Glyoxalase I A111E, paraoxonase 1 Q192R and L55M polymorphisms: Susceptibility factors of multiple sclerosis?

Department of Biomorphology and Biotechnologies, University of Messina, 98100, Italy.
Multiple Sclerosis (Impact Factor: 4.82). 06/2007; 13(4):446-53. DOI: 10.1177/13524585070130040201
Source: PubMed


Multiple sclerosis (MS) is characterized by chronic inflammation and demyelination of the central nervous system (CNS). Accumulating data indicate that oxidative stress, leading to reactive oxygen species (ROS) production and lipid peroxidation, as well as elevated levels of advanced glycation end products (AGE) in CNS neurons, might play a pivotal role in the pathogenesis of a number of diseases with a neurodegenerative aspect, such as MS. Therefore, polymorphisms of genes encoding endogenous free-radical scavenging systems, such as paraoxonase 1 (PON1), and anti-glycation defences, such as glyoxalase I (GI), could influence susceptibility to MS. In the present study, we have undertaken a case-control study to investigate the possible association of GI A111E, PON1 Q192R and L55M polymorphisms with the risk of MS. The three polymorphisms were characterized in 209 patients with relapsing-remitting MS (RRMS) and in 213 healthy controls by PCR/RFLP methods using DNA from lymphocytes. We found that individuals with the GI/AE-EE genotypes and PON55/LM-MM genotypes had a significantly higher risk of MS compared with the other genotypes. The two polymorphisms appear to be common genetic traits that are associated with an increased risk for MS--the analysis of both, in each single case, may be a revealing predictable factor for MS risk.

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Available from: Rosalia D'Angelo, Jan 15, 2014
    • "Moreover, it was reported that GLO1 expression is correlated with brain iron in mice [7], a pathway suggested to be important in RLS. GLO1 was previously associated with other traits, such as neuropathy in diabetic patients [8] and multiple sclerosis [9], as well as with several behavioral phenotypes, such as anxiety and depression [10], which are also associated with RLS [3]. Two common variations in GLO1, the amino acid variation p.E111A and the promoter variant rs1049346 (c.-7C > T), were suggested to reduce the activity of glyoxalase I [11] [12]. "
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    ABSTRACT: Background: Restless Legs Syndrome (RLS) is a common, age- and gender-related disorder. Although several genetic risk factors were identified, the actual genetic causes are unclear. Methods: Whole exome sequencing (WES) was performed in seven families with RLS, focusing on potential genetic causes around six known genetic loci; MEIS1, BTBD9, PTPRD, MAP2K5/SKOR1, TOX3 and the intergenic rs6747972. Subsequently, genotyping using specific TaqMan assays was performed in two case-control cohorts (627 patients and 410 controls), and in a familial cohort (718 individuals). Results: WES identified two potential candidate variants in the GLO1 gene (within the BTBD9 locus), the p.E111A variant and the promoter variant c.-7C>T, both co-segregated with the disease in four families. The GLO1 p.E111A variant was associated with RLS in the French-Canadian cohort (OR 1.38, p=0.02), demonstrated a similar trend in the US cohort (OR 1.26. p=0.09, combined analysis OR=1.28 and p=0.009). However, the original GWAS marker, BTBD9 rs9357271 was more strongly associated with RLS (OR=1.84, p=0.0003), and conditional haplotype analysis, controlling for the effect of the BTBD9 SNP, demonstrated that the association of GLO1 p.E111A turned insignificant (p=0.54). In the familial cohort, the two GLO1 variants were not associated with RLS. Other variants, identified using WES in the SKOR1 (p.W200R, p.A672V) and PTPRD (p.R995C, p.Q447E p.T781A, p.Q447E and c.551-4C>G) genes, did not co-segregate with the disease. Conclusions: The GLO1 variations studied here are not the source of association of the BTBD9 locus with RLS. It is likely that the genetic variants affecting RLS susceptibility are located in regulatory regions.
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    • "Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by demyelization (myelin loss), gliosis, varying degrees of axonal pathology, and progressive neurological dysfunction [1]. Accumulating data indicate the importance of oxidative stress in the pathogenesis of MS and suggest that genes mediating the cellular antioxidant response are candidates for MS development and progression [2] [3] [4] [5] [6] [7]. The role of oxidative stress is supported by biochemical studies in blood and cerebrospinal fluid, MRI findings, and studies in experimental autoimmune encephalomyelitis (EAE; the generally accepted animal model for the study of MS). "

    Full-text · Dataset · Sep 2012
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    • "Furthermore, the difference between our study and those reported by Ferretti et al. [11] may be due to different allele distribution in the population which has been studied. In another study Sidoti et al. [9] reported an increased risk of MS in a cohort of 209 Italian patients with the PON-55/LM-MM genotype. The odds ratios for the heterozygote LM and homozygote MM genotypes were 26.12 and 2.83 respectively. "
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    ABSTRACT: The aim of this study was to estimate the serum activity of paraoxonase 1(PON1) and assess the distribution of PON1 polymorphisms in MS patients in the relapse phase. PON1 and arylesterase (ARE) serum activities were measured in two equal groups (each group 63 cases) of relapsing-remitting MS patients and healthy individuals. Mean values for serum PON1 and ARE activities were 90.3±63.4 and 182.1±128.7IU/L for patients and 99.9±73.3 and 190.8±150.3IU/L for controls. Those values were not statistically significant (p=0.242 and p=0.378), respectively. Comparing genotype distributions and allele frequencies in both groups for PON1 Q192R and PON L55M polymorphisms did not show any statistical difference. In a selected group of MS patients in relapsing phase no statistically significant difference in PON1 and ARE activities was detected but the mean values for the serum enzyme activities were lower in MS patients.
    Full-text · Article · Jul 2011 · Clinical biochemistry
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