Influence of Elevated-CRP Level-related Polymorphisms in Non-rheumatic Caucasians on the Risk of Subclinical Atherosclerosis and Cardiovascular Disease in Rheumatoid Arthritis

Association between elevated C-reactive protein (CRP) serum levels and subclinical atherosclerosis and cardiovascular (CV) events was described in rheumatoid arthritis (RA). CRP, HNF1A, LEPR, GCKR, NLRP3, IL1F10, PPP1R3B, ASCL1, HNF4A and SALL1 exert an influence on elevated CRP serum levels in non-rheumatic Caucasians. Consequently, we evaluated the potential role of these genes in the development of CV events and subclinical atherosclerosis in RA patients. Three tag CRP polymorphisms and HNF1A, LEPR, GCKR, NLRP3, IL1F10, PPP1R3B, ASCL1, HNF4A and SALL1 were genotyped in 2,313 Spanish patients by TaqMan. Subclinical atherosclerosis was determined in 1,298 of them by carotid ultrasonography (by assessment of carotid intima-media thickness-cIMT-and presence/absence of carotid plaques). CRP serum levels at diagnosis and at the time of carotid ultrasonography were measured in 1,662 and 1,193 patients, respectively, by immunoturbidimetry. Interestingly, a relationship between CRP and CRP serum levels at diagnosis and at the time of the carotid ultrasonography was disclosed. However, no statistically significant differences were found when CRP, HNF1A, LEPR, GCKR, NLRP3, IL1F10, PPP1R3B, ASCL1, HNF4A and SALL1 were evaluated according to the presence/absence of CV events, carotid plaques and cIMT after adjustment. Our results do not confirm an association between these genes and CV disease in RA.

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References

Corrales A, Gonzalez-Juanatey C, Peiro M, Blanco R, Llorca J, Gonzalez-Gay M . Carotid ultrasound is useful for the cardiovascular risk stratification of patients with rheumatoid arthritis: results of a population-based study. Ann Rheum Dis. 2013; 73(4):722-7. DOI: 10.1136/annrheumdis-2012-203101. View

Dessein P, Norton G, Woodiwiss A, Joffe B, Wolfe F . Influence of nonclassical cardiovascular risk factors on the accuracy of predicting subclinical atherosclerosis in rheumatoid arthritis. J Rheumatol. 2007; 34(5):943-51. View

Gonzalez-Juanatey C, Llorca J, Martin J, Gonzalez-Gay M . Carotid intima-media thickness predicts the development of cardiovascular events in patients with rheumatoid arthritis. Semin Arthritis Rheum. 2008; 38(5):366-71. DOI: 10.1016/j.semarthrit.2008.01.012. View

Lopez-Mejias R, Genre F, Remuzgo-Martinez S, Robledo G, Llorca J, Corrales A . Vitamin D receptor GATG haplotype association with atherosclerotic disease in patients with rheumatoid arthritis. Atherosclerosis. 2016; 245:139-42. DOI: 10.1016/j.atherosclerosis.2015.12.011. View

Tedgui A, Mallat Z . Cytokines in atherosclerosis: pathogenic and regulatory pathways. Physiol Rev. 2006; 86(2):515-81. DOI: 10.1152/physrev.00024.2005. View

Danesh J, Wheeler J, Hirschfield G, Eda S, Eiriksdottir G, Rumley A . C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med. 2004; 350(14):1387-97. DOI: 10.1056/NEJMoa032804. View

Gonzalez-Gay M, Gonzalez-Juanatey C, Vazquez-Rodriguez T, Martin J, Llorca J . Endothelial dysfunction, carotid intima-media thickness, and accelerated atherosclerosis in rheumatoid arthritis. Semin Arthritis Rheum. 2008; 38(2):67-70. DOI: 10.1016/j.semarthrit.2008.02.001. View

Gonzalez-Gay M, Gonzalez-Juanatey C, Pineiro A, Garcia-Porrua C, Testa A, Llorca J . High-grade C-reactive protein elevation correlates with accelerated atherogenesis in patients with rheumatoid arthritis. J Rheumatol. 2005; 32(7):1219-23. View

Goodson N, Symmons D, Scott D, Bunn D, Lunt M, Silman A . Baseline levels of C-reactive protein and prediction of death from cardiovascular disease in patients with inflammatory polyarthritis: a ten-year followup study of a primary care-based inception cohort. Arthritis Rheum. 2005; 52(8):2293-9. DOI: 10.1002/art.21204. View

10.

