Enhanced risk for recurrent adverse cardiovascular events in homozygous carriers of the T-allele of CD40 SNP rs1883832.
Source: PubMed, NCBI / U.S. National Library of Medicine
The co-stimulatory signaling dyad of CD40 and CD40L is 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. Here, we interrogate whether this CD40 gene variant correlates with recurrent cardiovascular events after acute coronary syndromes. The Biomarkers in Acute Cardiac Care (BACC) cohort prospectively enrolled patients presenting to the emergency department with acute chest pain and suspected myocardial infarction. Genotype status (homozygous C/C or T/T, heterozygous: C/T) was determined by a TaqMan assay in 1298 patients with either confirmation of or ruled out acute myocardial infarction (AMI). The CD40 genotype-adjusted risk for major adverse cardiovascular events (MACE) during a median follow-up time of 5.2 years was studied by multivariate Cox regression. 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) in logistic regression analysis. MACE occurred more often in patients with the T/T genotype (HR 1.46, 95% CI 1.01-2.11, p = 0.046
Abstract
The co-stimulatory signaling dyad of CD40 and CD40L is 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. Here, we interrogate whether this CD40 gene variant correlates with recurrent cardiovascular events after acute coronary syndromes. The Biomarkers in Acute Cardiac Care (BACC) cohort prospectively enrolled patients presenting to the emergency department with acute chest pain and suspected myocardial infarction. Genotype status (homozygous C/C or T/T, heterozygous: C/T) was determined by a TaqMan assay in 1298 patients with either confirmation of or ruled out acute myocardial infarction (AMI). The CD40 genotype-adjusted risk for major adverse cardiovascular events (MACE) during a median follow-up time of 5.2 years was studied by multivariate Cox regression. 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) in logistic regression analysis. 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 age, sex, diabetes mellitus, hyperlipoproteinemia, arterial hypertension, smoking status and left ventricular ejection fraction in multivariable regression. 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 potentially protective role of CD40 in high-risk patients.