Genetic polymorphisms of GSTP1 and mEPHX correlate with oxidative stress markers and lung function in COPD.
The genetic susceptibility to COPD might depend on variations in detoxification enzymes that activate and detoxify cigarette smoke products, which otherwise generate oxidative stress causing pathogenesis. In a case-control study of 202 COPD patients and 136 normals, we examined the association of polymorphisms I105V, A114V of GSTP1 and Y113H, H139R of mEPHX individually or in combination with disease and their contribution to oxidative stress markers such as MDA, GSH, GPx and airflow obstruction. Patients were over-represented by the alleles 105V, 114V of GSTP1 and 113H, 139H of mEPHX (chi(2)=10.63, p=0.001, chi(2)=13.92, p<0.001, chi(2)=13.02, p<0.001 and chi(2)=4.48, p=0.034, respectively) and the haplotypes of same alleles i.e. 105V-114V and 113H-139H (chi(2)=14.58, p<0.001 and chi(2)=23.14, p<0.001). Moreover, there was marked over-representation of combination of genotypes, I105I+A114A of GSTP1 (53% vs. 36%) in controls; whereas, the combinations with 105V/114V alleles (64% vs. 47%) of GSTP1 (OR=1.99; 95% CI=1.28-3.09; p=0.002) and the homozygotes H113H+H139H (27% vs.10%) of mEPHX (OR=3.26; 95% CI=1.73-6.15; p=0.0001) in patients. Patients had significantly elevated MDA level (p<0.001) and decreased GSH level (p<0.001) and GPx activity (p=0.035), respectively. Of note, the genotypes, I105V/V105V, A114V/V114V of GSTP1 and Y113H/H113H of mEPHX associated with increased MDA level (p=0.04, p=0.03 and p=0.003), decreased GSH level (p=0.019, p=0.007 and p=0.0006) and lower FEV1 (p=0.23, p=0.037 and p=0.029), respectively, in patients; so was the correlation of these biomarkers and lung function with the combinations of the genotypes. In conclusion, 105V/114V alleles of GSTP1 and 113H/139H alleles of mEPHX and the combination of genotypes with same alleles associated with imbalanced oxidative stress and lung function in patients, signifying the importance in the disease.
Vibhuti
Arpana
A
Functional Genomics Unit, Institute of Genomics and Integrative Biology, New Delhi, India.
Arif
Ehtesham
E
Deepak
Desh
D
Singh
Bhawani
B
Qadar Pasha
M A
MA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000378:metabolism; D004851:Epoxide Hydrolases / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D051549:Glutathione S-Transferase pi / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D029424:Pulmonary Disease, Chronic Obstructive / Q000175:diagnosis* / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012129:Respiratory Function Tests
D015415:Biomarkers; D017382:Reactive Oxygen Species; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D004851:Epoxide Hydrolases