Enhanced risk for recurrent adverse cardiovascular events in homozygous carriers of the T-allele of CD40 SNP rs1883832

Background The co-stimulatory signaling dyad of CD40 and CD40L is known as a potent inducer of cardiovascular inflammation and vulnerability of atherosclerotic plaques. A cytosine-to-thymidine transition (-1C>T) in the Kozak sequence of the CD40 gene (rs1883832) lowers CD40 protein expression. The clinical implications of this variant in patients with acute coronary syndrome remains unkown. Purpose To determine whether CD40 rs1883832 genotypes are associated with acute myocardial infarction (AMI) at presentation and long-term major adverse cardiovascular events (MACE). Methods In the prospective Biomarkers in Acute Cardiac Care (BACC) cohort, 1,298 patients presenting with acute chest pain were genotyped for rs1883832 using a TaqMan assay (C/C, C/T, T/T). Patients were followed up to 7 years on a census-based system for the occurrence of MACE, defined as a composite of cardiovascular mortality, acute myocardial infarction, coronary revascularization, and hospitalization due to cardiac disease. The genotype-adjusted risk for MACE was tested using multivariable cox regression analysis. Associations between CD40 genotypes, presence of cardiovascular risk factors and confirmation of AMI were assessed by logistic regression. Results Relative abundances of the genotypes among all participants were 55.8% for C/C, 37.1% for C/T, and 7.2% for T/T. None of the genotype variants was associated with diabetes, hypertension, hyperlipoproteinemia, or a history of coronary artery disease (CAD). T/T carriers showed a strong trend towards an increased sex- and age-adjusted risk for AMI at admission (OR 1.58, 95% CI 0.95-2.64, p=0.078) and had a significantly increased risk for a composite endpoint of confirmed AMI and a history of previous AMI (OR 1.66 95% CI 1.04-2.65, p=0.035) in logistic regression analysis. During a median follow-up period of 5.2 years MACE occurred more often in patients with the T/T genotype (HR 1.46, 95% CI 1.01-2.11, p=0.046) compared to C/T (HR 0.96, 95% CI 0.77-1.19, p=0.70) and C/C (HR 0.94, 95% CI 0.76-1.16, p=0.54) carriers. This effect was independent of diabetes mellitus, hyperlipoproteinemia, arterial hypertension, smoking status and left ventricular ejection fraction in multivariable regression analysis. Conclusion Our data indicate that – unexpectedly – the T/T genotype of rs1883832 is associated with an enhanced risk for myocardial infarction and subsequent MACE. As this SNP impedes effective CD40 translation, our findings suggest a previously unrecognized protective dimension of CD40 signalling in human cardiovascular disease.