Tumor necrosis factor gene polymorphism and cardiac allograft vasculopathy.
BACKGROUND
Cardiac allograft vasculopathy (CAV) limits survival after cardiac transplantation. Tumor necrosis factor-alpha (TNF-alpha) may be a key factor in the development of CAV. Two bi-allelic polymorphisms associated with high TNF-alpha production have been identified in the TNF gene locus, TNFA1/2, at position -308 and TNFB1/2 at +252. We hypothesized that recipient TNFA2 and TNFB2 homozygosity is associated with the development of CAV after heart transplantation.


METHODS
TNF gene polymorphisms were analyzed by multiplex fluorescent solid-phase mini-sequencing in 70 cardiac transplant recipients. Recipients homozygous for TNFA2 or TNFB2 (Group A, n = 29) were compared with recipients heterozygous or homozygous for TNFA1 and TNFB1 (Group B, n = 41). Coronary arteriography was performed annually or when indicated. Cumulative freedom from CAV and survival was calculated according to the Kaplan-Meier test.


RESULTS
Mean follow-up was 3.8 +/- 0.3 years. In Group A, 11 of 29 recipients (38%) developed CAV compared with 9 of 41 (22%) in Group B (p = 0.12). Cumulative freedom from CAV at 3 years was 42% in Group A and 80% in Group B (p = 0.043). In Group A, 11 of 29 recipients (38%) died during follow-up compared with 4 of 41 (10%) in Group B (p = 0.006). Cumulative survival at 3 years was 72% in Group A and 93% in Group B (p = 0.003).


CONCLUSIONS
The results suggest that TNFA2 and TNFB2 allele homozygosity is associated with cardiac allograft vasculopathy and mortality in heart transplant recipients.
Ternstrom
Lisa
L
Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, Göteborg, Sweden.
Jeppsson
Anders
A
Ricksten
Anne
A
Nilsson
Folke
F
D000328:Adult; D017023:Coronary Angiography; D003324:Coronary Artery Disease / Q000097:blood* / Q000000981:diagnostic imaging / Q000209:etiology; D003331:Coronary Vessels / Q000473:pathology*; D005260:Female; D005500:Follow-Up Studies; D005787:Gene Frequency; D005819:Genetic Markers; D006084:Graft Rejection / Q000097:blood / Q000517:prevention & control; D006085:Graft Survival / Q000235:genetics; D016027:Heart Transplantation / Q000009:adverse effects* / Q000401:mortality; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D015996:Survival Rate; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics*
D005819:Genetic Markers; D007166:Immunosuppressive Agents; D014409:Tumor Necrosis Factor-alpha