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From: ironjustice on 6 Sep 2008 13:39
Research article
Detection of Catalase as a major protein target of the lipid
peroxidation product 4-HNE and the lack of its genetic association as
a risk factor in SLE
Anil D'souza1,2 , Biji T Kurien1 , Rosalie Rodgers1 , Jaideep
Shenoi1 , Sadamu Kurono2,3 , Hiroyuki Matsumoto2 , Kenneth Hensley1 ,
Swapan K Nath1,2 and R Hal Scofield1,2,4

1Department of Arthritis and Immunology, Oklahoma Medical Research
Foundation, Oklahoma City, Oklahoma, USA

2College of Medicine, University of Oklahoma Health Sciences Center,
Oklahoma City, Oklahoma, USA

3Iberica Co., Ltd., Kurume University Translational Research Center,
Kurume-shi, Fukuoka 830-0011, Japan

4Dept. of Veterans Affairs Medical Center, Oklahoma City, Oklahoma,
USA

BMC Medical Genetics 2008, 9:62doi:10.1186/1471-2350-9-62

Published: 7 July 2008

Abstract
Background
Systemic lupus erythematosus (SLE) is a multifactorial disorder
characterized by the presence of autoantibodies. We and others have
implicated free radical mediated peroxidative damage in the
pathogenesis of SLE. Since harmful free radical products are formed
during this oxidative process, including 4-hydroxy 2-nonenol (4-HNE)
and malondialdehyde (MDA), we hypothesized that specific HNE-protein
adducts would be present in SLE red blood cell (RBC) membranes.
Catalase is located on chromosome 11p13 where linkage analysis has
revealed a marker in the same region of the genome among families with
thrombocytopenia, a clinical manifestation associated with severe
lupus in SLE affected pedigrees. Moreover, SLE afflicts African-
Americans three times more frequently than their European-American
counterparts. Hence we investigated the effects of a genetic
polymorphism of catalase on risk and severity of SLE in 48 pedigrees
with African American ancestry.

Methods
Tryptic digestion followed by matrix assisted laser desorption/
ionization time-of-flight mass spectrometry (MALDI-TOFMS) analysis was
used to identify the protein modified by HNE, following Coomassie
staining to visualize the bands on the acrylamide gels. Genotyping
analysis for the C $B"*(B T, -262 bp polymorphism in the promoter region of
catalase was performed by PCR-RFLP and direct PCR-sequencing. We used
a "pedigree disequilibrium test" for the family based association
analysis, implemented in the PDT program to analyze the genotyping
results.

Results
We found two proteins to be HNE-modified, migrating around 80 and 50
kD respectively. Tryptic digestion followed by matrix assisted laser
desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS)
analysis of the Coomassie stained 80 kD band revealed that the target
of HNE modification was catalase, a protein shown to associate with
RBC membrane proteins. All the test statistics carried out on the
genotyping analysis for the C $B"*(B T, -262 bp polymorphism in the
promoter region of catalase were non-significant (p > 0.05) in our
data, which suggested that this SNP is not associated with SLE.

Conclusion
Our results indicate that catalase is one of the proteins modified due
to oxidative stress. However, catalase may not be a susceptibility
gene for SLE. Nonetheless, catalase is oxidatively modified among SLE
patients. This suggests a possible role between oxidative modification
of catalase and its affects on enzymatic activity in SLE. An
oxidatively modified catalase could be one of the reasons for lower
enzymatic activity among SLE subjects, which in turn could favor the
accumulation of deleterious hydrogen peroxide. Furthermore, HNE-
products are potential neoantigens and could be involved in the
pathogenesis of SLE. Decrease in catalase activity could affect the
oxidant-antioxidant balance. Chronic disturbance of this balance in
patients with SLE may work favorably for the premature onset of
atherogenesis with severe vascular effect.


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