Extended haplotypes at the complement factor H gene locus are associated with liver transplant rejection

Acute T-cell-mediated rejection (ACR) remains an important complication after liver transplantation. Polymorphisms in the factor H gene (CFH) and factor H-related protein genes (CFHRs) affect the risk of multiple complement-related diseases. Given the complement system's key role in alloimmunity, we hypothesized that variants in CFH and CFHRs associate with ACR risk after liver transplantation.

In 689 donor-recipient pairs, the deletion of CFHR1 and CFHR3 (CFHR3,1Δ), a low-expression variant of CFHR2, and CFH haplotypes were extracted from both donor and recipient genotypes following appropriate imputation and quality control steps.

Kaplan-Meier survival curves and multivariable Cox regression analysis showed increased ACR incidence after transplantation of donor livers carrying 2 copies of the CFHR3,1Δ (log-rank p=0.03, HR: 2.76, 95% CI: 1.18-6.45) or the related CFH-H4a haplotype (log-rank p=0.03, HR: 1.65, 95% CI: 1.04-2.63). In contrast, a lower ACR incidence was observed after transplanting donor livers with a low-expressing CFHR2 variant (log-rank p=0.04, HR: 0.66, 95% CI: 0.45-0.96) or the related CFH-H2 haplotype (log-rank p=0.01, HR: 0.58, 95% CI: 0.37-0.92). When analyzing recipient genotypes, only CFHR3,1Δ was associated with ACR (log-rank: p=0.01, HR: 2.55, 95% CI: 1.15-5.65).

Common functional variants in the CFH-CFHR region are associated with rejection risk after liver transplantation, highlighting a previously overlooked relevance of the complement system in liver transplantation.