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European Journal of Heart Failure 2003 5(2):161-163; doi:10.1016/S1388-9842(02)00238-6
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© 2002 European Society of Cardiology

Tumor necrosis factor-{alpha} polymorphism in Turkish patients with dilated cardiomyopathy

Mehmet Alikasifoglua, Lale Tokgözoglub,*, Tayfun Acilb, Enver Atalarb, Mehmet Ali Otob, Süleyman Sirri Kesb and Ergül Tuncbileka

a Faculty of Medicine, Department of Pediatrics, Division of Genetic Diseases, Hacettepe University Ankara, Turkey
b Hacettepe University, Faculty of Medicine, Department of Cardiology Ankara, Turkey

* Corresponding author. Kuveyt caddesi No. 9, 06540 Kavaklidere, Ankara, Turkey. Tel.: +90-312-4683013; fax: +90-312-4661906 E-mail address: mehmet{at}gen.hun.edu.tr lalet{at}bim.net.tr tacil{at}lycos.com enveratalar{at}hotmail.com alioto{at}superonline.com

Received May 14, 2002; Revised August 7, 2002; Accepted September 17, 2002


   1. Background
Top
 1. Background
2. Aims
 3. Methods
 4. Results
 5. Conclusion
 References
 
Tumor necrosis factor-{alpha} (TNF-{alpha}) is a proinflammatory cytokine with pleiotropic biological effects. Numerous studies have indicated a role of TNF-{alpha} in the pathophysiology of congestive heart failure [1–4]. Since genetic polymorphisms in the TNF locus were known to be related to several autoimmune, infectious, and neoplastic diseases [5], the association between TNF-{alpha} gene polymorphism and dilated cardiomyopathy (DCM) was also studied [6–8]. However, the results obtained were contradictory. Studies done in patients with different ethnic origins yielded contrasting results [6,7].


   2. Aims
Top
 1. Background
 2. Aims
3. Methods
 4. Results
 5. Conclusion
 References
 
We aimed to investigate the association between the –238 and –308 (G/A) polymorphisms of the TNF-{alpha} gene and DCM in a Turkish population to evaluate the possible variability of the consequences of TNF-{alpha} gene polymorphism concerning the pathophysiology of heart failure in patients with different ethnic origins.


   3. Methods
Top
 1. Background
 2. Aims
 3. Methods
4. Results
 5. Conclusion
 References
 
Sixty-three consecutive patients having the diagnosis of DCM with different etiologies and 93 healthy age- and sex-matched subjects were included in this study. The diagnosis of ischemic (n=33), valvular (n=15), and idiopathic cardiomyopathy (n=15) was confirmed according to the report of the 1995 World Health Organization [9]. All patients underwent transthoracic echocardiography (Toshiba SSH-160-System, Japan) and had left ventricular dilatation (end diastolic diameter >=5.5 cm) and showed impaired left ventricular function (left ventricular ejection fraction <40%, or fractional shortening <25%). Echocardiographic evaluations of all control subjects were normal. Patients with a history of alcohol abuse, skeletal myopathy, and with a DCM certainly known to be secondary to myocarditis were excluded. Also, patients who were not evaluated by cardiac catheterization and coronary angiography were excluded from the study. An informed consent was obtained from all study subjects. The study conforms with the principles outlined in the Declaration of Helsinki.

3.1. Serum samples and analysis of the TNF-{alpha} gene polymorphisms
Blood samples were obtained from the patients with cardiomyopathy and healthy control subjects. They were mixed with EDTA and stored at –80 °C before further processing.

DNA was extracted from whole blood and 238 G/A and 308 G/A polymorphisms were analysed using the PCR technique [6].

3.2. Statistical analysis
The statistical software SPSS was used to analyze the results. The results are shown as the mean±S.D. The {chi}2 test was used for statistical analysis of frequencies of TNF-{alpha} polymorphisms between the groups. Differences were considered significant at a value of P<0.05.


   4. Results
Top
 1. Background
 2. Aims
 3. Methods
 4. Results
5. Conclusion
 References
 
The TNF-{alpha} genotypes of patients and controls are summarized in Table 1. The observed allele frequencies, for both TNF-{alpha}/-238 and -308 of patients did not differ from that of controls (P=0.56, Odds ratio=0.99, 95% CI=0.53–1.88 and P=0.34, Odds ratio=0.84, 95% CI=0.46–1.54, respectively). The TNF-{alpha}/-238 allele frequencies (G/A) were 0.85/0.15 and 0.85/0.15, for patients and controls, respectively. The TNF-{alpha}/-308 allele frequencies (G/A) were 0.83/0.17 and 0.85/0.15, for patients and controls, respectively. The observed allele frequencies for TNF-{alpha}/-308 were similar to previous reports [6,10,11], whereas those for TNF-{alpha}/-238 differed from a previous report revealing a G/A allele frequency of 0.95/0.05 [11]. The observed allele frequencies, for both TNF-{alpha}/-238 and -308 of controls did not differ from that of patients, irrespective of the etiology of DCM. Furthermore, no difference was observed between the three etiologic groups (Table 2).


