Polymorphism of glutathione S-transferase M1 and T1 gene LOCI in COPD

Polymorphism of glutathione S-transferase M1 and T1 gene LOCI in COPD
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  Polymorphism of glutathione S-transferase M1 and T1 gene LOCI inCOPD S. Mehrotra*, A. Sharma†, S. Kumar‡, P. Kar‡, S. Sardana§ & J. K. Sharma†Summary Chronic obstructive pulmonary disease (COPD) is acomplex combination of signs and symptoms in patientswith chronic bronchitis and emphysema, diseases thatlargely result from cigarette smoking. A little informa-tion is available for the underlying molecular mecha-nisms that are responsible for its occurrence.Polymorphisms in genes of xenobiotics metabolizingenzymes are expected to modulate individual responsesto genotoxic carcinogens. Present study was a case–control study of COPD patients and healthy controls.Genetic polymorphisms of   GSTM1  and  GSTT1  genes in50 COPD patients and 50 healthy controls wereinvestigated using multiplex polymerase chain reac-tion–restriction fragment length polymorphism tech-niques to determine whether polymorphisms of thesegenes are linked to genetic susceptibility to COPD. Allsubjects were males and smokers. The frequency of  GSTM1  homozygous null genotype was 28.0% inCOPD cases when compared with controls (32.0%).The difference was not significant showing that risk of COPD was not associated with the  GSTM1  nullgenotypes. The frequencies of homozygous null geno-types of   GSTT1  were significantly higher in COPDcases as compared with controls (40% versus 14.0%)suggesting that the theta-glutathione S-transferases nullgenotype may be associated with the susceptibility toCOPD. No significant differences were observed whencomparisons were performed according to severity of disease and smoking for  GSTM1  and  GSTT1.  It wasalso observed that COPD developed in the early age andwith a shorter pack-year history in Indian population. Introduction Chronic obstructive pulmonary disease (COPD) ischaracterized by the progressive and irreversible air-flow in the lung airway. Cigarette smoking is themost important risk factor leading to the develop-ment of COPD. Smoking accounts for as much as80–85% cases of COPD while only 15% smokersdevelop clinically symptomatic COPD (Yim  et al. ,2000). Recent studies have reported that genetic vari-ations in the enzymes that detoxify cigarette smokeproducts might be associated with the development of COPD. Glutathione S-transferase (GST) is one of these enzymes.Glutathione S-transferases are a large family of enzymes, participating in detoxification of endogenousand environmental xenobiotics. Cytosolic GSTenzymes are divided into eight classes: alpha (GSTA),mu (GSTM), theta (GSTT), pi (GSTP), zeta, sigma,kappa and chi (Strange  et al. , 2001). The  GSTM1 ,  T1 and  P1  genes are located on chromosome 1p13,22q11.2 and 11q13 respectively.  GSTM1  is involvedin detoxification of active metabolites of polycyclicaromatic hydrocarbons (Ketterer  et al. , 1988). Thehomozygous  GSTM1  null genotype has been reportedto show some association with the pathogenesis of lung cancer (Lan  et al. , 2000; Hengstler  et al. , 1998;Dialyna  et al. , 2003), emphysema (Harrison  et al. ,1997), asthma patients (Tamer  et al. , 2004) andCOPD (Harrison  et al. , 1997; Cheng  et al. , 2004;Tkacova  et al. , 2004; Hemimi  et al. , 2008; Dimov et al. , 2008). GSTT1 participates in detoxification of small hydrocarbons of tobacco smoke (such as monohalomethanes and ethylene oxide) (Lan  et al. , 2000). GSTT1  null genotype has also been suggested as a riskfactor in many diseases (Tamer  et al. , 2004; Cheng et al. , 2004; Chenevix-Trench  et al. , 1995; Chen et al. , 1996b; Elexpuru-Camiruaga  et al. , 1995).Generally, the homozygous null genotype of   GSTM1 is more frequent than the  GSTT1  null genotype(Hengstler  et al. , 