I T IS NOW RECOGNIZED THAT VARIOUS CYTOKINES play an important role in the development of ven- tricular dysfunction and heart failure. 1–9 In partic- ular, the pro-inflammatory cytokine, tumor necrosis factor-a, has been implicated in the pathophysiol- ogy of heart failure. 1–5 Other pro-inflammatory cyto- kines, such as interleukin 6, are elevated in heart failure, 2,6–8 while anti-inflammatory cytokines, such as interleukin 10, may be inadequately expressed. 7 It is known that there is a wide variation in produc- tion of cytokines between individuals. At least part of the explanation for these differences lies in the pres- ence of genetic polymorphisms within many cytokine genes. 10 Some cytokine genes have several associated polymorphisms, but not all have been associated with altered expression of the cytokine protein. Several functional polymorphisms have been recognized for cytokines that are considered important in the patho- physiology of heart failure. For example, in the tumor necrosis factor-a gene, a polymorphism at position 2308 (G/A) was associated with altered tumor necrosis factor-a production; allele “A” having 6–7 times more transcriptional activity than the “G” Cardiol Young 2002; 12: 461–464 © Greenwich Medical Media Ltd. ISSN 1047-9511 Original Article Polymorphisms in cytokine genes do not predict progression to end-stage heart failure in children Steven A. Webber, 1 Gerard J. Boyle, 1 Steven Gribar, 1 Yuk Law, 1 Pamela Bowman, 1 Susan A. Miller, 1 Mohammed R. Awad, 2 Mamun Ahmed, 2 Joan Martell, 2 Adriana Zeevi 2 Departments of 1 Pediatrics and 2 Pathology, University of Pittsburgh School of Medicine, Children’s Hospital of Pittsburgh and Thomas E. Starzl Transplant Institute, Pittsburgh, USA Abstract A number of cytokines have been implicated in the pathophysiology of congestive heart failure. Genetic polymorphisms of several cytokine genes are known to result in altered gene expression, enabling us to charac- terize patients as “high” or “low” producers of specific cytokines. We speculate that the cytokine genotypes for a population of children who underwent heart transplantation for end-stage ventricular failure due to cardio- myopathy or congenital heart disease would be enriched for “high producers” of pro-inflammatory cytokines and “low producers” of anti-inflammatory cytokines. Methods: Cytokine genotyping was performed for the following cytokines on 94 transplanted children using polymerase chain reaction-sequence specific technique: tumor necrosis factor-a (2308), interleukin 10 (21082, 2819, 2592), interleukin 6 (2174), transforming growth factor-b 1 (codons 10 & 25), and interferon- g (1874). Patients with ventricular failure after transplan- tation for dilated cardiomyopathy, numbering 37, or for congenital heart disease, numbering 34, were compared to 15 children transplanted for structural disease, such as hypoplastic left heart syndrome, without ventricular failure, and to data from healthy children. An additional 8 children with restrictive or hypertrophic cardio- myopathy were also studied. Results: No differences in genotypic distribution were seen between the groups, and all patients were comparable to genotypic distributions as assessed from published normal data. Conclusion: No evidence is found to support the hypothesis that these polymorphisms for cytokine genes influence progression to end-stage heart failure in children undergoing transplantation because of cardiomyopathy or congenital heart disease. Keywords: Heart failure; cytokines; genetic polymorphisms Correspondence to: Steven Webber, MBChB, Division of Cardiology, Children’s Hospital of Pittsburgh, 3705 Fifth Avenue, Pittsburgh, PA 15213, USA. Tel: 412 692 5541; Fax: 412 692 6991; E-mail: steve.webber@chp.edu This work was supported by a Grant-in-Aid from the Pennsylvania and Delaware affiliate of the American Heart Association. Accepted for publication 15 May 2002