Egyptian Journal of Chest Diseases and Tuberculosis (2012) 61, 275–280

The Egyptian Society of Chest Diseases and Tuberculosis Egyptian Journal of Chest Diseases and Tuberculosis

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ORIGINAL ARTICLE Effect of a and metalloprotease 33 (ADAM33) polymorphisms and smoking in COPD

Ayman H. Abd El-Zaher a,*, Hala Nagy b, Gihan Farouk b, Ahmed Sh. Mohamed a, Naglaa F. Ghoname c a Department of Chest, Faculty of Medicine, Tanta University, Egypt b Department of Clinical Pathology, Faculty of Medicine, Tanta University, Egypt c Department of Microbiology & Immunology, Faculty of Medicine, Tanta University, Egypt

Received 3 August 2012; accepted 15 August 2012 Available online 26 January 2013

KEYWORDS Abstract Background: COPD is characterized by air flow limitation that is not fully reversed and COPD; associated with an influx of neutrophils, macrophages and CD8 T lymphocytes in the airways. The Disintegrin; disease is characterized by airflow limitation and is associated with an abnormal inflammatory Metalloprotease; response of the lungs in response to noxious particles or gases and associated with systemic man- Gene polymorphisms ifestation. Methods: Sixty consecutive patients with COPD and 40 normal healthy individuals were included. All cases and controls were subjected to detection of 2 polymorphic loci (S1 AND Q1) of ADAM33 by PCR-RFLP technique. Results: The percentage of S1 and Q1 AA genotype and A allele were significantly increased in control than in COPD patients while there was significant increase in S1 and Q1 GG genotype and G allele in COPD patients than in control (p < 0.001). No significant difference was found between smoker and non-smoker among the two studied groups in genotype and alleles distribution of ADAM33 SNPs S1 and Q1 p > 0.05, whereas there was significant increase in ADAM33 S1 G allele and Q1 G allele in smoker and non-smoker in COPD patients as compared to their corresponding fellows in control group (p < 0.05). As regard to Pulmonary function test there was significant decrease in % of FEV1 in COPD patients as compared to control group for both smokers and non-smokers (p < 0.001). Within both control and COPD groups smokers had significant decrease in FEV1 % as compared to non-smokers (p < 0.001). There was a significant

* Corresponding author. Address: Department of Chest diseases, Tanta University Hospitals, Tanta Faculty of Medicine, Tanta, Egypt. Tel.: +20 1005071284. E-mail address: [email protected] (A.H. Abd El-Zaher). Peer review under responsibility of The Egyptian Society of Chest Diseases and Tuberculosis.

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0422-7638 ª 2012 The Egyptian Society of Chest Diseases and Tuberculosis. Production and hosting by Elsevier B.V. Open access under CC BY-NC-ND license. http://dx.doi.org/10.1016/j.ejcdt.2012.08.005 276 A.H. Abd El-Zaher et al.

decrease in FEV1 % among all genotypes in smoker as compared to non-smoker COPD patients (p < 0.001), the most prominent decrease was found in smoker GG genotype for both ADAM33 S1 and Q1 in COPD patients. Conclusion: In conclusion, we found that polymorphisms in the SNPs (Q1 and S1) of ADAM33 gene are associated with COPD in the general population. In addition, smoker patients with GG genotype in (S1 and Q1) ADAM33 will have more pronounced decline in the pulmonary function test (FEV1). ª 2012 The Egyptian Society of Chest Diseases and Tuberculosis. Production and hosting by Elsevier B.V. Open access under CC BY-NC-ND license.

