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

Area of Science:

• Immunogenetics
• Transplantation immunology
• Complement system biology

Background:

• Acute T-cell-mediated rejection (ACR) is a significant post-liver transplant complication.
• Polymorphisms in factor H gene (CFH) and factor H-related protein genes (CFHRs) are implicated in complement-related diseases.
• The complement system plays a crucial role in alloimmunity, suggesting a link to transplant rejection.

Purpose of the Study:

• To investigate the association between variants in the CFH-CFHR gene region and the risk of ACR after liver transplantation.
• To determine if donor or recipient genetic variations in CFH and CFHRs impact ACR incidence.

Main Methods:

• Genotyping of 689 donor-recipient pairs for CFHR1, CFHR3, CFHR2, and CFH variants.
• Analysis included the deletion of CFHR1 and CFHR3 (CFHR3,1Δ), a low-expression CFHR2 variant, and CFH haplotypes.
• Statistical analysis using Kaplan-Meier curves and multivariable Cox regression.

Main Results:

• Donor livers with two copies of CFHR3,1Δ or the CFH-H4a haplotype showed increased ACR incidence (HR > 1.6).
• Conversely, donor livers with a low-expressing CFHR2 variant or the CFH-H2 haplotype were associated with lower ACR incidence (HR < 1).
• Recipient CFHR3,1Δ genotype was also significantly associated with increased ACR risk (HR: 2.55).

Conclusions:

• Functional variants in the CFH-CFHR region are associated with ACR risk in liver transplantation.
• These findings underscore the importance of the complement system in liver transplant outcomes.
• Genetic screening of CFH-CFHR variants may aid in personalized risk assessment for liver transplant recipients.