Winton H L, Bidwell J L, Armitage W J
Ophthalmology, School of Clinical Sciences, University of Bristol, Bristol Eye Hospital, Lower Maudlin Street, Bristol, United Kingdom.
School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom.
Transplant Proc. 2014 Jun;46(5):1548-53. doi: 10.1016/j.transproceed.2014.02.029.
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.
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.
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.
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).
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.
