Tumour necrosis factor gene polymorphism: a predictive factor for the development of post-transplant lymphoproliferative disease

BACKGROUND: Epstein-Barr virus-positive post-transplant lymphoproliferative disease (PTLD) is a potentially lethal complication of iatrogenic immunosupression after transplantation. Predicting the development of PTLD allowing early and effective intervention is therefore of importance. Polymorphisms within cytokine genes are implicated in susceptibility to, and progression of, disease however the published data are often conflicting. We undertook investigation of polymorphic alleles within cytokine genes in PTLD and non-PTLD transplant cohorts to determine risk factors for disease. METHODS: SSP-PCR was used to analyse single nucleotide polymorphism within tumour necrosis factor (TNF)-alpha, interleukin-1,-6,-10 and lymphotoxin-alpha genes. The TNF-alpha levels were measured by standard enzyme-linked immuno-absorbant assay. RESULTS: We show an association between variant alleles within the TNF-a promoter (-1031C (P = 0.005)); -863A (P = 0.0001) and TNF receptor I promoter regions (-201T (P = 0.02)); -1135C (P = 0.03) with the development of PTLD. We also show an association with TNF-alpha promoter haplotypes with haplotype-3 significantly increased (P = 0.0001) and haplotype-1 decreased (P 0.02) in PTLD patients compared to transplant controls. Furthermore, we show a significant increase (P 0.02) in the level of TNF-a in PTLD patient plasma (range 0-97.97 pg ml(-1)) compared to transplant controls (0-8.147 pg ml(-1)), with the highest levels found in individuals carrying the variant alleles. CONCLUSION: We suggest that genetic variation within TNF-a loci and the level of plasma cytokine could be used as a predictive risk factor for the development of PTLD. British Journal of Cancer (2009) 101, 1019-1027. doi:10.1038/sj.bjc.6605278 www.bjcancer.com (C) 2009 Cancer Research UK