Genetic variants of FOXP3 influence graft survival in kidney transplant patients

Anja Grohnert¹, Annemiek M.A. Peeters¹, Judith A. Kal-van Gestel¹, Fernando Rivadeneira^2,3, Willem Weimar¹, Carla C. Baan¹

¹Department of Internal Medicine, Transplantation Laboratory; ²Department of Internal Medicine, Endocrinology Laboratory; ³Department of Epidemiology; Erasmus MC, University Medical Center Rotterdam, the Netherlands

Introduction: Regulatory T cells (Treg) play a role in controlling alloreactivity. A functional (GT)_n dinucleotide repeat polymorphism has been described within the promoter region of the transcription factor FOXP3, the master gene for Treg development and function. Increased promoter activity is associated with 15 or less (GT) repeats. The present study aimed to investigate the influence of the (GT)_n FOXP3 gene polymorphism on renal allograft survival.
Methods: Genotypes of 632 first-time transplant patients (mean follow-up time 6.7 years) were determined and grouped according to the length of the (GT) repeats; alleles with ≤ (GT)₁₅ were categorized as short (S) and alleles with ≥ (GT)₁₆ as long (L). Hemizygous males were included in the respective female homozygous SS or LL groups leading to the three genotype groups S/SS, SL and L/LL.
Results: S-allele carriers with graft survival of at least 3 months and acute rejection episodes showed superior graft survival when compared to patients who only expressed the L-allele (Kaplan-Meier, p = 0.009). No impact of the FOXP3 genotypes on renal graft survival was found when patients did not experience acute rejection (p = 0.311). Carriers of the S-allele who experienced acute rejection showed similar graft survival rates as non-rejecting S-allele carriers. No association between the causes of graft failure and the FOXP3 (GT)_n polymorphism was observed (p = 0.56). Cox proportional hazard regression analysis defined the (GT)_n FOXP3 gene polymorphism as an independent factor for renal allograft survival (S/SS FOXP3 gene variant: HR = 0.67, 95% CI 0.46 – 0.98, p = 0.037; SL FOXP3 gene variant: HR = 0.54, 95% CI 0.32 – 0.9, p = 0.018; the L/LL FOXP3 gene variant was regarded as reference).
Conclusion: This study is the first gene association analysis in kidney transplant patients which identified the beneficial effect of FOXP3 gene variants on graft survival.