1998; Lin  et al. , 1994).Susceptibility to COPD is not a single-gene event.Ethnic differences also exist. Data about COPD arescarce. We are reporting  GSTM1  and  GSTT1  genepolymorphism in Indian COPD patients. * Department of Cardiology, Nehru Hospital, PGI, Chandigarh, India,† Division of Molecular Diagnostics, Institute of Cytology and Pre-ventive Oncology (ICMR), Noida, India,  ‡  Department of Medicine,Maulana Azad Medical College, New Delhi, India, and § Division ofEpidemiology & Biostatistics, Institute of Cytology and PreventiveOncology (ICMR), Noida, IndiaReceived 22 July 2009; revised 20 January 2010; accepted 12February 2010Correspondence: J.K. Sharma, ICPO (ICMR), I-7, Sector 39, Noida(UP), India 201301. Tel: +91 9313010054; Fax: +91 1202579473;E-mail: ª  2010 Blackwell Publishing Ltd,  International Journal of Immunogenetics   37 , 263–267  263 doi: 10.1111/j.1744-313X.2010.00918.x  Materials and methods Study population The study group comprised 50 cases of COPD and 50normal controls. All control subjects were male andwere current smokers, free from any pulmonary dis-ease found through a pulmonary function test (PFT),which was normal. None of the control subjects hadany family history of COPD. Cases were collectedfrom Lok Nayak Hospital, New Delhi, from the out-patient department as well as from indoors. Men withCOPD were in the age group of 30–60 years. COPDwas diagnosed on the basis of history, clinical exami-nation, radiological examination, arterial blood gasanalysis (ABG) and PFT. PFT, such as FEV1 (forcedexpiratory volume), FVC (forced vital capacity),FEV1   ⁄   FVC, MMEF and PO 2,  PCO2, pH was per-formed in all cases and controls. Any patient with ahistory of bronchial asthma, diabetes, hypertensionand any other associated primary neoplasm, or havinga history of it was excluded from the study. Criteriafor inclusion of cases included patients suffering fromexertional dyspnoea of varying severity throughout theyear, and with a history of cough with expectorationfor more than 2 years, the expectoration being mucoidor occasionally mucopurlent, and present on mostdays for two consecutive years. Routine laboratoryinvestigations like examination of blood, haemogram,serum electrolytes, blood urea, blood sugar, examina-tion of the sputum for Gram stain, acid fast bacilli,etc. were carried out. Postero–anterior view of thechest X-ray was taken as a rule in all the patients.Patients gave a written consent prior to blood anddata collection. Ethical clearance was taken fromthe Ethical committee of the Maulana Azad MedicalCollege. DNA isolation High molecular weight DNA from peripheral blood of COPD cases was isolated using standard procedures of proteinase K digestion and phenol-chloroform extrac-tion (Maniatis  et al. , 1982). Genotyping assays The homozygous null polymorphisms of   GSTM1  and GSTT1  genotypes were analysed by multiplex poly-merase chain reaction (PCR) method (Arand  et al. ,1996) with slight modifications (Sharma  et al. , 2004)by using three sets of primers, GSTM1 forwardGSTM1, 5 ¢ -GAACTCCCTGAAAAGCTAAAGC-3 ¢ andreverse 5 ¢ -GTTGGGCTCAAATATACGGTGG-3 ¢ ; GS-TT1, 5 ¢ -TTCCTTACTGGTCCTCACATCTC-3 ¢ and 5 ¢ -TCACCGGATCATGGCCAGCA-3 ¢ ; Albumin, 5 ¢ - GCCCTCTGCTAACAAGTCCTAC-3 ¢  and 5 ¢ - GCCCTAAAAA-GAAAATCGCCAATC-3 ¢ . PCR were performed in25  l L of reaction volume containing 50–100 ng of genomic DNA, 50 m M  KCl, 2.5 m M  MgCl 2,  200 m M Tris–HCl (pH 8.4), 200 m M  of dNTP, GSTM1,GSTT1 and Albumin primers at 0.2  l M  each and1.5 U DNA AmpliTaq DNA polymerase (Cetus,Emeryville, CA, USA) in a Perkin-Elmer thermalcycler (Norwalk, CT, USA). After an initial denatur-ation at 95  C for 5 min, amplification was carriedout for 35 cycles at 94  C for 1 min, 56  C for 1 minand 72  C for 1 min., followed by final extension at72  C for 7 min. The products of multiplex PCR wereseparated