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Prediction of genetic risk for cardiovascular disease in patients with rheumatoid arthritis: Present and promises
Atherosclerosis 216 (2011) 21–22
Contents lists available at ScienceDirect
Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Invited commentary
Prediction of genetic risk for cardiovascular disease in patients with rheumatoid arthritis: Present and promises Enzo Emanuele ∗ Department of Health Science, University of Pavia, Via Bassi, 21, I-27100 Pavia, Italy
a r t i c l e
i n f o
Article history: Received 5 October 2010 Accepted 7 October 2010 Available online 1 March 2011 Keywords: Genetics Cardiovascular disease Rheumatoid arthritis
Patients with rheumatoid arthritis (RA) experience a markedly increased frequency of cardiovascular disease (CVD) as compared with the general population [1,2]. Cardiovascular disease is not oftenly present in patients with early RA, but can also develop during the course of the disease [3]. Consequently, a distinction must be made between the contributions of general risk factors to the development of cardiovascular disease, risk factors related to RA itself, and risk factors specifically related to peculiar clinical and laboratory findings of the disease. The success of risk prediction models for CVD in RA is tightly linked to our understanding of the molecular basis of accelerated atherosclerosis occurring in this condition. Current prediction models, however, remain unable to anticipate many cases of incident vascular events in RA, thus motivating the identification of new reliable risk markers. Genetic factors may underlie susceptibility to cardiovascular disease in RA [4–6], and identification of predisposing genotypes may improve prevention strategies by facilitating early screening of carriers for specific genetic biomarkers. The elegant paper by Rodríguez-Rodríguez et al. [7] in the present issue of Atherosclerosis suggests that the tumor necrosis factor alpha (TNFA) rs1800629 (G > A) polymorphism is significantly and independently associated with cardiovascular complications in patients with RA. To note, this polymorphism was unrelated neither to measures of subclinical atherosclerosis nor to the response to biological therapies. The authors’ efforts to dissect the contribution of the TNFA rs1800629 polymorphism to several distinct clinical and surrogate endpoints of CVD are important for at least two reasons. First, the authors were able to explore multiple related cardiovascular phenotypes. For
∗ Corresponding author. Tel.: +39 338 5054463. E-mail addresses: [email protected], [email protected] 0021-9150/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2010.10.053
example, they have included both the phenotypes “cardiovascular events” and “surrogate markers of subclinical atherosclerosis”. Second, they were able to demonstrate that the association between the carriage of the minor allele A and CVD is only present in carriers of the shared epitope (a 5-aminoacid sequence motif in the third allelic hypervariable region of the HLA-DR chain). The latter finding clearly indicates that the carriage of at least one A allele of the TNFA rs1800629 polymorphism is a genetic cardiovascular risk factor specifically related to a peculiar clinical and laboratory findings of RA, and not to RA per se. Despite the sound methodological approach and the robustness of the findings, we have unfortunately much work to do before we will know how to apply these data in practice for at least three reasons. First, the mechanisms governing the development of atherosclerosis in RA are incredibly intricate, possibly with timedependent environmental interactions during the course of the disease [3]. Although a common genetic polymorphism may be robustly associated with the risk of a given disease, it may explain only a small proportion of the risk variance. Second, in the candidate gene philosophy approach used by Rodríguez-Rodríguez et al. [7], some genes are actually more important than others. This view is clinically difficult to sustain as it rests on the questionable assumption that one single preselected polymorphism (which can obviously explain only a small proportion of the overall clinical variance) would lead to very different outcomes. Finally, the study shares the limitations of genetic association studies, i.e. the need for replication in one or more additional populations, the issue of multiple testing and comparisons, and the lack of functional studies, which can counterbalance the common methodological deficiencies of this kind of studies. While the study by Rodríguez-Rodríguez et al. [7] cannot be considered practice changing at this juncture, the authors were clearly able to provide intriguing finding on the
22
E. Emanuele / Atherosclerosis 216 (2011) 21–22
potential clinical usefulness of genetic risk prediction for cardiovascular disease in RA patients. The extent to which the authors in the future be able to address the shortcomings inherent in their current study, plus the novelty and importance of their observations, will certainly play a major role in increasing the clinical value of prediction of genetic risk to CVD in rheumatoid arthritis. References [1] Dhawan SS, Quyyumi AA. Rheumatoid arthritis and cardiovascular disease. Curr Atheroscler Rep 2008;10:128–33. [2] Gonzalez-Gay MA, Gonzalez-Juanatey C, Miranda-Filloy JA, et al. Cardiovascular disease in rheumatoid arthritis. Biomed Pharmacother 2006;60:673–7. [3] Kaplan MJ. Cardiovascular complications of rheumatoid arthritis: assessment, prevention, and treatment. Rheum Dis Clin North Am 2010;36:405–26.
