Functional Tumor Necrosis Factor Alpha Polymorphisms and Haplotype Analysis in High-Risk Corneal Transplantation

Helen L Winton, Jeffrey L Bidwell, W J Armitage

Research output: Contribution to journalArticle (Academic Journal)peer-review

5 Citations (Scopus)

Abstract

Abstract
Background
Tumor necrosis factor alpha (TNF-α) plays a critical role in diverse cellular processes including ocular immune tolerance, inflammation, and allograft rejection. The ubiquitous transcription factor nuclear factor kappa B (NF-κB) regulates expression of numerous genes. Induction of the TNF-α pathway is involved in the inflammatory response and loss of transplant tolerance.

Objectives
We investigated functional single nucleotide polymorphisms (SNPs) in the promoter region of TNF-α and an insertion/deletion (indel) polymorphism of NF-κB1 in corneal transplant recipients considered to be at increased risk of immunological rejection (ie, high-risk corneal transplantations) and looked for any associations with corneal transplantation outcome.

Patients and Methods
Three hundred eighty-four full thickness corneal transplant recipients were followed for 3 years and episodes of reversible and irreversible allograft rejection were recorded. Using DNA obtained from these patients, 5 SNPs located in the promoter region −1031 T/C rs1799964, −863 C/A (rs1800630), −857 C/T (rs1799724), −308 G/A (rs1800629), and −238 G/A (rs361525), and one SNP upstream from the transcription start site (+489) rs1800610 of TNF-α were analyzed using induced heteroduplex generation. A functional NF-κB1 indel (−94) was also investigated. Haplotypes were inferred by PHASE and associations with rejection were determined by chi-square analysis.

Results
The TNF-α haplotype TCTGGA was significantly associated with reduced risk of corneal graft rejection (Pc < .005) and TCTAGA was associated with increased risk of rejection (Pc < .005) in high-risk corneal transplants. There was no association with the NF-κB1 indel (Pc > .05).

Conclusion
According to haplotype frequencies, our results suggest that the TCTGGA haplotype may confer additional protection against risk of immunological rejection whereas TCTAGA may increase risk of corneal allograft rejection in the high-risk setting. However, both haplotypes were relatively rare and thus would not warrant genotyping for individual patient selection for anti-TNF therapy.
Original languageEnglish
Article numberS0041-1345(14)00186-9
Pages (from-to)1548-1553
Number of pages5
JournalTransplantation Proceedings
Volume46
Issue number5
DOIs
Publication statusPublished - Jun 2014

Keywords

  • Corneal Transplantation
  • tumor necrosis factor alpha
  • haplotype
  • rejection

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