The Impact of Complement Factor H-Related Protein Gene Deletions on Kidney Transplantation

We recently reported that a homozygous deletion in the complement factor H-related (CFHR) locus predisposed kidney transplant patients to rejection. As donors carried intact genes, the susceptibility may have resulted from an alloimmune reaction to FHR proteins. However, we found no evidence for an anti-FH response. It is therefore possible that CFHR deletions as such affect the rejection risk. Here, we used MLPA and WGS to fine-map and sequence the CFHR region in rs7542235-GG patients, a SNP tagging for ΔCFHR3-1 deletion. Our results confirmed that all patients with this SNP harboured deletions of various sizes encompassing CFHR1. Furthermore, patients with homozygous ΔCFHR3-1 were homozygous for rs6677604-A, a SNP tagging for deletions of CFHR3-1 locus, confirming that allele A tags for deletion of both CFHR3 and CFHR1. Proteomics analyses in a larger population demonstrated that rs7542235-G and rs6677604-A associate with expression levels of several proteins involved in regulating alloimmune response. We observed that while increasing the rejection risk, the ΔCFHR3-1 did not associate with baseline disease or specific clinical characteristics. To conclude, the various deletion types found in patients shared the deletion of the CFHR1 gene confirming its association with variant rs7542235. Also, both deletion-tagging alleles are associated with altered expression of FHR proteins.