Introduction observed in the ADAM33 gene and were not performed in a population of chronic cigarette smoker, the appropriate tar- Chronic obstructive pulmonary disease (COPD) is highly pre- get population for studies of genetic susceptibility in COPD valent and the only disease with increasing mortality rates [1]. worldwide [1]. The disease is characterized by air flow limita- The aim of the present study is to assess the role of the tion that is not fully reversed and associated with an influx SNPs of ADAM33 gene in smoker and non smoker COPD pa- of neutrophils, macrophages and CD8 T lymphocytes in the tients on the disease course. airways [2]. The disease is characterized by airflow limitation and is associated with an abnormal inflammatory response Subjects and methods of the lungs in response to noxious particles or gases and asso- ciated with systemic manifestation [3]. The severity of AHR is We conducted a case-control study for COPD. The case positively associated with inflammation in lung tissue [4]. groups comprised 60 patients with stable COPD (36 men Tobacco smoking is the most important risk factor for and 24 women) with a mean age of 65.7 ± 8.03 years who developing COPD. The deleterious effect of smoking is mainly had not been previously treated with theophylline, b2-adrener- mediated through an accelerated decline in forced expiratory gic receptor agonists, or glucocorticosteroids were recruited volume in 1 s (FEV1) in adulthood, which over the years re- from chest department, Tanta University Hospitals for this sults in a substantial reduction in lung function leading to study. The diagnosis of COPD was established using the fol- symptomatic disease. Many longitudinal studies have provided lowing criteria: (1) history of cigarette smoking (a minimum data on the increased relative risk of developing COPD in of 10 pack years) in patients who were current smokers at smokers compared with non-smokers [5]. the time of evaluation; (2) no exposure (occupational or other- Genetic factors appear to predispose some individuals with wise) to other substances known to cause lung disorders; (3) tobacco exposure to the development of smoking related respi- absence of atopy; (4) no history of systemic or other pulmon- ratory disease. Additionally, COPD tends to occur more fre- ary disease or congenital and/or acquired systemic immunode- quently in smokers with a family history of obstructive ficiency; (5) forced expiratory volume in the first second airways disorders such as asthma and COPD [6,7]. (FEV1)/forced vital capacity (FVC) <70% and FEV1 after ADAM33, is a member of the ADAM (a disintegrin and inhalation of 200 mg salbutamol <80%. The control group metalloprotease) family. ADAM proteins are involved in cell consisted of 40 unrelated healthy subjects 24 men and 16 wo- adhesion, cell fusion, cell signaling, and proteolysis [8]. The lat- men), Ventilatory function tests (FVC, FEV1 and FEV1%) ter can be illustrated by the capacity to shed cytokines, growth of all subjects were recorded using (spirolab II 125–00155, factors, or their receptors from the cell surface and the remod- ROMA, ITALY). with a mean age of 55.75 ± 5.86 years with eling of components. Garlisi demonstrated healthy pulmonary function and no known medical illnesses or that ADAM33 is an active proteinase that is able to cleave a2- family disorders. They were matched for age, gender, and macroglobulin [9] and synthetic peptides [10]. smoking history with the case group. It has been speculated that the ADAM33 gene is located on 20p13 and 37 SNPs have initially been identified Sampling [11], expressed in airway smooth muscle cells and fibroblasts of the lung, codes for a protein important for cell fusion, cell Blood samples (3 mL) were obtained from patients and con- adhesion, cell signaling and proteolysis. Furthermore, trols, collected to an EDTA tube for performing DNA extrac- ADAM33 was suggested to play a role in airway remodeling tion. All cases and controls were subjected to detection of 2 [12]. polymorphic loci (S1 AND Q1) of ADAM33 by PCR-RFLP SNPs within the ADAM33 are associated with accel- technique [16]. erated decline of lung function in the general population and in asthma patients [13,14]. The ADAM33 gene is expressed in airway smooth muscle cells and fibroblasts in the lung [15].In Extraction of genomic DNA a longitudinal study from a general population, van Diemen and coworkers showed associations between SNPs in Blood was collected in EDTA-tubes and stored at room tem- ADAM33 and annual decline in FEV1 in cigarette smokers perature until the genomic DNA was extracted using QIA who were compared to the larger population [14]. These stud- amp DNA Mini Kit from QIAGEN according to the manufac- ies did not comprehensively investigate the genetic variations turer‘ s instructions [16]. Effect of a disintegrin and metalloprotease 33 (ADAM33) gene polymorphisms and smoking in COPD 277

Genotyping by PCR-RFLP

Genotyping was performed by polymerase chain reaction- restriction fragment length polymorphism (PCRRFLP) analy- sis. The polymorphic region was amplified by PCR using a step one real time PCR system (Applied Biosystems) in a 25 ll reac- tion solution containing 0.3 lg genomic DNA, 10 · PCR buf- fer, 0.3 mM MgCl2, 0.2 mM dNTPs, 2 U TaqDNA polymerase (Takara, Japan), and 0.1 lmol of each primer (Invitrogen, USA). Genotyping primers were:

