Mismatches in gene deletions and kidney-related proteins are novel histocompatibility factors in kidney transplantation

ABSTRACT Background The genomic mismatch level between donor and recipient is associated with the risk of acute rejection and long-term graft survival. In the present study, we determined the association of genome-level matching with acute rejection in a single-center kidney transplantation cohort. Methods Altogether, 1025 pairs of deceased donors and kidney transplant recipients transplanted in 2007–2017 were genotyped. The associations between the sums of whole genome missense variant mismatches and missense mismatches in transmembrane, secretory, and kidney-related proteins, with acute rejection were estimated using Cox proportional hazards model. Additionally, we analyzed 40 common deletion-tagging variants using Cox model. Results The increasing mismatch sum in kidney-related proteins associated with acute rejection with an unadjusted HR of 1.15 (95% CI, 1.01–1.30; P=0.029) when dividing the sum into quartiles. The sums of other mismatches were not associated with acute rejection. In deletion analysis, a mismatch in rs7542235 (NC_000001.11:g.196854483A>G), genotype GG tagging a homozygous deletion at the complement Factor H-related (CFHR) proteins locus, predisposed to acute rejection with adjusted HR of 2.97 (95% CI, 1.46–6.05; P=0.003). Conclusions The present study supports that mismatches in gene deletions and kidney-related proteins are novel histocompatibility factors in kidney transplantation. The relative importance of different gene deletions varies between populations, as we found evidence for CFH-related gene deletion but not for the previously reported LIMS1 deletion. SIGNIFICANCE STATEMENT The first genome-wide association studies have not identified strong candidate genes for complication risks of kidney transplantation whereas matching of non-HLA genes may be promising. The current study determined the association of genome-level matching with acute rejection among 1025 kidney transplant pairs. The increasing mismatch sum in kidney-related proteins was associated with acute allograft rejection. Also, an association between acute allograft rejection and rs7542235 genotype GG, tagging a homozygous deletion at the complement factor H-related (CFHR) loci on chr 1 was found. The present study suggests that mismatches in gene deletions and kidney-related proteins are important novel histocompatibility factors in kidney transplantation.