[4] Palomino-Morales R, Gonzalez-Juanatey C, Vazquez-Rodriguez TR, et al. A1298C polymorphism in the MTHFR gene predisposes to cardiovascular risk in rheumatoid arthritis. Arthritis Res Ther 2010;12(2):R71. [5] Panoulas VF, Stavropoulos-Kalinoglou A, Metsios GS, et al. Association of interleukin-6 (IL-6)-174G/C gene polymorphism with cardiovascular disease in patients with rheumatoid arthritis: the role of obesity and smoking. Atherosclerosis 2009;204:178–83. [6] Farragher TM, Goodson NJ, Naseem H, et al. Association of the HLA-DRB1 gene with premature death, particularly from cardiovascular disease, in patients with rheumatoid arthritis and inflammatory polyarthritis. Arthritis Rheum 2008;58:359–69. [7] Rodriguez-Rodriguez L, Gonzalez-Juanatey C, Palomino-Morales R, VazquezRodriguez T, Miranda-Filloy JA, Fernandez-Gutierrez B, Llorca J, Martin J, Gonzalez-Gay MA. TNFA – 308 (rs1800629) polymorphism is associated with a higher risk of cardiovascular disease in patients with rheumatoid arthritis. Atherosclerosis 2011;216:125–30.
Contents lists available at ScienceDirect
Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Invited commentary
Prediction of genetic risk for cardiovascular disease in patients with rheumatoid arthritis: Present and promises Enzo Emanuele ∗ Department of Health Science, University of Pavia, Via Bassi, 21, I-27100 Pavia, Italy
a r t i c l e
i n f o
Article history: Received 5 October 2010 Accepted 7 October 2010 Available online 1 March 2011 Keywords: Genetics Cardiovascular disease Rheumatoid arthritis
Patients with rheumatoid arthritis (RA) experience a markedly increased frequency of cardiovascular disease (CVD) as compared with the general population [1,2]. Cardiovascular disease is not oftenly present in patients with early RA, but can also develop during the course of the disease [3]. Consequently, a distinction must be made between the contributions of general risk factors to the development of cardiovascular disease, risk factors related to RA itself, and risk factors specifically related to peculiar clinical and laboratory findings of the disease. The success of risk prediction models for CVD in RA is tightly linked to our understanding of the molecular basis of accelerated atherosclerosis occurring in this condition. Current prediction models, however, remain unable to anticipate many cases of incident vascular events in RA, thus motivating the identification of new reliable risk markers. Genetic factors may underlie susceptibility to cardiovascular disease in RA [4–6], and identification of predisposing genotypes may improve prevention strategies by facilitating early screening of carriers for specific genetic biomarkers. The elegant paper by Rodríguez-Rodríguez et al. [7] in the present issue of Atherosclerosis suggests that the tumor necrosis factor alpha (TNFA) rs1800629 (G > A) polymorphism is significantly and independently associated with cardiovascular complications in patients with RA. To note, this polymorphism was unrelated neither to measures of subclinical atherosclerosis nor to the response to biological therapies. The authors’ efforts to dissect the contribution of the TNFA rs1800629 polymorphism to several distinct clinical and surrogate endpoints of CVD are important for at least two reasons. First, the authors were able to explore multiple related cardiovascular phenotypes. For
∗ Corresponding author. Tel.: +39 338 5054463. E-mail addresses: [email protected], [email protected] 0021-9150/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2010.10.053