S1 F : 50TGTGCAGGCTGAAAGTATGC-30 R : 50AGAGCTCTGAGGAGGGGAAC-30 Figure 2 Agarose gel electrophoresis for RFLP-PCR product of Q1 ADAM33 SNPs (Q1) stained with ethiduim bromide. M; repre- F : 50GGATTCAAACGGCAAGGAG-30 sents DNA marker. Lanes 2, 4 & 5 represent homozygote AA R : 50GTTCACCTAGATGGCCAGGA-30. genotype. Lane 6 represent heterozygote AG genotype. Lanes 1, 3 & 7 represent homozygote GG genotype. The PCR conditions for the detection of S1 were as fol- lows: initial denaturation at 94 C for 5 min followed by 35 cy- cles of 30 s at 94 C; 30 s at 50 C; 30 s at72 C and a final Statistical analysis extension at 72 C for 5 min, while the PCR conditions for the detection of Q1 were as follows: initial denaturation at The statistical software package SPSS 15.0 was used for statisti- 94 C for 5 min followed by 35 cycles of 30 s at 94 C; 30 s cal calculations. Data are presented as mean ± SD for continu- at 60 C; 30 s at72 C and a final extension at 72 C for 5 min. ous variables and as proportions for categorical variables. PCR products were digested overnight with restriction en- zymes Hinfl for S1 (NEB, UK) according to the manufac- Comparisons of means between 2 groups were analyzed by using t turer’s protocol and analyzed by agarose gel electrophoresis. the Student unpaired -test while comparisons of means among 3 groups were performed using one-way ANOVA test. The allele In the samples with a AA genotype the digestion resulted 304-bp band. In the samples carrying the mutation in hetero- and genotype frequencies among cases and controls were com- zygous form (AG), 132-, 172- and 304-bp digestion products pared by Chi-square test and odds ratio with 95%CI. Two-tailed P 6 were detected. In the samples with a GG genotype, 132- and -value of 0.05 was considered significant. 172-bp products were formed (see Figs. 1 and 2). We use BtsCl restriction for Q1 (NEB, UK) Results according to the manufacturer’s protocol and analyzed by aga- rose gel electrophoresis. In the samples with a AA genotype the This study was performed on 60 subjects with chronic obstruc- digestion resulted in 20- (non-visible), and 138-bp (visible) tive pulmonary disease (COPD) with mean age was bands. In the samples carrying the mutation in heterozygous 46.7 ± 8.03 years and 40 normal healthy subjects as control form (AG), 20- (non-visible), 138 and 158-bp (visible) diges- group with mean age was 45.75 ± 5.86 years. The both groups tion products were detected. In the samples with a GG geno- (control & COPD) were matched as regards to age and sex type, 158-bp (visible) products were formed. with male predominance as M/F ratio was (24/16, 36/24) respectively all other Clinical characteristics of studied groups were shown in (Table 1). Table 2 illustrates genotype and alleles of ADAM33 SNPs (S1 and Q1) in chronic obstructive pulmonary disease (COPD) and control. The percentage of S1 and Q1 AA genotype and A allele were significantly increased in control than in COPD pa- tients while there was significant increase in S1 and Q1 GG genotype and G allele in COPD patients than in control (p < 0.001). The frequency of ADAM33 S1 G allele and Q1 G allele were significantly higher in COPD patients than in control (p < 0.001, OR = 0.171, 95% CI = 0.091 0.321;

Table 1 Clinical characteristics of studied groups. Control COPD Number of patients 40 60 Figure 1 Agarose gel electrophoresis for RFLP-PCR product of Age (years) 55.75 ± 5.86 56.7 ± 8.03 ADAM33 SNPs (S1) stained with ethiduim bromide. M; repre- Male: female 24/16 36/24 sents DNA marker. Lanes 1, 3 & 5 represent homozygote AA Pack years of smoking 31.44 34.51 genotype. Lanes 6 & 7 represent heterozygote AG genotype. Lanes FEV1 (% predicted) 86.65 ± 5.96 56.02 ± 7.71 2 & 4 represent homozygote GG genotype. 278 A.H. Abd El-Zaher et al.

Table 2 Prevalence of ADAM33 SNPs (S1 and Q1) in all studied groups. ADAM33 SNPs Control COPD P-value Odd ratio N % N % Value LU S1 AA 25 62.50 14 23.33 0.000* 5.476 2.280 13.152 AG 9 22.50 11 18.33 0.396 1.293 0.481 3.477 GG 6 15.00 35 58.33 0.000* 0.126 0.046 0.345 A allele 59 73.75 39 32.50 0.000* 5.835 3.115 10.931 G allele 21 26.25 81 67.50 0.000* 0.171 0.091 0.321 Q1 AA 26 65.00 18 30.00 0.001* 4.333 1.847 10.165 AG 11 27.50 13 21.67 0.331 1.371 0.543 3.465 GG 3 7.50 29 48.33 0.000* 0.087 0.024 0.312 A allele 63 78.75 49 40.83 0.000* 5.370 2.810 10.262 G allele 17 21.25 71 59.17 0.000* 0.186 0.097 0.356 * Significance p6 0.001.

