Vibhuti Arpana, Arif Ehtesham, Deepak Desh, Singh Bhawani, Qadar Pasha M A
Functional Genomics Unit, Institute of Genomics and Integrative Biology, New Delhi, India.
Biochem Biophys Res Commun. 2007 Jul 20;359(1):136-42. doi: 10.1016/j.bbrc.2007.05.076. Epub 2007 May 22.
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.
慢性阻塞性肺疾病（COPD）的遗传易感性可能取决于解毒酶的变异，这些酶可激活香烟烟雾产物并使其解毒，否则这些产物会产生氧化应激导致发病机制。在一项对202例COPD患者和136例正常人的病例对照研究中，我们分别或联合检测了谷胱甘肽S-转移酶P1（GSTP1）的I105V、A114V多态性以及微粒体环氧化物水解酶（mEPHX）的Y113H、H139R多态性与疾病的关联及其对氧化应激标志物如丙二醛（MDA）、谷胱甘肽（GSH）、谷胱甘肽过氧化物酶（GPx）和气流阻塞的影响。GSTP1的105V、114V等位基因以及mEPHX的113H、139H等位基因在患者中的比例过高（分别为χ² = 10.63，p = 0.001；χ² = 13.92，p < 0.001；χ² = 13.02，p < 0.001；χ² = 4.48，p = 0.034），相同等位基因的单倍型即105V - 114V和113H - 139H也是如此（χ² = 14.58，p < 0.001；χ² = 23.14，p < 0.001）。此外，GSTP1的I105I + A114A基因型组合在对照组中的比例显著过高（53%对36%）；而GSTP1的105V/114V等位基因组合（64%对47%）（比值比[OR] = 1.99；95%置信区间[CI] = 1.28 - 3.09；p = 0.002）以及患者中mEPHX的纯合子H113H + H139H（27%对10%）（OR = 3.26；95% CI = 1.73 - 6.15；p = 0.0001）在患者中的比例也显著过高。患者的MDA水平显著升高（p < 0.001），GSH水平显著降低（p < 0.001），GPx活性降低（p = 0.035）。值得注意的是，GSTP1的I105V/V105V、A114V/V114V基因型以及mEPHX的Y113H/H113H基因型分别与患者MDA水平升高（p = 0.04，p = 0.03，p = 0.003）、GSH水平降低（p = 0.019，p = 0.007，p = 0.0006）以及第一秒用力呼气容积（FEV1）降低（p = 0.23，p = 0.037，p = 0.029）相关；这些生物标志物和肺功能与基因型组合之间的相关性也是如此。总之，GSTP1的105V/114V等位基因、mEPHX的113H/139H等位基因以及相同等位基因的基因型组合与患者氧化应激失衡和肺功能相关，表明其在该疾病中的重要性。
