The genetics of kidney transplantation

Abstract

Over the last decade, the search for gene variants with the potential to influence transplant outcomes or predispose individuals to host-recipient-related phenotypes has generated a considerable number of studies with conflicting results. Thousands of genotypes have been associated with complex traits related to transplant medicine, including acute rejection, immunosuppressive drug metabolism and side effects, infections, long-term outcomes, and cardiovascular complications. However, these efforts have given disappointing results, both in terms of gaining understanding of the biological basis of disease and in patient management. The methodological weaknesses that constitute the major limitations of most of these studies have been discussed widely. A new generation of approaches is needed to understand the relationship between gene variants and complex kidney transplantation traits. These approaches should be global, to generate original pathophysiological hypotheses, and should rely on advanced genomic tools, including Genome Wide Association studies and Whole Genome Sequencing technologies. Such enterprises will only be successful with the creation of international consortiums that connect partners in clinical, industrial, and academic transplant medicine.

Exome Sequencing and Prediction of Long-Term Kidney Allograft Function

“…Their discovery might foster the development of new immunosuppressive agents targeting the expression of these immuno-dominant epitopes. However, our study also raises a novel mechanistic hypothesis: the total burden of allogenomics mismatches might be more predictive of graft function, than mismatches at specific loci, as was previously widely expected [ 17 ].…”

“…Recipients of a kidney transplant have two genomes in their body: their germline DNA, and the DNA of the donor. It is clear that a Mendelian genetic transmission mechanism is not at play in transplantation, yet, this assumption has been made in most of the transplantation genomic studies published to date [ 16 , 17 ]. While several case-control studies have been conducted with large organ transplant cohorts, the identification of genotype/phenotype associations has been limited to the discoveries of polymorphisms with small effect, that have been reviewed in [ 18 ], and have often not been replicated [ 19 – 21 ].…”

Analysis of 75 Candidate SNPs Associated With Acute Rejection in Kidney Transplant Recipients: Validation of rs2910164 in MicroRNA MIR146A

“…There are many reasons for the high number of variants that did not replicate in this study (87, 88). For the most part, most of the published studies are underpowered.…”

Long- and short-term outcomes in renal allografts with deceased donors: A large recipient and donor genome-wide association study

“…Some of the reasons for this may include small sample sizes, variations in genotyping methodology and strategy, and, perhaps most importantly, a lack of consistency in clinical phenotyping. 20 Genome-wide association studies (GWAS) have contributed greatly to an increased understanding of complex common conditions such as inflammatory bowel disease, hypertension, type 2 diabetes, and schizophrenia. 21 A small number of GWAS have been reported in the field of renal transplantation, describing SNPs associated with cardiovascular adverse events in recipients taking calcineurin inhibitor immunosuppression, 22 2 SNPs associated with serum creatinine levels at 5 years posttransplant, 23 and a number of SNPs associated with the development of new-onset diabetes after transplantation.…”

“…In general, candidate gene studies in renal transplantation have so far failed to provide consistent and reproducible results. Some of the reasons for this may include small sample sizes, variations in genotyping methodology and strategy, and, perhaps most importantly, a lack of consistency in clinical phenotyping . Genome‐wide association studies (GWAS) have contributed greatly to an increased understanding of complex common conditions such as inflammatory bowel disease, hypertension, type 2 diabetes, and schizophrenia .…”