Table 3 Prevalence of ADAM33 SNPs (S1 and Q1) in all studied groups. ADAM33 SNPs Control COPD P1 P2 P3 P4 Smoker Non smoker Smoker Non smoker N % N % N % N % S1 AA 11 44.00 7 46.67 9 22.50 4 20.00 0.564 0.552 0.061 0.095 AG 8 32.00 5 33.33 7 17.50 3 15.00 0.599 0.559 0.148 0.192 GG 6 24.00 3 20.00 24 60.00 13 65.00 0.546 0.466 0.005 0.010 A allele 30 60.00 19 63.33 25 31.25 11 27.50 0.478 0.420 0.001 0.003 G allele 20 40.00 11 36.67 55 68.75 29 72.50 0.478 0.420 0.001 0.003 Q1 AA 13 52.00 8 53.33 7 17.50 3 15.00 0.597 0.559 0.004 0.020 AG 5 20.00 4 26.67 12 30.00 5 25.00 0.454 0.466 0.276 0.606 GG 7 28.00 3 20.00 21 52.50 12 60.00 0.432 0.393 0.045 0.020 A allele 31 62.00 20 66.67 26 32.50 11 27.50 0.431 0.367 0.001 0.001 G allele 19 38.00 10 33.33 54 67.50 29 72.50 0.431 0.367 0.001 0.001 P1 – Smoker and non smoker in control group. P2 – Smoker and non smoker in COPD group. P3 – Control and COPD in smoker group. P4 – Control and COPD in non smoker group.

Table 4 Pulmonary function test FEV1 (% predicted) in all studied groups. FEV1 (% predicted) Control COPD T-test N Mean ± SD N Mean ± SD tP-value Smoker 25 78.156 ± 4.33 40 50.64 ± 6.884 17.869 <0.001* Non smoker 15 100.81 ± 7.68 20 66.785 ± 8.81 11.931 <0.001* T-test t 11.971 7.789 P-value <0.001* <0.001* * Significance p6 0.001. p < 0.001, OR = 0.186, 95% CI = 0.097 0.356 As regard to Pulmonary function test there was significant respectively). decrease in% of FEV1 in COPD patients as compared to con- Table 3 shows no significant difference was found between trol group for both smokers and non-smokers (p < 0.001). smoker and non-smoker among the two studied groups in Within both control and COPD groups smokers had signifi- genotype and alleles distribution of ADAM33 SNPs S1 and cant decrease in FEV1% as compared to non-smokers Q1 p > 0.05, whereas there was significant increase in (p < 0.001) Table 4. ADAM33 S1 G allele and Q1 G allele in smoker and non-smo- There was a significant decrease in FEV1% among all geno- ker in COPD patients as compared to their corresponding fel- types in smoker as compared to non-smoker COPD patients lows in control group (p < 0.05). (p < 0.001), the most prominent decrease was found in smoker Effect of a disintegrin and metalloprotease 33 (ADAM33) gene polymorphisms and smoking in COPD 279

Table 5 Pulmonary function test FEV1 (% predicted) in ADAM33 SNPs (S1 and Q1) of COPD group. ADAM33 SNPs FEV1 (% predicted) Smoker Non smoker T-test N Mean ± SD N Mean ± SD tP-value S1 AA 9 58.2 ± 1.563 4 73.8 ± 1.02 18.085 <0.001* AG 7 52.44 ± 1.11 3 71.62 ± 0.65 27.391 <0.001* GG 24 46.8 ± 1.91 13 66.8 ± 1.088 34.688 <0.001* ANOVA F 16.542 13.55 P-value <0.001* <0.001* Q1 AA 7 58.9 ± 1.055 3 75.27 ± 0.779 23.884 <0.001* AG 12 53.33 ± 0.871 5 71.8 ± 1.16 26.272 <0.001* GG 21 47.912 ± 1.721 12 68.3 ± 1.41 34.832 <0.001* ANOVA F 14.664 15.56 P-value <0.001* <0.001* * Significance p6 0.001.

