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

PubMed, vol. 10

Abstract

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.

Authors 14

1. Lianne M. Nieuwenhuis

   University Medical Center Groningen · University of Groningen

   Affiliation as printed

   Department of Surgery, Section of Hepatopancreatobiliary Surgery and Liver Transplantation, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

   Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

2. Bao‐Li Loza

   University of Pennsylvania

   Affiliation as printed

   Department of Surgery, Penn Transplant Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

3. Stefan P Berger

   University Medical Center Groningen · University of Groningen

   Affiliation as printed

   Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

4. Bernadien H. Jansen

   University Medical Center Groningen · University of Groningen

   Affiliation as printed

   Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

5. Hans Blokzijl

   University Medical Center Groningen · University of Groningen

   Affiliation as printed

   Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

6. Daha Mr Aachen Department of Nephrology, Leiden University Medical Center

   University Medical Center Groningen · University of Groningen · Leiden University Medical Center

   Affiliation as printed

   Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

   Department of Nephrology, Leiden University Medical Center, University of Leiden, Leiden, The Netherlands

7. Rosa G. M. Lammerts

   University Medical Center Groningen · University of Groningen

   Affiliation as printed

   Transplantation Immunology, Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

8. Avi Shaked

   University of Pennsylvania

   Affiliation as printed

   Department of Surgery, Penn Transplant Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

9. S G Asrani

   Baylor University Medical Center

   Affiliation as printed

   Baylor University Medical Center, Dallas, Texas, USA

10. Ton Lisman

    University Medical Center Groningen · University of Groningen

    Affiliation as printed

    Department of Surgery, Section of Hepatopancreatobiliary Surgery and Liver Transplantation, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

11. Rinse Karel Weersma

    University Medical Center Groningen · University of Groningen

    Affiliation as printed

    Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

12. E Festen

    University Medical Center Groningen · University of Groningen

    Affiliation as printed

    Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

13. V de Meijer

    University Medical Center Groningen · University of Groningen

    Affiliation as printed

    Department of Surgery, Section of Hepatopancreatobiliary Surgery and Liver Transplantation, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

14. Felix Poppelaars

    University Medical Center Groningen · University of Groningen

    Affiliation as printed

    Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands