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

Abstract

Genetic variation across the human leukocyte antigen loci is known to influence renal‐transplant outcome. However, the impact of genetic variation beyond the human leukocyte antigen loci is less clear. We tested the association of common genetic variation and clinical characteristics, from both the donor and recipient, with posttransplant eGFR at different time‐points, out to 5 years posttransplantation. We conducted GWAS meta‐analyses across 10 844 donors and recipients from five European ancestry cohorts. We also analyzed the impact of polygenic risk scores (PRS), calculated using genetic variants associated with nontransplant eGFR, on posttransplant eGFR. PRS calculated using the recipient genotype alone, as well as combined donor and recipient genotypes were significantly associated with eGFR at 1‐year posttransplant. Thirty‐two percent of the variability in eGFR at 1‐year posttransplant was explained by our model containing clinical covariates (including weights for death/graft‐failure), principal components and combined donor‐recipient PRS, with 0.3% contributed by the PRS. No individual genetic variant was significantly associated with eGFR posttransplant in the GWAS. This is the first study to examine PRS, composed of variants that impact kidney function in the general population, in a posttransplant context. Despite PRS being a significant predictor of eGFR posttransplant, the effect size of common genetic factors is limited compared to clinical variables.

The Clinical Impact of the C0/D Ratio and the CYP3A5 Genotype on Outcome in Tacrolimus Treated Kidney Transplant Recipients

“…In a meta-analysis Rojas found that the CYP3A5 expresser genotype might be associated with a higher risk of acute rejection (OR 1.32, 95% CI 1.02-1.71) and a trend towards more chronic nephrotoxicity (OR 1.81, 95% CI 0.89-3.68) (Rojas et al, 2015). However, a large-scale genome-wide association study did not identify strong donor or recipient genetic predictors of allograft survival or renal function outside the HLA region (Hernandez-Fuentes et al, 2018;Stapleton et al, 2019). Also a candidate gene association study of allograft loss in renal transplant recipients CYP3A5 was not related to outcome (Woillard et al, 2018).…”

Recycling of predictors used to estimate glomerular filtration rate: Insight into lateral collinearity

“…This simulation analysis shows that creatinine, age, ethnicity, and gender are not independently associated with eGFR but a result of lateral collinearity (Fig 2). Such misleading associations have been described in several studies (Das et al [10] and Stapleton et al [11]). We also considered that the collinearity arises when the predictors used to estimate GFR were present in the equations.…”

“…As an example of lateral collinearity in the study by Das et al [10], glomerular filtration was estimated with laboratory data and conclusions are drawn from regression based on age, ethnicity, and sex, variables that are also used to estimate GFR. Similarly, in a recent study by Stapleton et al [11], the eGFR calculated by CKD-EPI was used as the outcome variable and the log 10 eGFR was correlated with several predictors including recipient age [11]. In this example, the explanatory capacity of the statistical model has been compromised.…”

Genetic background and transplantation outcomes: insights from genome-wide association studies

“…Recent study evaluated the performance of a genome-wide PRS in predicting allograft function in 10,844 donor-recipient pairs (46). The PRS was expressed as an effect sizeweighted sum of independent risk alleles that reached P-value of less than 1×10 −4 in the recent population-based GWAS for kidney function (47).…”