[1945] Mannose-Binding Lectin: Analysis of Structural Gene Mutations, Promoter Polymorphisms and Serum Protein Concentrations in a Large Population of Organ Transplant Patients

Heather L Stevenson, Alexandra Amador, Jennifer McCue, Gaetano Ciancio, Linda Chen, Adela Mattiazi, Junichiro Sageshima, Giselle Guerra, Warren Kupin, George Burke, III, Si Pham, Andreas Tzakis, Phillip Ruiz. University of Texas Medical Branch, Galveston, TX; UM Miller School of Medicine, Miami, FL

Background: Mannose-binding lectin (MBL) is a plasma protein critical in mediating complement activation. Point mutations occur within the structural region of the MBL2 gene that result in allelic variants B, C, and D; the normal allele is A. Single-nucleotide polymorphisms (SNP) are found within the promoter and 5' untranslated regions, resulting in 28 genotypes. These variations may result in high or low levels of MBL protein, which has been shown to increase susceptibility to autoimmunity or infection, respectively. Our objective was to determine MBL genotype frequencies in immunocompromised transplant patients that receive induction and maintenance immunosuppressant therapy. This is the largest single-center cohort for studying MBL-2 gene variations in a given population.
Design: DNA was extracted from peripheral blood leukocytes in 1687 patients during 2010-2011. Genotyping was performed by TaqMan SNP assay, and serum protein concurrently measured in 808 patients by ELISA. Genotypes were stratified into homozygous normal (A/A), heterozygous variant (A/O), and homozygous variant (O/O) groups. Patient demographics and transplanted organ types were included in our analyses.
Results: All 28 MBL genotypes were identified. A/A genotypes were most common (n=923), followed by A/O (n=620), and O/O (n=144). The most common were LYQA/HYPA (n=178, 10.55%), LXPA/LYQA (n=144, 8.53%), and LXPA/HYPA (n=121, 7.17%), all considered homozygous normal. The lowest frequencies were observed for HYPD/HYPD (n=5, 1.6%) and the LYQC/HYPD (n=10, 0.6%), both homozygous variant genotypes. Serum MBL protein levels were significantly different between A/A, and A/O (p<0.001) and O/O (p<0.001) genotypes. The B allele occurred with low frequency in blacks, while the C allele was common, and rare among whites. The D allele was less common overall, and virtually absent in blacks.
Conclusions: MBL2 haplotypes in transplant patients are similar to other population frequencies and correlate with MBL protein levels. Serum protein levels were significantly different between the normal and variant genotypes. Since low MBL protein levels predispose to higher infection rates and recurrent disease (e.g., Hepatitis C), these data show that MBL variant identification is useful for predicting the most susceptible transplant patients to post-transplant complications, and may be used for optimizing pre- and post-transplant evaluation, prophylaxis and treatment.
Category: Pathobiology

Monday, March 19, 2012 9:30 AM

Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 285, Monday Morning

 

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