example, they have included both the phenotypes “cardiovascular events” and “surrogate markers of subclinical atherosclerosis”. Second, they were able to demonstrate that the association between the carriage of the minor allele A and CVD is only present in carriers of the shared epitope (a 5-aminoacid sequence motif in the third allelic hypervariable region of the HLA-DR chain). The latter finding clearly indicates that the carriage of at least one A allele of the TNFA rs1800629 polymorphism is a genetic cardiovascular risk factor specifically related to a peculiar clinical and laboratory findings of RA, and not to RA per se. Despite the sound methodological approach and the robustness of the findings, we have unfortunately much work to do before we will know how to apply these data in practice for at least three reasons. First, the mechanisms governing the development of atherosclerosis in RA are incredibly intricate, possibly with timedependent environmental interactions during the course of the disease [3]. Although a common genetic polymorphism may be robustly associated with the risk of a given disease, it may explain only a small proportion of the risk variance. Second, in the candidate gene philosophy approach used by Rodríguez-Rodríguez et al. [7], some genes are actually more important than others. This view is clinically difficult to sustain as it rests on the questionable assumption that one single preselected polymorphism (which can obviously explain only a small proportion of the overall clinical variance) would lead to very different outcomes. Finally, the study shares the limitations of genetic association studies, i.e. the need for replication in one or more additional populations, the issue of multiple testing and comparisons, and the lack of functional studies, which can counterbalance the common methodological deficiencies of this kind of studies. While the study by Rodríguez-Rodríguez et al. [7] cannot be considered practice changing at this juncture, the authors were clearly able to provide intriguing finding on the
22
E. Emanuele / Atherosclerosis 216 (2011) 21–22
potential clinical usefulness of genetic risk prediction for cardiovascular disease in RA patients. The extent to which the authors in the future be able to address the shortcomings inherent in their current study, plus the novelty and importance of their observations, will certainly play a major role in increasing the clinical value of prediction of genetic risk to CVD in rheumatoid arthritis. References [1] Dhawan SS, Quyyumi AA. Rheumatoid arthritis and cardiovascular disease. Curr Atheroscler Rep 2008;10:128–33. [2] Gonzalez-Gay MA, Gonzalez-Juanatey C, Miranda-Filloy JA, et al. Cardiovascular disease in rheumatoid arthritis. Biomed Pharmacother 2006;60:673–7. [3] Kaplan MJ. Cardiovascular complications of rheumatoid arthritis: assessment, prevention, and treatment. Rheum Dis Clin North Am 2010;36:405–26.
[4] Palomino-Morales R, Gonzalez-Juanatey C, Vazquez-Rodriguez TR, et al. A1298C polymorphism in the MTHFR gene predisposes to cardiovascular risk in rheumatoid arthritis. Arthritis Res Ther 2010;12(2):R71. [5] Panoulas VF, Stavropoulos-Kalinoglou A, Metsios GS, et al. Association of interleukin-6 (IL-6)-174G/C gene polymorphism with cardiovascular disease in patients with rheumatoid arthritis: the role of obesity and smoking. Atherosclerosis 2009;204:178–83. [6] Farragher TM, Goodson NJ, Naseem H, et al. Association of the HLA-DRB1 gene with premature death, particularly from cardiovascular disease, in patients with rheumatoid arthritis and inflammatory polyarthritis. Arthritis Rheum 2008;58:359–69. [7] Rodriguez-Rodriguez L, Gonzalez-Juanatey C, Palomino-Morales R, VazquezRodriguez T, Miranda-Filloy JA, Fernandez-Gutierrez B, Llorca J, Martin J, Gonzalez-Gay MA. TNFA – 308 (rs1800629) polymorphism is associated with a higher risk of cardiovascular disease in patients with rheumatoid arthritis. Atherosclerosis 2011;216:125–30.