DOI: 10.1097/hc9.0000000000000997 ISSN: 2471-254X

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

Lianne M. Nieuwenhuis, Bao-Li Loza, Stefan P. Berger, Bernadien H. Jansen, Hans Blokzijl, Mohamed R. Daha, Rosa G.M. Lammerts, Abraham Shaked, Sumeet Asrani, , Ton Lisman, Rinse K. Weersma, Eleonora A. M. Festen, Vincent E. de Meijer, Felix Poppelaars
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Background:

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.

Methods:

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.

Results:

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).

Conclusions:

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.

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