by electrophoresis with ethidium bromidestained 3% agarose gel. Presence of amplicons of 218, 460 and 350 bp revealed the presence of GSTM1, GSTT1 and Albumin (internal control)respectively (Fig. 1). Results The study was conducted on 50 stable patients of COPD and 50 healthy control male individuals. Indi-viduals of both groups were matched for age and allwere smokers. In all 100 individuals the parametersthat were measured included: ABG, pack years, PFT(FEV1, FVC and FEV1   ⁄   FVC) and  GSTM1  and GSTT1  genotype. Statistical analysis was carried outusing the chi-square test for categorical variables andthe students  t  -test for continuous variables. The datawere tabulated and analysed. Age distribution between the study and control group The mean age of COPD patients was51.67 ± 8.9 years while in the control group it was51.40 ± 7.65 years. The individuals were categorizedaccording to age, severity of disease, smoking status,etc. (Table 1). The minimum age was 32 years andthe maximum 70 years. When the data were analysedaccording to age groups i.e.  £ 44,  ‡ 45–54 and>55 years, the differences in frequencies of GSTM1and both GSTM1T1 null genotype frequencies werenot significant between COPD cases and controls. Figure 1.  Representative multiplex polymerase chain reaction analy-sis of GSTM1 and GSTT1 gene products resolved on 3% agarosegel electrophoresis. A 350 bp DNA fragment corresponding to Albu-min gene product provide an internal positive control, seen in alllanes. A 218 bp product seen only in lanes 2–5 and 8 indicates thepresence of at least one copy of GSTM1gene, while a 460 bp prod-uct of GSTT1 gene seen in lane 2, 4, 5, 7 and 8 indicates GSTT1positive. Lane 6 indicates the absence of both GSTM1 and GSTT1genes. Lane 1 is Phi X Hae III digested marker. 264 S. Mehrotra  et al. ª  2010 Blackwell Publishing Ltd,  International Journal of Immunogenetics   37 , 263–267  Whereas differences in  GSTT1  null genotype frequen-cies were statistically significant ( P  = 0.02 and 0.04) inboth the age groups i.e.  £ 44 and  ‡ 45–54 years but notin  ‡ 55 years of age group (data not shown). Grading of severity of COPD in study group The minimum FEV1 in the study group was 23.2%and the maximum 65.5%. Of the 50 patients in thestudy group, 22 (44%) were in the moderate category(FEV1 between 40% and 59%), 18 (36%) in thesevere (FEV1 < 40%), and 10 (20%) in the mild cate-gory (FEV1 between 60% and 80%; Table 1). No sig-nificant differences were observed between thesegroups for  GSTM1 and  GSTT1  genotypes (results notshown). Smoking history All individuals in both study and control groups weresmokers. The number of individuals smoking bidi wasgreater than that of smoking cigarette. The mean num-ber of pack years in the study group was 20.77 yearsas against 10.27 years in the control group, which wasstatistically significant ( P  < 0.001; Table 1). Distribution of  GSTM1   and  GSTT1   null genotypes inpatients with COPD and healthy controls The prevalence of the  GSTM1  null genotype in COPDcases was 28.0% (14   ⁄   50) while that of controls was32.0% (16   ⁄   50; Table 2). There was a decrease in thefrequency of   GSTM1  null genotype in COPD cases ascompared with controls. However, the differenceswere not statistically significant ( P  = 0.83; Table 2).About 40% (20   ⁄   50) of COPD cases were havinghomozygous deletion of   GSTT1  genotype as comparedwith 14.0% (7   ⁄   50) of the controls (Table 2). The dif-ferences in the frequencies of   GSTT1  null genotypewere significant between COPD cases and controls( P  = 0.007). The proportion of the cases that hadsimultaneously null genotype for both  GSTM1  and GSTT1  genes were 14.0% (7   ⁄   50) and 12% (6   ⁄   50) inCOPD cases and controls respectively. The resultsindicate a slightly higher proportion of COPD caseswith simultaneous  GSTM1  and  GSTT1  