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HLA Variants Key to Predicting Kidney Transplant Outcomes

NEW YORK (GenomeWeb) – Variants within the human leukocyte antigen (HLA) locus are likely the most important for predicting whether a kidney transplant will be successful, a new study has found.

While kidney transplant outcomes have improved over the past decade, there are a number of factors that affect long-term outcomes, including HLA mismatch. The HLA gene complex helps the immune system tell friend from foe, and close matches are needed in organ transplants to limit rejection.

Researchers led by King's College London's Graham Lord conducted a genome-wide association study of organ donor and recipient DNA from about 8,000 pairs of donors and recipients. As they reported in the American Journal of Transplantation this week, they replicated known links between the HLA region and outcomes, but were unable to find any genetic link to outcomes outside that region.

"[W]e identified that this area of DNA alone can tell us whether the match between a kidney donor and recipient will work in the long term," Lord said in a statement. "This has the potential to improve outcomes for transplant patients and deliver treatments that are more personalized to the health needs of individual patients."

As part of the Wellcome Trust Case Control Consortium, renal transplant centers in the UK and Ireland formed their own consortium, the United Kingdom and Ireland Renal Transplant Consortium, which collected 3,936 samples, including 2,094 complete donor-recipient pairs. This cohort formed the discovery phase of the GWAS.

After genotyping, quality control, and imputation, Lord and his colleagues tested whether any genetic region among the pairs was associated with graft survival, acute rejection, end-stage renal failure, or intracranial hemorrhage. While they uncovered no SNPs associated with these outcomes in the discovery phase that reached significance, the researchers went forward with a replication analysis in a further 5,866 donor-recipient pairs from the University of Heidelberg's Transplant Study DNA Biobank using the most significant 139 SNPs.

However, that replication study and a meta-analysis of both phases again didn't reveal any SNPs with genome-wide significance. Although their study involved thousands of participants, the researchers noted that it still was small compared to other GWAS analyses and might not have been able to tease out variants with small effect sizes. Additionally, analyses of recipient-donor pairs often require even larger samples, they said.

They also pointed out that their outcomes data came from national registries and thus might have been heterogeneous. Further, batch effects might have influenced their findings as the discovery and replication datasets were collected from multiple sites over a number of years, they said.

But, Lord and his colleagues reported that the serological typing data collected on the pairs confirmed known associations at HLA-A and HLA-DRB. This suggested to the researchers that genetic signals outside the HLA region are weaker than the established ones within it. This led them to suggest that genes outside the HLA region are unlikely to have value in clinical prediction of transplant outcomes, though they might be able to shed additional light on the biological processes involved.

They noted in their paper that an international consortium called iGeneTrain has been established to share and analyze data from large transplant cohorts and that efforts to collect more detailed phenotypes might give better genetic resolution.