Lectin Complement Pathway Gene Profile of Donor and Recipient Determine the Risk of Bacterial Infections After Orthotopic Liver Transplantation†,‡

Abstract

Infectious complications after orthotopic liver transplantation (OLT) are a major clinical problem. The lectin pathway of complement activation is liver-derived and a crucial effector of the innate immune defense against pathogens. Polymorphisms in lectin pathway genes determine their functional activity. We assessed the relationship between these polymorphic genes and clinically significant bacterial infections, i.e., sepsis, pneumonia, and intra-abdominal infection, and mortality within the first year after OLT, in relation to major risk factors in two cohorts from different transplant centers. Single-nucleotide polymorphisms in the mannose-binding lectin gene (MBL2), the ficolin-2 gene (FCN2), and the MBL-associated serine protease gene (MASP2) of recipients and donors were determined. Recipients receiving a donor liver in the principal cohort with polymorphisms in all three components i.e., MBL2 (XA/O; O/O), FCN216359T, and MASP21371A, had a cumulative risk of an infection of 75% as compared to 18% with wild-type donor livers (P 5 0.002), an observation confirmed in the second cohort (P 5 0.04). In addition, a genetic (mis)match between donor and recipient conferred a two-fold higher infection risk for each separate gene. Multivariate Cox analysis revealed a stepwise increase in infection risk with the lectin pathway gene profile of the donor (hazard ratio 5 4.52; P 5 8.1 3 10 26 ) and the donor-recipient (mis)match genotype (hazard ratio 5 6.41; P 5 1.9 3 10 27 ), independent from the other risk factors sex and antibiotic prophylaxis (hazard ratio > 1.7 and P < 0.02). Moreover, patients with a lectin pathway gene polymorphism and infection had a six-fold higher mortality (P 5 0.9 3 10 28 ), of which 80% was infectionrelated. Conclusion: Donor and recipient gene polymorphisms in the lectin complement pathway are major determinants of the risk of clinically significant bacterial infection and mortality after OLT. (HEPATOLOGY 2010;52:1100-1110 Abbreviations: CI, confidence interval; CSI, clinically significant bacterial infection; HR, hazard ratio; MASP, MBL-associated serine protease; MBL, mannosebinding lectin; MELD, Model for End-Stage Liver Disease; OLT, orthotopic liver transplantation; SNP, single-nucleotide polymorphism.From the

Fc-Gamma Receptor Polymorphisms Predispose Patients to Infectious Complications After Liver Transplantation

“…The lectin pathway of complement activation is liver-derived and a crucial effector of the innate immune defense against pathogens. One study has demonstrated that SNPs within donor genes involved in the lectin complement pathway (mannosebinding lectin 2 [MBL2], ficolin-2 [FCL2], and mannanbinding lectin-associated serine protease 2 [MASP2]) determine the risk of bacterial infections after LT (35). The value of the donor MBL2 genotype as a risk factor for infection after LT has been also supported by prior studies (36,37).…”

Mannose-binding lectin and Ficolin-2 gene polymorphisms predispose to cytomegalovirus (re)infection after orthotopic liver transplantation

“…Results were considered statistically significant when p values were <0.05. Bonferroni correction for multiple comparison tests was not performed because SNPs were selected on the basis of a deducible hypothesis, i.e., the reported associations with bacterial infections [2] and preliminary studies on CMV in OLT [9] consequence of the SNP on the function of the respective proteins and the liver as their production organ. All analyses were performed with SPSS Statistical Software Package (version 16.02, SPSS Inc., Chicago, IL).…”

“…The structurally similar pattern-recognition receptors mannose-binding lectin (MBL) and Ficolin-2 bind carbohydrate ligands on pathogens and initiate the lectin pathway of complement activation via MBL-associated serine proteases (MASPs), predominantly through MASP-2. Common single nucleotide polymorphisms (SNPs) in the genes coding for these three members of the lectin complement pathway result in diverse protein variants and altered protein levels with potentially important functional implications, as recently shown by us for bacterial infections after OLT [2].…”

“…SNPs in the MBL2, FCN2, and MASP2 genes were determined with the use of high resolution DNA melting assays (HRMA) with the oligonucleotide primers as indicated in Supplementary Table 1 [2,13,14]. Briefly, HRMA of PCR products, amplified in the presence of a saturating double-stranded DNA dye (LCGreenPlus, Idaho Technology) and a 3 0 -blocked probe, identifies both heterozygous and homozygous sequence variants by a change in melting temperature curves, verified by DNA sequenced controls.…”

Complement—here, there and everywhere, but what about the transplanted organ?

“…MBL levels may also be used as lectin pathway complement biomarkers with higher risks of infections reported in those with low MBL expression post liver transplant reflecting underlying inactivity of the lectin pathway [140]. In kidney transplants, high levels of MBL correlate with aggressive rejection and graft failure [55].…”