Maira Giannelou1, Andrianos Nezos2, Sofia Fragkioudaki3, Dimitra Kasara4, Kyriaki Maselou5, Nikolaos Drakoulis6, Dimitris Ioakeimidis7, Haralampos M Moutsopoulos8, Clio P Mavragani9. 1. Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, Greece; Department of Rheumatology, General Hospital of Athens "G.Gennimatas", Greece. Electronic address: apomayr@windtools.gr. 2. Department of Physiology, School of Medicine, National and Kapodistrian University of Athens, Greece. Electronic address: anezos@med.uoa.gr. 3. Department of Physiology, School of Medicine, National and Kapodistrian University of Athens, Greece. Electronic address: sofiefrag@med.uoa.gr. 4. Department of Rheumatology, General Hospital of Athens "G.Gennimatas", Greece. 5. Department of Immunology, General Hospital of Athens, "G.Gennimatas", Greece. 6. Department of Pharmaceutical Technology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece. Electronic address: drakoulis@pharm.uoa.gr. 7. Department of Rheumatology, General Hospital of Athens "G.Gennimatas", Greece. Electronic address: dioakim@otenet.gr. 8. Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, Greece. Electronic address: hmoutsop@med.uoa.gr. 9. Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, Greece; Department of Physiology, School of Medicine, National and Kapodistrian University of Athens, Greece; Joint Academic Rheumatology Program, National and Kapodistrian University of Athens School of Medicine, Athens, Greece. Electronic address: kmauragan@med.uoa.gr.
Abstract
OBJECTIVE: Elevated concentrations of homocysteine have been previously identified as an independent risk factor for subclinical atherosclerosis in patients with systemic lupus erythematosus (SLE). Given that heightened homocysteine levels are known to be strongly influenced by genetic factors, in the current study we investigated the contribution of high homocysteine levels as well as of functional polymorphisms of the gene encoding for the enzyme 5, 10- methylenetetrahydrofolate reductase (MTHFR) to atherosclerotic disease characterizing SLE patients. METHODS: Peripheral DNA samples from 150 SLE patients, 214 rheumatoid arthritis (RA) patients and 561 age/sex matched apparently healthy volunteers (HC) were genotyped by PCR-based assays for the detection of the MTHFR gene polymorphisms (c. 677C > T and c. 1298A > C). All SLE patients and 30 age sex matched RA patients underwent assessment for subclinical atherosclerosis [ultrasound measurement of intima-media thickness scores (IMT) and detection of carotid and/or femoral (C/F) plaque] and complete clinical and laboratory evaluation including serum homocysteine levels. Data were analyzed using univariate and multivariate models (SPSS 21.0). RESULTS: Hyperhomocysteinemia was detected in 26.0% of SLE patients compared to 6.7% of age/sex matched RA controls (p = 0.02). Higher serum B12 levels and decreased frequency of the MTHFR 677TT variant in RA patients could potentially account for the observed differences between the groups. In SLE patients, both hyperhomocysteinemia and MTHFR 677TT genotype were identified as independent contributors for plaque formation, following adjustment for traditional cardiovascular risk factors and disease related features, including age, sex, BMI, cholesterol and triglyceride levels, presence of arterial hypertension, smoking (pack/years), disease duration and total steroid dose [OR 95% (CI): 5.8 (1.0-35.8) and 5.2 (1.1-24.0), respectively]. MTHFR 677TT genotype, but not hyperhomocysteinemia was also found to confer increased risk for arterial wall thickening, after the above confounders were taken into account [OR (95%) CI: 4.9 (1.2-20.6)]. CONCLUSIONS: Hyperhomocysteinemia and MTHFR 677TT genetic variant emerged as independent risk factors for subclinical atherosclerosis in SLE patients, implying genetic influences as potential contributors to the increased burden of atherosclerotic disease characterizing SLE.
OBJECTIVE: Elevated concentrations of homocysteine have been previously identified as an independent risk factor for subclinical atherosclerosis in patients with systemic lupus erythematosus (SLE). Given that heightened homocysteine levels are known to be strongly influenced by genetic factors, in the current study we investigated the contribution of high homocysteine levels as well as of functional polymorphisms of the gene encoding for the enzyme 5, 10- methylenetetrahydrofolate reductase (MTHFR) to atherosclerotic disease characterizing SLEpatients. METHODS: Peripheral DNA samples from 150 SLEpatients, 214 rheumatoid arthritis (RA) patients and 561 age/sex matched apparently healthy volunteers (HC) were genotyped by PCR-based assays for the detection of the MTHFR gene polymorphisms (c. 677C > T and c. 1298A > C). All SLEpatients and 30 age sex matched RApatients underwent assessment for subclinical atherosclerosis [ultrasound measurement of intima-media thickness scores (IMT) and detection of carotid and/or femoral (C/F) plaque] and complete clinical and laboratory evaluation including serum homocysteine levels. Data were analyzed using univariate and multivariate models (SPSS 21.0). RESULTS:Hyperhomocysteinemia was detected in 26.0% of SLEpatients compared to 6.7% of age/sex matched RA controls (p = 0.02). Higher serum B12 levels and decreased frequency of the MTHFR 677TT variant in RApatients could potentially account for the observed differences between the groups. In SLEpatients, both hyperhomocysteinemia and MTHFR 677TT genotype were identified as independent contributors for plaque formation, following adjustment for traditional cardiovascular risk factors and disease related features, including age, sex, BMI, cholesterol and triglyceride levels, presence of arterial hypertension, smoking (pack/years), disease duration and total steroid dose [OR 95% (CI): 5.8 (1.0-35.8) and 5.2 (1.1-24.0), respectively]. MTHFR 677TT genotype, but not hyperhomocysteinemia was also found to confer increased risk for arterial wall thickening, after the above confounders were taken into account [OR (95%) CI: 4.9 (1.2-20.6)]. CONCLUSIONS:Hyperhomocysteinemia and MTHFR 677TT genetic variant emerged as independent risk factors for subclinical atherosclerosis in SLEpatients, implying genetic influences as potential contributors to the increased burden of atherosclerotic disease characterizing SLE.