null genotypesas compared with controls but the differences werenot statistically significant ( P  = 1; Table 2). Discussion Chronic obstructive pulmonary disease is a complexand polygenic ailment suggesting that susceptibility tothis disease depends on the coincident actions of sev-eral genetic events. Recent reports have suggested thatseveral polymorphisms of genes encoding the detoxify-ing enzymes have been reported with increased fre-quency among COPD patients in different ethnicityand environmental backgrounds (Yim  et al. , 2000).Although studies in experimental animals and humanssupport a role for imbalance in oxidant–antioxidantsystems in the pathogenesis of smoking-induced COPD(He  et al. , 2002) there are relatively few studies thatinvestigated the role of polymorphisms of antioxidantgenes in COPD. In the present study, we have investi-gated whether polymorphisms of   GSTM1  and  GSTT1 genes are associated with susceptibility to COPD.The baseline frequencies of null genotypes for GSTM1  and  GSTT1  in different populations areremarkably different. The difference in frequencies of genotypes might be relevant to different metabolizingenzyme activities and types of dominant functionalenzymes against oxidative stress in different races(Cheng  et al. , 2004). Ethnic differences in the preva-lence of COPD are difficult to separate from environ-mental factors (Yim  et al. , 2000). Our study indicatesthat frequency of   GSTM1  null genotype was 28.0%(14   ⁄   50) among COPD cases as compared with 32.0%(16   ⁄   50) in controls, Similar trend of lower frequencyof   GSTM1  null genotype in lung cancer patients hasbeen reported in many studies (Dialyna  et al. , 2003;Tkacova  et al. , 2004; Elexpuru-Camiruaga  et al. ,1995; Smith & Harrison, 1997) and  GSTM1  homozy-gous null genotype has been correlated with decreasedrisk for lung cancer in Caucasians (Lewis  et al. ,2002). Our results are in contrast to other studies that Table 1.  Frequency distribution of variables and risk factorsCOPD cases no. (%) Controls no. (%)Age (years) £ 44 9 (18) 12 (24)45–54 28 (56) 21 (42) ‡ 55 13 (26) 17 (34)Mean age 51.67 ± 8.9 51.40 ± 7.65Severity of disease (forced expiratory volume) (%)Mild (60–80) 10 (20) –Moderate (40–59) 22 (44) –Severe (<40) 18 (36) –Smoking status in pack years £ 10 7 (14) 24 (48)11–20 25 (50) 16 (32) ‡ 21 18 (36) 10 (20)Average pack years 20.77 ± 4.7 10.27 ± 2.9COPD, chronic obstructive pulmonary disease; FEV1, forcedexpiratory volume. Table 2.  Distribution of  GSTM1  and  GSTT1  genotypes in chronicobstructive pulmonary disease (COPD) cases and controlsGenotypeControls( n  = 50), n  (%)COPDcases( n  = 50), n  (%)OddsratioConfidenceinterval P-value GSTM1  null 16 (32.0) 14 (28.0) 0.82 0.32–2.12 0.83 GSTT1  null 7 (14.0) 20 (40.0) 4.1 1.41–12.31 0.007 GSTM1  and GSTT1  null6 (12.0) 7 (14.0) 1.19 0.32–4.43 1.0 GSTM1 and GSTT1 polymorphisms in COPD 265 ª  2010 Blackwell Publishing Ltd,  International Journal of Immunogenetics   37 , 263–267  have shown positive correlation between  GSTM1  nullgenotypes and COPD (Harrison  et al. , 1997; Baranova et  al. , 1997; Sandford & Pare, 2000; Hemimi  et al. ,2008; Dimov  et al. , 2008; Faramawy  et al. , 2009).There are few reports where the risk of COPD is notassociated with GSTM1 null geneotype (Gaspar  et al. ,2004; Chan-Yeung  et al. , 2007; Zidzig  et al. , 2008.The association of   GSTM1  and COPD was also notobserved in a Korean population suggesting that thisgene is not associated with the pathogenesis of COPD inKoreans (Yim  et al. , 2000).A total of 40% (20   ⁄   50) cases presented homozygousdeletion of   GSTT1  gene as compared with controls14.0% (7   ⁄   50), which was statistically significant( P  = 0.007). Tamer  et al.  (2004) also reported thatpatients with atopic asthma had a higher prevalence of the  GSTT1  homozygous null genotype than the non-atopic asthma patients. In a few studies no associationwas found between  GSTT1  and COPD (Yim  et al. ,2000; Gaspar  et al. , 2004; Hemimi  et al. , 2008;Korytina  et al. , 2004; Calikoglu  et al. , 2006; Dimov et  al. , 2008).It was observed that COPD cases had marginally ahigher proportion of subjects who had the homozy-gous null genotypes of both  GSTM1  and  GSTT1  ascompared with controls. However, differences werenot statistically significant ( P  = 1). To-Figueras  et al. (1997) have also observed similar results in lung can-cer cases.Studies on COPD patients in the Western popula-tion have reported a higher mean age of patients.Most studies reported mean age between 60 and69 years (Redelmeier  et al. , 1997; Taioli  et al. , 2003;Pauwels, 2000). According to the National Health andNutrition Examination Survey III held in the USA,most patients of COPD were >60 years old, where asin the present study, the mean age of COPD patientswas 51.67 years. This difference may be attributed tothe genetic make-up of the Indian population, environ-mental factors, poor living conditions or smoking hab-its. The exact cause is still not known. We did notfind any significant differences for  GSTM1  null geno-types in individuals from various age groups i.e.  £ 44,45–54 and  ‡ 55 years, but we observed that COPDpatients in younger groups i.e. between  £ 44 and 45–54 years age group exhibited  GSTT1  null genotypemore frequently and the differences are very significant( P  = 0.02 and 0.04 respectively; results not shown).Taioli  et al.  (2003) have also reported that lung can-cer patients younger than 45 years exhibit the  GSTT1 null genotype more frequently.Association between smoking and COPD has beenreported in many studies. Pauwels (2000) has reportedthat 50% patients were smokers in their study, withan average of 39 pack years. Further they havereported that individuals had a higher probability of having COPD if they were living in urban areas, wereof male gender, were >60 years old, had higher educa-tional levels, had >15 pack-year smoking history, orhad symptoms of chronic bronchitis It was observed inpresent study, that COPD develops earlier in theIndian population with a shorter pack-year history.Although most patients in our study smoked bidis, thisform of smoking can be equally hazardous. In a com-plex polygenic ailment such as COPD, it is likely thatgenetic susceptibility is dependent on the action of sev-eral gene polymorphisms operating in combination.Polymorphisms in individual genes may impart only asmall relative risk of COPD and it is likely that thecumulative effect of many polymorphisms will beimportant in its pathogenesis. This association couldbe explained by the fact that tobacco smoke is knownto contain multiple substrates for GSTM1, GSTT1and GSTP1. Individuals having a defective genotypefor more than one of these genes would therefore beat greater risk for smoking induced decline in lungfunction than those having defective genotype for onlyone gene (Dialyna  et al. , 2003; Cheng  et al. , 2004;Rebbeck, 1997). The limitations of the study wererelated to the fact that controls were younger than thepatients with COPD. This could have reduced theeffects of polymorphic genotypes of this enzyme in thepathogenesis of COPD as some of the control subjectscould be destined to develop COPD in the future.In summary, individuals with  GSTT1  homozygousnull genotype might be at higher risk of developingCOPD and individuals with  GSTM1  null genotypeshowed that it is not a critical factor in COPD devel-opment. It was also observed that COPD developed inthe early age and with a shorter pack-year history inIndian population as compared with Western popula-tion. In terms of the number of subjects examined, thisstudy is a preliminary work. 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