Single Nucleotide Polymorphisms and Long-Term Clinical Outcome in Renal Transplant Patients: A Validation Study

Abstract

Genome-wide association studies (GWAS) are designed to investigate single nucleotide polymorphisms (SNPs) and the association with a clinical phenotype. A previous GWAS performed in 300 renal transplant recipients identified two SNPs (rs3811321 and rs6565887) associated with serum creatinine and clinical outcome. We sought to validate these findings. Genotyping of the two SNPs was performed using Taqman assays in 1638 Caucasians participating in the Assessment of LEscol in Renal Transplant (ALERT) study. Primary endpoint was death-censored graft loss, and secondary endpoint was all-cause mortality. Applying Cox regression, no crude association to graft loss was found for rs3811321 on chromosome 14 (hazard ratio [HR] 0.87, 95% CI 0.59-1.29, p = 0.50) or rs6565887 on chromosome 18 (HR 0.88, CI 0.62-1.25, p = 0.48). Multivariable adjustments did not change results, nor did evaluation of the number of risk alleles formed by the two SNPs. No association with mortality was detected. In conclusion, an impact of two SNPs on chromosomes 14 and 18 on death-censored graft survival or all-cause mortality was not confirmed. Our results emphasize the importance of validating findings from high-throughput genetics studies and call for large collaborative research initiatives in the field of transplantation outcomes.

Using omics to explore complications of kidney transplantation

“…However, the study did not include a validation cohort. Attempted validation of the significance of these SNPs was performed in a separate Caucasian cohort of 1638 participants from the ALERT study, using the outcomes of death‐censored graft survival or mortality . No association was demonstrated in this study for either endpoint.…”

Concepts of Genomics in Kidney Transplantation

“…In an attempt to validate results of an earlier GWAS reporting two variants associated with death-censored graft survival, Pihlstrøm was unable to find a significant association with either variant. 10 In the latest GWAS reported by Ghisdal et al, using a DNA pooling approach, rs10765602 in the CCDC67 gene and rs7976329 in the PTPRO gene, associated with AR, were significant in both a discovery and a validation cohort but have not yet been validated by other investigators.…”

The impact of donor and recipient common clinical and genetic variation on estimated glomerular filtration rate in a European renal transplant population

“…[6][7][8] A study from 2013 identified recipient genotype loci on chromosomes 14 and 18 which significantly associated with 5 years serum creatinine and long-term graft survival. 9 This highlights the need for larger, robust GWAS of allograft outcome to determine the extent to which common variation affects the outcome of kidney transplantation. 9 This highlights the need for larger, robust GWAS of allograft outcome to determine the extent to which common variation affects the outcome of kidney transplantation.…”