Lectin Complement Pathway Gene Polymorphisms and LifeThreatening Infections after Orthotopic Liver Transplantation
BF de Rooij1, B van Hoek1, WR ten Hove1, A Roos2, LH Bouwman4, AF Schaapherder4,
RJ Porte5, MR Daha3, JJ van der Reijden1, MJ Coenraad1, J Ringers4, AG Baranski4, BG
Hepkema6, DW Hommes1, HW Verspaget1
Depts of Gastroenterology and Hepatology1, Clinical Chemistry2, Nephrology3, Surgery4,
Leiden University Medical Center, Leiden, The Netherlands, Depts of Hepatobiliary
Surgery and Liver Transplantation5, Laboratory Medicine6, University Medical Center
Groningen, University of Groningen, Groningen, The Netherlands
The study was supported by grants from the Dutch Digestive Foundation (WO 07-18)
and the Stichting Prof. A.A.H. Kassenaar Fonds from the Leiden University Medical
Center.
ABSTRACT
Background. Components of the lectin complement pathway are liver-derived and
crucial effectors of the innate immune response to pathogens. Immunosuppressed
orthotopic liver transplantation (OLT) recipients almost completely rely on their innate
immunity. We examined the role of gene polymorphisms (SNPs) in the complete lectin
complement activation pathway, which affect the functional activity of the respective
proteins, in association with the risk of developing clinically significant infections after
OLT.
Methods. We analyzed 13 SNPs in the mannose-binding lectin gene (MBL2), the
Ficolin-2 gene (FCN2) and the MBL-associated serine protease gene (MASP2) in 143
recipients and their donor liver, and in a confirmation cohort of 167 OLT patients.
Multivariate Cox analysis was used to assess the contribution of these SNPs to infection
risk in the first year after transplantation.
Results. The intergenic haplotype with mutations in all three components of the lectin
pathway, i.e., MBL2 (XA/O; O/O), FCN2+6359T and MASP2+371A, in the donor liver
increased the cumulative risk of clinically significant infection from 18% up to 75% (Χ2=
14.7, P=0.002). The confirmation study showed a similar association of donor haplotype
and infection (Χ2= 8.2, P=0.04). The intergenic haplotypes of the recipients did not
contribute to the infection risk after transplantation, although genotypically MBL-sufficient
recipients receiving a genotypically MBL-insufficient donor liver had a significantly higher
infection risk (52% vs 26%, P<0.002). The multivariate Cox analysis including all patients
revealed a stepwise increase in infection risk with the intergenic gene dose haplotype
(up to an adjusted HR of 4.52; 95% CI 1.81 to 11.31; P=0.001), independent from
gender and antibiotic prophylaxis treatment algorithm (both with adjusted HR > 2.2 and
P<0.02). Moreover, within the group of patients receiving a liver with one or more lectin
pathway gene mutations those with an infection had a significantly higher mortality than
those without an infection (28% vs 4%, P<0.9x10-8).
Conclusions. The intergenic donor liver haplotype of the lectin complement pathway is
a major determinant of the risk of clinically significant infection and mortality after OLT. In
addition, MBL-sufficient recipients receiving an MBL-insufficient donor liver are at high
risk. Screening of the lectin complement pathway haplotype is advocated to improve
postoperative infection prevention and patient survival in OLT.