Lopez-Mejias R, Genre F, Remuzgo-Martinez S, Robustillo-Villarino M, Garcia-Bermudez M, Llorca J . Protective Role of the Interleukin 33 rs3939286 Gene Polymorphism in the Development of Subclinical Atherosclerosis in Rheumatoid Arthritis Patients. PLoS One. 2015; 10(11):e0143153. PMC: 4646618. DOI: 10.1371/journal.pone.0143153. View

11.

Aletaha D, Neogi T, Silman A, Funovits J, Felson D, Bingham 3rd C . 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010; 62(9):2569-81. DOI: 10.1002/art.27584. View

12.

Gonzalez-Gay M, Gonzalez-Juanatey C, Lopez-Diaz M, Pineiro A, Garcia-Porrua C, Miranda-Filloy J . HLA-DRB1 and persistent chronic inflammation contribute to cardiovascular events and cardiovascular mortality in patients with rheumatoid arthritis. Arthritis Rheum. 2007; 57(1):125-32. DOI: 10.1002/art.22482. View

13.

Dehghan A, Dupuis J, Barbalic M, Bis J, Eiriksdottir G, Lu C . Meta-analysis of genome-wide association studies in >80 000 subjects identifies multiple loci for C-reactive protein levels. Circulation. 2011; 123(7):731-8. PMC: 3147232. DOI: 10.1161/CIRCULATIONAHA.110.948570. View

14.

Naredo E, Moller I, Gutierrez M, Bong D, Cobo T, Corominas H . Multi-examiner reliability of automated radio frequency-based ultrasound measurements of common carotid intima-media thickness in rheumatoid arthritis. Rheumatology (Oxford). 2011; 50(10):1860-4. DOI: 10.1093/rheumatology/ker206. View

15.

Lopez-Mejias R, Garcia-Bermudez M, Gonzalez-Juanatey C, Castaneda S, Miranda-Filloy J, Gomez-Vaquero C . NFKB1-94ATTG ins/del polymorphism (rs28362491) is associated with cardiovascular disease in patients with rheumatoid arthritis. Atherosclerosis. 2012; 224(2):426-9. DOI: 10.1016/j.atherosclerosis.2012.06.008. View

16.

Gonzalez-Juanatey C, Llorca J, Garcia-Porrua C, Martin J, Gonzalez-Gay M . Effect of anti-tumor necrosis factor alpha therapy on the progression of subclinical atherosclerosis in severe rheumatoid arthritis. Arthritis Rheum. 2006; 55(1):150-3. DOI: 10.1002/art.21707. View

17.

Lopez-Mejias R, Garcia-Bermudez M, Gonzalez-Juanatey C, Castaneda S, Perez-Esteban S, Miranda-Filloy J . Lack of association between IL6 single nucleotide polymorphisms and cardiovascular disease in Spanish patients with rheumatoid arthritis. Atherosclerosis. 2011; 219(2):655-8. DOI: 10.1016/j.atherosclerosis.2011.07.124. View

18.

Ridker P, Cushman M, Stampfer M, Tracy R, Hennekens C . Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997; 336(14):973-9. DOI: 10.1056/NEJM199704033361401. View

19.

Elliott P, Chambers J, Zhang W, Clarke R, Hopewell J, Peden J . Genetic Loci associated with C-reactive protein levels and risk of coronary heart disease. JAMA. 2009; 302(1):37-48. PMC: 2803020. DOI: 10.1001/jama.2009.954. View

20.

Touboul P, Hennerici M, Meairs S, Adams H, Amarenco P, Bornstein N . Mannheim carotid intima-media thickness consensus (2004-2006). An update on behalf of the Advisory Board of the 3rd and 4th Watching the Risk Symposium, 13th and 15th European Stroke Conferences, Mannheim, Germany, 2004, and Brussels, Belgium, 2006. Cerebrovasc Dis. 2006; 23(1):75-80. DOI: 10.1159/000097034. View