GG genotype for both ADAM33 S1 and Q1 in COPD patients splicing of the b-variant [23] and disturb the maturation of (see Table 5). ADAM33. 2. The most appropriate control group for studies on COPD Discussion should consist of chronic cigarette smokers who are at risk for COPD and yet have normal lung function. To this end, COPD is the fifth leading cause of mortality in 2001 worldwide the controls in this report have comparable exposure to tobac- according to the World Health Organization. Because the co smoke as the affected cases [1]. prevalence and mortality due to COPD are expected to in- Although smoking is considered a risk factor for predispos- crease, this disease will become an even larger social and eco- ing COPD, this study did not found significant association be- nomic burden [17]. tween smoking and genotypic distribution of ADAM33 SNPs In this study we genotyped 2 SNPs in ADAM33 gene (S1 S1 and Q1 in both groups, but there was significant decrease in and Q1) in COPD patients. It was found that there was signif- % of FEV1 in COPD patients as compared to control group icant increase in S1 and Q1 GG genotype and G allele in for both smokers and non-smokers. Within both control and COPD patients as compared to control. These results were COPD groups smokers had significant decrease in FEV1 % in accordance with another study of van Diemen et al. who re- as compared to non-smoker. These results were in accordance with a study of Sadeghn- ported that In a Dutch population, the SNPs S1, S2, and Q1 were associated with FEV1 decline, and the SNPs S1, S2, jad et al. who found a relationship between ADAM33 varia- F+1, and T2 were associated with the presence of COPD [17]. tion and COPD in a Dutch general population including A study by Gosman et al. found that prevalence of the smokers and non-smokers. This study showed that individuals ADAM33 SNPs in their COPD population was comparable homozygous for the minor alleles of SNPs S2 and Q1 and to those recently reported by van Diemen et al. [17] and minor heterozygous for SNP S1 had an excess annual decline in alleles for SNPs F+1, S_1 and S_2 were more prevalent in pa- FEV1 compared to their respective wild type in subjects with tients with COPD than in healthy participants. Regarding SNP COPD compared to the entire general population that in- cluded non-smokers [1]. Q1 they showed a significantly higher prevalence of the min- or allele in patients with COPD compared with healthy con- O’Shaughnessy et al. showed an increased number of neu- trols [18]. trophils and CD8 lymphocytes in bronchial biopsies of smok- ers with air flow limitation, and this increase was inversely The SNP Q1 is located in the intron immediately before exon 16, which contains an epidermal growth factor (EGF) do- associated with the level of lung function. We, therefore, main [19]. EGF signaling is important in lung morphogenesis. hypothesized that individuals with a genetic predisposition EGFR signaling regulates matrix metalloproteases, which for a higher number of CD8 cells were more susceptible to a mediate epithelial–mesenchymal interactions during lung mor- further increase in CD8 cells, which might finally result in air phogenesis [20]. ADAM33 is closely related to matrix metallo- flow limitation. Interestingly, we found an association of , but may bind EGF directly. A disturbance in the SNP ST+5 with both the presence of COPD (see online data EGF domain will likely affect regulation of ADAM33. repository) and the number of CD8 cells in our patients with Through alterative splicing, exon 16 can be spliced out, giving COPD [24]. rise to the b-variant of ADAM33. This variant was found in There is an association between ADAM33 and the severity 30% of ADAM33 mRNA transcripts in pulmonary fibroblasts of airway hyper-responsiveness (AHR) in COPD. AHR is [21]. Because the EGF domain is incomplete, it has been sug- important to COPD given its association with accelerated gested that the b-variant prevents maturation of ADAM33 FEV1 decline and increased risk of COPD mortality. The ex- and may exert a dominant-negative effect on its activ- act pathophysiology underlying AHR is unclear, but it is thought to result from an inflammatory process in the airways ity [22].The intronic Q1 SNP may therefore influence the 280 A.H. Abd El-Zaher et al. in addition to geometric changes owing to airway remodeling. [10] J. Zou, F. Zhu, J. Liu, W. Wang, R. Zhang, C.G. Garlisi, Y.H. It is possible that ADAM33 has a role in both these processes Liu, S. Wang, H. Shah, Y. Wan, S.P. Umland, Catalytic activity thereby contributing to the severity of AHR [25]. of human ADAM33, J. Biol. Chem. 279 (11) (2004) 9818–9830. SNPs S_1 was associated with both excessive FEV1 decline [11] P. Van Eerdewegh, R.D. Little, J. Dupuis, R.G. Del Mastro, K. in the general population and development of COPD. These Falls, J. Simon, D. Torrey, S. Pandit, J. McKenny, K. Braunschweiger, A. Walsh, Association of the ADAM33 gene SNPs are located in exon S, which encodes the transmembrane with asthma and bronchial hyperresponsiveness, Nature 418 region. The S_1 SNP causes an amino acid change (valine to (2002) 426–430. isoleucine), but it is unknown whether this also modifies the [12] D.S. Postma, T. 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