular disease, such as atrial fibrillation, heart valve disease, and aortic syndromes, and addressing major sources of non-cardiovascular comorbidity 8 may provide more detailed and personalized risk prediction calculators for the population of the Island.

Further research into the upstream and downstream pathways of Cx37, using data from Reactome (a free, peer-reviewed, and manually curated knowledge base for biological pathways), suggests that interest in this compound extends beyond prognostication. There are potential associated targets of interest, such as OPRM1 (opioid receptor mu 1) 9 and TMEM86B (transmembrane protein 86B), with the former having 88 potential drugs and clinical candidates listed in the Open Targets Platform10.

The link between GJA4/Cx37 and cardiovascular disease is not new, but this study by Mendonça et al. reminds us that there is still a lot that remains to be explored and understood.