Cheryl S Sultan1, Michael Weitnauer2, Martin Turinsky1, Thorsten Kessler3, Maik Brune4, Christian A Gleissner5, Florian Leuschner5, Andreas H Wagner1, Markus Hecker1. 1. Department of Cardiovascular Physiology, Institute of Physiology and Pathophysiology, Heidelberg University, Im Neuenheimer Feld 326, 69120 Heidelberg, Germany. 2. Department of Medical Microbiology and Hygiene, Heidelberg University, Heidelberg, Germany. 3. German Heart Centre Munich, Technical University Munich, Munich, Germany. 4. Department of Internal Medicine 1 and Clinical Chemistry, Heidelberg University, Heidelberg, Germany. 5. Department of Cardiology, Angiology and Pneumology, Heidelberg University, Heidelberg, Germany.
Abstract
AIMS: Endothelial dysfunction is a major contributor to the pathogenesis of atherosclerosis. CD40-CD40 ligand interactions confer a pro-inflammatory phenotype to endothelial cells (ECs). Recently, a thymine to cytosine transition (-1T>C) in the Kozak sequence of the CD40 gene (rs1883832) has been associated with coronary heart disease (CHD) in an Asian population. As there are no reports yet regarding its role in other ethnic groups, this study determines if the -1T>C single-nucleotide polymorphism (SNP) could be a risk factor for CHD in Caucasians by performing an association study and elucidates its functional consequence in cultured ECs. METHODS AND RESULTS: Molecular and biochemical techniques, cell adhesion assays were used for genotype-stratified human EC characterization. SNP distribution in Caucasians was examined in a hospital-based case-control CHD study and serum levels of soluble CD40 (sCD40) were quantified by ELISA. The SNP in the CD40 gene affected baseline CD40 protein abundance on ECs. There was a genotype-dependent difference in CD40-mediated expression of pro-inflammatory genes. Monocyte adhesion was highest on the surface of cells homozygous for the C allele. Homozygosity for the C allele was associated with significant 2.32-fold higher odds of developing CHD as compared to TT genotype carriers. sCD40 plasma levels were genotype-dependently elevated in CHD patients, indicating a possible prognostic value. CONCLUSION: The C allele of the CD40 SNP provokes a pro-inflammatory EC phenotype, compensated by an enhanced CD40 shedding to neutralize excess CD40 ligand. Homozygosity for the C allele is the cause for a genetic susceptibility to atherosclerosis and its sequelae. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Endothelial dysfunction is a major contributor to the pathogenesis of atherosclerosis. CD40-CD40 ligand interactions confer a pro-inflammatory phenotype to endothelial cells (ECs). Recently, a thymine to cytosine transition (-1T>C) in the Kozak sequence of the CD40 gene (rs1883832) has been associated with coronary heart disease (CHD) in an Asian population. As there are no reports yet regarding its role in other ethnic groups, this study determines if the -1T>C single-nucleotide polymorphism (SNP) could be a risk factor for CHD in Caucasians by performing an association study and elucidates its functional consequence in cultured ECs. METHODS AND RESULTS: Molecular and biochemical techniques, cell adhesion assays were used for genotype-stratified human EC characterization. SNP distribution in Caucasians was examined in a hospital-based case-control CHD study and serum levels of soluble CD40 (sCD40) were quantified by ELISA. The SNP in the CD40 gene affected baseline CD40 protein abundance on ECs. There was a genotype-dependent difference in CD40-mediated expression of pro-inflammatory genes. Monocyte adhesion was highest on the surface of cells homozygous for the C allele. Homozygosity for the C allele was associated with significant 2.32-fold higher odds of developing CHD as compared to TT genotype carriers. sCD40 plasma levels were genotype-dependently elevated in CHD patients, indicating a possible prognostic value. CONCLUSION: The C allele of the CD40 SNP provokes a pro-inflammatory EC phenotype, compensated by an enhanced CD40 shedding to neutralize excess CD40 ligand. Homozygosity for the C allele is the cause for a genetic susceptibility to atherosclerosis and its sequelae. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Laura A Bosmans; Lena Bosch; Pascal J H Kusters; Esther Lutgens; Tom T P Seijkens Journal: J Cardiovasc Transl Res Date: 2020-03-28 Impact factor: 4.132