TheCD40Gene Polymorphism rs1883832 Is Associated with Risk of Acute Coronary Syndrome in a Chinese Case–Control Study

Abstract

Numerous reports in the past few years have demonstrated that atherosclerosis is a lipid-driven, chronic inflammatory disease of the vessel. Recent studies have indicated that the immune mediator CD40-CD40L (CD40 ligand), which is expressed on several inflammatory cells within human atherosclerotic lesions, has roles in atherogenesis. A functional polymorphism (-1C>T, rs1883832) in the 5' untranslated region of TNFRSF5 gene has been reported to affect CD40 expression and be associated with several chronic inflammatory and autoimmune diseases. The aim of the present study was to validate the potential coronary artery disease susceptibility marker in a Chinese case-control study. A total of 160 patients with acute coronary syndrome (ACS) and 180 control subjects were used to genotype and identify this single-nucleotide polymorphism by polymerase chain reaction-restriction fragment length polymorphism and sequencing, respectively. Peripheral blood mononuclear cells were isolated and incubated with interferon-γ with or without pretreatment of fluvastatin, followed by measurement of CD40 expression using flow cytometry. In addition, soluble CD40L was determined by ELISA as another biomarker of coronary artery disease. The distribution of the rs1883832 genotypes (CC, CT, and TT) was 33.1%, 54.4%, and 12.5% in the ACS group and 22.8%, 53.3%, and 23.9% in controls, respectively. The frequency of the C allele was significantly higher among ACS patients compared with controls (60.3% vs. 49.4%, odds ratio=1.554, 95% confidence intervals: 1.146-2.107, p<0.05). ACS patients showed a significant increase of CD40 and sCD40L coexpression compared with controls (p<0.05). Cell culture experiments showed that CC carriers presented significantly higher CD40 expression levels than CT and TT subjects (p<0.05). Additionally, fluvastatin suppressed CD40 expression in all three genotypes. These data suggest that the single-nucleotide polymorphism of CD40 gene is associated with susceptibility to ACS in Chinese population, and the polymorphism may influence the CD40 production. These expand the understanding of inflammatory mechanisms during atherogenesis.

Association of CD40 -1C/T Polymorphism in the 5′-Untranslated Region with Chronic HBV Infection

“…In this study, we showed that the CD40 -1 C/T polymorphism can cause the alteration of CD40 translation on human B cells. The expression of CD40 in the individuals with TT genotype was significantly lower than those with CC and CT genotypes in both ASC and control groups, which is agreement with other studies [25,33]. Our findings that the frequency of TT genotype was significantly higher in ASC groups might be understood as follows: TT genotype of CD40-1C/T polymorphism decreases CD40 expression on cell surface as we and others confirmed.…”

“…Co., Ltd. Hangzhou, China). CD40-1C/T polymorphism was determined by polymerase chain reaction (PCR) and the analysis of restriction fragment lengths polymorphism (RFLP) as previously reported [25]. PCR was performed to amplified the 5'-untranslated region of CD40 using the following primers: 5'-GAAACTCCTGCGCGGTGAAT-3' and 5'-CCTCTTCCC- CGAAGTCTTCC-3' (NCBI Reference Sequence: NC_000020.11).…”

“…CD40-1 C/T polymorphism located in Kozak sequence can influence the initiation of CD40 translation [22], which was reported to be associated with the susceptability of many immune-related, chronic inflammatory diseases such as autoimmune thyroid disease, multiple sclerosis, coronary syndrome, etc [23,24,25,26]. But few studies have been found to focus on this polymorphism association with chronic HBV infections.…”

The SNP rs1883832 in CD40 Gene and Risk of Atherosclerosis in Chinese Population: A Meta-Analysis

“…Ultimately, 7 studies (5 on coronary artery disease [CAD] and 2 on ischemic stroke [IS]) involving a total of 4024 subjects (2129 patients and 1895 controls) met our criteria and were included in this meta-analytical study [6], [7], [13]–[17]. The corresponding authors of our included studies were contacted and they confirmed that there were no duplicate results utilized in multiple studies to be deleted.…”

“…In Grave’s disease, up-regulation of CD40 by rs1883832 places an individual at an increased disease risk [28]. Similarly, C allele appeared to contribute to the over-expression of CD40 on not only platelets which are central to the formation of thrombosis in ACS patients, but also B lymphocytes and monocytes [7], [15], [17]. C allele is also positively associated with an increased risk of rupture of complex coronary atherosclerotic plagues underlying ACS [17].…”