CLINICAL AND TRANSLATIONAL RESEARCH Cardiovascular Disease in Kidney Transplant Recipients: The Prognostic Value of Inflammatory Cytokine Genotypes Gaetano La Manna, 1,4 Maria L. Cappuccilli, 1,2 Giuseppe Cianciolo, 1 Diletta Conte, 1,2 Giorgia Comai, 1 Elisa Carretta, 1,3 Maria P. Scolari, 1 and Sergio Stefoni 1 Background. Cardiovascular disease (CVD) represents the main cause of morbidity and mortality after renal trans- plantation. In view of the modern paradigm of atherosclerosis as an inflammatory disease, this study investigated the impact of inflammatory cytokine polymorphisms on posttransplant CVD. Methods. The association between cytokine polymorphisms and CVD was assessed in a case-control study to identify the differences in genotype distributions between kidney allografts with or without posttransplant CVD. To validate our results in two independent groups, we divided a cohort of 798 renal transplant recipients according to geographic area: an evaluation cohort of 478 patients from Emilia-Romagna and a validation cohort of 320 patients from the rest of Italy. Tumor necrosis factor (TNF)-, transforming growth factor-1, interleukin (IL)-10, IL-6, interferon-, and IL-8 polymorphisms were analyzed, and thereafter, the cytokine production genotype was assigned. Results. In the evaluation cohort, the patients in the CVD and no-CVD groups differed significantly in TNF- and IL-10 genotype frequencies. Using multivariate analyses to test the association with CVD, the TNF- high-producer genotype was associated with a significantly increased cardiovascular risk (odds ratio [OR]=4.41, 95% confidence interval (CI)=2.53–7.67). Conversely, the IL-10 high-producer genotype resulted protective against CVD (OR=0.07, 95% CI=0.02– 0.29). These findings were confirmed in the validation cohort where the carriers of the TNF- high- producer genotype proved to be at 2.45-fold increased cardiovascular risk (OR=2.45, 95% CI=1.29 – 4.63), whereas the IL-10 high-producer genotype was associated with a 0.08-fold reduced risk (OR=0.08, 95% CI=0.02– 0.36). Conclusions. This work suggests a prognostic value of TNF- and IL-10 genotypes, which might represent cardiovas- cular risk markers in renal transplant. Keywords: Kidney transplant, Cardiovascular disease, Cytokine polymorphisms, Inflammation. (Transplantation 2010;89: 1001–1008) I n the past two decades, cardiovascular death has become the main cause of graft loss in renal transplant recipients (1, 2), who have been shown to have a dramatically high cardiov- ascular mortality rate, with up to a 46-fold increased risk above the general population (3–6). In these patients, time of dialysis, anemia, and chronic immunosuppression are likely to trigger a combination of immunologic responses, pro- thrombotic state, dysmetabolic alterations, and inflamma- tory abnormalities, which lead to a substantially increased cardiovascular risk in comparison with the general popula- tion. The Framingham Heart Study equation has been dem- onstrated to be a poor predictor of cardiovascular risk after This work was supported in part by the Fondazione del Monte di Bologna e Ravenna, Project “Il rigetto a medio e lungo termine nei trapianti d’organo” (S.S.). The authors declare no conflict of interest. 1 Department of Internal Medicine, Aging and Renal Diseases, University of Bologna, Bologna, Italy. 2 Center for Applied Biomedical Research, University of Bologna, St. Orsola Hospital, Bologna, Italy. 3 Department of Medicine and Public Health, University of Bologna, Bologna, Italy. 4 Address correspondence to: Gaetano La Manna, MD, PhD, Department of Internal Medicine, Aging and Renal Diseases, Section of Nephrology, St. Orsola University Hospital (Pad. 15), Via G. Massarenti, 9 40138 Bolo- gna, Italy. E-mail: gaetano.lamanna@unibo.it G.L.M. is a main investigator and participated in design and coordination of the research plan, selection of patients, review of clinical charts, manage- ment of a database to collect the essential clinical and demographic data of the transplanted patients recruited for the study, and preparation of the manuscript. M.L.C. participated in design of the research plan, genotyp- ing, laboratory assays for serum cardiovascular markers, review of clinical charts, contribution to the statistic analysis, and preparation of the manu- script. G.C. participated in design of the research plan, definition of the characteristics of patient population (inclusion/exclusion criteria, sample size), review of clinical charts, and contribution to the preparation of the manuscript. D.C. participated in sample storage, DNA extraction, and geno- typing. G.C. participated in selection of patients, management of a database to collect the essential clinical, and demographic data of the transplanted patients recruited for the study. E.C. participated in statistic analysis and contribution to the preparation of the manuscript. M.P.S. participated in coordination of the research plan, selection of patients, and review of clinical charts. S.S. is a major research supervisor. Received 27 November 2009. Accepted 1 December 2009. Copyright © 2010 by Lippincott Williams & Wilkins ISSN 0041-1337/10/8908-1001 DOI: 10.1097/TP.0b013e3181ce243f Transplantation • Volume 89, Number 8, April 27, 2010 www.transplantjournal.com | 1001