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  		Table 1 Profiles of study subjects and TNF-{alpha} genotypes

 


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  		Table 2 Comparisons of TNF-{alpha}/-238 and -308 allele frequencies

 

   5. Conclusion
Top
 1. Background
 2. Aims
 3. Methods
 4. Results
 5. Conclusion
References
 
In this study we examined 63 Turkish patients with DCM, and could not find any association between the TNF-{alpha}-238 and -308 (G/A) polymorphisms and DCM. This is in parallel with the studies which also could not show any association between the TNF-{alpha}/-308 (G/A) polymorphism and DCM [6,8].

Kubota et al. included patients with different etiologies of DCM and also failed to demonstrate any association between the TNF-{alpha}/-308 (G/A) polymorphism and DCM [6]. Another study also revealed no association between the TNF-{alpha}/-238 and -308 (G/A) polymorphisms and ischemic heart disease [11]. Similarly, we could not show any difference in allele frequencies when the etiology of DCM was considered.

In a recent study, it was found that the TNF-{alpha}/-308 A allele was overexpressed in patients with end-stage non-ischemic DCM [12]. Our study included mainly patients who were in class II or III according to the New York Heart Association criteria. The small number of patients with end-stage heart failure included in our study could be an explanation of this contrasting result. Another possibility is that end-stage heart failure patients did not have the chance to reach the hospital because of high mortality and therefore could not be screened for TNF-{alpha} polymorphism, although having a high frequency of a specific allele.

Unlike our study, Ito et al. found that the TNF-{alpha}/-308 A allele was more frequent in Japanese patients with the diagnosis of idiopathic DCM [7]. This suggests a variability of TNF-{alpha} polymorphisms in patients with DCM having different ethnic origins. The frequencies of TNF-{alpha}/-238 (G/A) alleles found in our study (0.85/0.15) differed from those observed in a previous report which included patients from France and Northern Ireland (0.95/0.05) [11]. This supports the suggestion of a variability of TNF-{alpha} polymorphisms in the genesis of DCM in different ethnic populations.

It can be concluded that at least in Turkish patients with DCM, there is no association between the TNF-{alpha}/-238 (G/A) and -308 (G/A) polymorphisms, and the disease. Ethnic factors might play a role in the variability of results in different populations. Therefore, additional studies are needed to clarify this issue.


   References
Top
 1. Background
 2. Aims
 3. Methods
 4. Results
 5. Conclusion
 References
 

  1. Levine B., Kalman J., Mayer L., Fillit H.M., Packer M. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med (1990) 323:236–241.[Abstract]
  2. McMurray J., Abdullah I., Dargie H.J., Shapiro D. Increased concentrations of tumour necrosis factor in ‘cachectic’ patients with severe chronic heart failure. Br Heart J (1991) 66:356–358.[Abstract/Free Full Text]
  3. Dutka D.P., Elborn J.S., Delamere F., Shale D.J., Morris G.K. Tumour necrosis factor alpha in severe congestive cardiac failure. Br Heart J (1993) 70:141–143.[Abstract/Free Full Text]
  4. Katz S.D., Rao R., Berman J.W., et al. Pathophysiological correlates of increased serum tumor necrosis factor in patients with congestive heart failure. Relation to nitric oxide-dependent vasodilation in the forearm circulation. Circulation (1994) 90:12–16.[Abstract/Free Full Text]
  5. Wilson A.G., di Giovine F.S., Duff G.W. Genetics of tumour necrosis factor-alpha in autoimmune, infectious, and neoplastic diseases. J Inflamm (1995) 45:1–12.[Web of Science][Medline]
  6. Kubota T., McNamara D.M., Wang J.J., et al. Effects of tumor necrosis factor gene polymorphisms on patients with congestive heart failure. VEST investigators for TNF genotype analysis. Vesnarinone survival trial. Circulation (1998) 97:2499–2501.[Abstract/Free Full Text]
  7. Ito M., Takahashi H., Fuse K., et al. Polymorphisms of tumor necrosis factor-alpha and interleukin-10 genes in Japanese patients with idiopathic dilated cardiomyopathy. Jpn Heart J (2000) 41:183–191.[CrossRef][Medline]
  8. Tiret L., Mallet C., Poirier O., et al. Lack of association between polymorphisms of eight candidate genes and idiopathic dilated cardiomyopathy: the CARDIGENE study. J Am Coll Cardiol (2000) 35:29–35.[Abstract/Free Full Text]
  9. Richardson P., McKenna W., Bristow M., et al. Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the definition and classification of cardiomyopathies. Circulation (1996) 93:841–842.[Free Full Text]
  10. Stuber F., Petersen M., Bokelmann F., Schade U. A genomic polymorphism within the tumor necrosis factor locus influences plasma tumor necrosis factor-alpha concentrations and outcome of patients with severe sepsis. Crit Care Med (1996) 24:381–384.[CrossRef][Web of Science][Medline]
  11. Herrmann S.M., Ricard S., Nicaud V., et al. Polymorphisms of the tumour necrosis factor-alpha gene, coronary heart disease and obesity. Eur J Clin Invest (1998) 28:59–66.[CrossRef][Web of Science][Medline]
  12. Densem C.G., Hutchinson I.V., Yonan N., Brooks N.H. Tumour necrosis factor alpha gene polymorphism: a predisposing factor to non-ischaemic myocardial dysfunction? Heart (2002) 87:153–155.[Abstract/Free Full Text]

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