The RAGE Glycine 82 Serine Polymorphism and Cardiovascular Disease in Rheumatoid Arthritis.

Carroll, Lisa (2007). The RAGE Glycine 82 Serine Polymorphism and Cardiovascular Disease in Rheumatoid Arthritis. MPhil Thesis, School of Medicine, University of Queensland.

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Author Carroll, Lisa
Thesis Title The RAGE Glycine 82 Serine Polymorphism and Cardiovascular Disease in Rheumatoid Arthritis.
School, Centre or Institute School of Medicine
Institution University of Queensland
Publication date 2007
Thesis type MPhil Thesis
Supervisor Associate Professor Ranjeny Thomas
Subjects 1102 Cardiovascular Medicine and Haematology
Abstract/Summary Over the last few decades, the importance of inflammation in the initiation and perpetuation of cardiovascular (CV) disease has become increasingly recognized. Patients with Rheumatoid Arthritis (RA) have been shown to have an increased risk of premature death, occurring predominantly due to an increased rate of premature CV disease. The presence of an adverse risk factor profile in RA is well established, but does not fully explain the excess risk. It is clear that chronic inflammation is a major pathogenic mechanism in atherosclerosis, and this is likely to explain at least some of the increased risk of CV disease in subjects with RA. Carotid intima-media thickness (cIMT) measured by ultrasound, is a good non-invasive approach to measurement of atherosclerotic burden, and is increased in preclinical atherosclerotic disease. cIMT is significantly higher in patients with RA than age and sex matched controls. The Receptor for Advanced Glycation End Products (RAGE) may be important for the perpetuation of chronic inflammation. This cell surface receptor molecule is upregulated at sites of chronic vascular inflammation, and can be signalled by a range of proinflammatory ligands as well as advanced glycation end-products. The gene has a number of polymorphisms, and the Glycine 82 Serine polymorphism has a prevalence of about 10% in Caucasians. Patients with RA are more likely to have this polymorphism than control subjects, as the gene is in linkage disequilibrium with DRB1*0401, one of the RA susceptibility alleles. There is evidence that ligation of RAGE in monocytes derived from donors with the Ser 82 allele signals an enhanced NF-kB and p38 MAP Kinase cellular response, associated with production of pro-inflammatory cytokines. In this study, I hypothesized an association between the RAGE 82 Ser polymorphism of this receptor, which is enriched in RA, and the risk of CV disease in subjects with RA. To investigate whether RAGE 82Ser is associated with CV disease in RA, I examined events, risk factors, features of RA and RAGE 82Ser, in 232 patients with RA attending a tertiary referral hospital. Carotid intima-media thickness was measured using carotid duplex scanning in 137 of those patients. CV events, duration and severity of RA, and CV disease risk factors were determined using patient questionnaires, chart review, laboratory analysis, and radiographs. DNA was typed for HLA-DRB1 genes and the RAGE 82Ser polymorphism. Twenty percent of patients carried the RAGE 82Ser allele. More than 20% of the cohort had suffered a vascular event. Increasing age, elevated fasting glucose, a history of hypercholesterolemia, and a shorter duration of RA were significantly associated with events. RAGE 82Ser was protective against CV events in this cohort. RA patients with RAGE 82Ser had lower LDL levels and LDL/HDL ratio. cIMT was independently and significantly associated with increasing age, male sex, hypertension, low BMI, and the number of pack years of smoking, but not RAGE genotype. Multiple factors, both CV and RA disease-related, contribute to atherosclerosis in established RA. These data suggest RAGE genotype may contribute to the risk of CV events in RA. The role of RAGE genotype requires further study in inception cohorts examining CV events to better understand its contribution to RA-associated CV disease.
Keyword Arthritis
Rheumatoid; Cardiovascular Diseases; Advanced Glycation End-Product Receptor;

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Created: Fri, 21 Nov 2008, 16:06:38 EST