Polymorphisms In GSTT1, GSTM1 And CYP1A1 Genes And Risk Of Sporadic Amyotrophic Lateral Sclerosis

Objictive: Amyotrophic lateral sclerosis (ALS) is an age- dependent, progressive neurodegenerative disease selectively affecting motoneurons. It is a rapidly progressive disease that results in progressive paralysis until death occurs, usually within 3 to 5 years of onset. Approximately 10% of cases are familial (fALS), of which approximately 20% can be explained by mutations in SOD1. The remaining 90% or more of cases are sporadic ALS (sALS), and are thought to be multifactorial, with both environmental and genetic components. The cause of motor neuron degeneration in sporadic ALS is unknown, but the many possible mechanisms include oxidative stress, glutamate- mediated excitotoxicity, inflammation and apoptosis. Although multiple mechanisms clearly can contribute to the pathogenesis of motor neuron injury, recent advances suggest that oxidative stress may play a significant role in the amplification, and possibly the initiation of the disease. There is increasing evidence that environmental toxins and carcinogenic com- pounds may damage motor neuron by way of reactive oxygen species(ROS) induced cellular injury. Increased ROS levels may cause oxidative damage within motor neurons. Researches in molecular genetics have revealed that polymorphisms of some metabolizing enzyme genes, causing the enzymes with lower or losing functions of detoxification and antioxidant, may related to the development of sporadic ALS. In this study, we aimed primarily to evaluate whether polymorphisms of genes encoding the metabolic enzymes such as glutathione S-transferaseT1 (GSTT1), M1 (GSTM1) and Cytochrome P450 1A1 (CYP1A1) might contribute to the variability in individual susceptibility to sporadic ALS.Methods: The study population comprised 135 china patients with sporadic ALS and 210 control subjects. Controls were all healthy subjects matched by age and sex with sALS patients. All patients fulfilled the El Escorial criteria. Cases with familial ALS were excluded. Control subjects had no history of neurological disease and no family history of ALS. All cases and controls were of China ethnicity. The polymorphic deletion of the GSTM1 and GSTT1 genes were genotyped using the multiplex PCR approach described previously, CYP1A1 polymorphism were determined by the Method of Restriction fragment length polymorphism analysis (RFLP). Statistical analysis was done using the Statistical Analysis System (SAS) for Windows (version 8.0). Data are presented as mean±SD. The CYP1A1 genotypes distributions was compared with that as expected from Hardy-Weinberg equilibrium byχ2 tests. The difference in frequency distributions of genotypes and phenol- types between the two groups was tested byχ2 test. The association between GSTT1, GSTM1 and CYP1A1 genotypes and sporadic ALS risk was analyzed by calculating the crude odds ratios (OR) and 95% confidence intervals (95% CI) using theχ2 test.Results: Hardy-Weinberg analysis was performed to compare the observed and expected genotype frequencies of CYP1A1 usingχ2 tests, finally shows P>0.05, indicated in choosing the community the candidate gene has reached the heredity balance. The frequencies of GSTT1 null genotype in sporadic ALS patients groups and control groups were 44.4% and 48.6% respectively, The percentage of GSTM1 null genotype in cases and controls were 49.6% and 30.6% respectively. There were no significant differences in GSTT1 and GSTM1 genotype frequencies between cases and controls (p=0.4535 and 0.0859 respectively), and no statistically significant associations between the GSTT1/GSTM1 polymor- phisms and sporadic ALS risk (p=0.2067). In the CYP1A1 group, although no significant differences in total t and c allelic frequencies were noted between sporadic ALS patients and controls(P=0.4162, OR=1.14, 95%CI 0.83- 1.56), and analysis of the genotype distribution also failed to detect a significant difference between sporadic ALS and controls (P=0.1034), we found a modest association of C/C genotype of CYP1A1 with increased risk of sALS in our male population (P=0.0108).Conclusion: This is the first observational study to examine the association between the polymorphisms of The GSTT1, GSTM1 and CYP1A1 and the risk of sporadic ALS. We find that GSTT1, GSTM1 polymorphism does not influence the overall risk of sporadic ALS in Chinese population, CYP1A1 polymorphisms maybe affect incidence rate of sporadic ALS in Chinese male population.