COPD is mainly characterized by airflow restriction due to emphysema or obstructive bronchitis, thus leading to pulmonary failure. To determine the genetic variance association in COPD, ADAM33 gene SNP rs528557 was genotyped and analyzed in the Pakistani population by using the case–control methodology.

ADAM 33 is characterized as Zn + 2-dependent metalloproteinases with different functions and encompass signal transduction. A total of seven domains are present in ADAM33, including a pro-domain, a catalytic domain, a metalloprotease domain, a disintegrant domain (which interacts with integrins), a transmembrane domain, and a cytoplasmic domain [11, 12]. Previous studies have associated the polymorphism in ADAM33 in COPD patients [13,14,15,16]. Studies have found ADAM 33 expressed in smooth muscle cells of the airway and lung fibroblasts. ADAM 33 also plays the main role in airway remodeling due to its high expression in fibroblast and smooth muscle cells. As higher ADAM 33 expression has been found in lung smooth muscle and fibroblast, the ADAM 33 under and over expression usually results in changes in airway remodeling and repair process [13,14,15,16]. Considering this, the present study is carried out to concentrate on the ADAM 33 gene polymorphism and its role in COPD. The findings have shown that polymorphism impacts COPD, which may be due to ethnic variation and genetic background. It has been demonstrated that SNPs located in the ADAM 33 gene functional domain mainly contribute to the expression and transcription of the ADAM 33 proteins and mRNA. The expression of these proteins then influences the ADAM 33 function in COPD pathogenesis. S2 encodes Gly717Gly, which does not alter the amino acid sequence but changes the translation process, m RNA stability and mRNA folding. There is a need for further studies to determine the S2 variation impact on the function of ADAM33.

The findings of this study demonstrated a significant association between age and COPD patients. This shows that older people are more vulnerable to COPD. The aging process is mainly characterized by the increased rigidity of the chest wall, reduced lung recoil elasticity and loss of power of respiratory muscles responsible for the loss of function of FEV1 and increased residual volume. This finding is also in line with the previous studies in which it has been demonstrated that changes in lungs structurally and functionally over age made the lungs more vulnerable to the development of COPD [9]. In the current study, males were overrepresented, and a strong association has been found between gender and susceptibility to disease, which is in accordance with the findings [17]. Through the history evaluation regarding symptoms, it was found that 96.1% of individuals presented chronic cough symptoms and 88.2% with breathlessness; however, a smoking history was found in 60.8% of patients, which is in contrast to other western studies where no significant difference have been found between gender and COPD [15]. In the current population, the prevalence of smoking is higher in males, which could support the increased ratio of COPD in men as compared to females. The present study also showed that 22 Packs per year of smoking (p = < 0.001) is significantly associated with COPD, which explains the fact that the intensity of smoking is also associated with the development and severity of the disease, which is also evident from previous studies [12, 15]. Tobacco smoking is highly associated with chronic sputum production, which aggravates bronchial infection leading to alveolar and airway damage that could result in airflow restriction. Breathlessness and Chronic sputum production are also significantly associated with smoking. Excessive production of sputum declined the FEV1 and raised the hospitalization risk due to COPD which supports the finding of the current study clearly showing the significant association of breathlessness and chronic sputum production in patients suffering from COPD as compared to a healthy individual. The present study described the COPD association with lower body weight, undernutrition due to chronic inflammatory processes, dyspnea, diabetes mellitus, hypertension, cardiac illness and osteoporosis and found that except DM and cardiac disease, hypertension, lower body weight, dyspnea and osteoporosis are significantly associated risk factors of COPD. These findings are in line with the previous studies [12, 15, 18].

The present study has demonstrated a lower frequency of the minor SNP S2 in the Pakistani population compared to the major allele in patients of COPD when compared with healthy controls that are comparable with previous studies [12, 15]. Figarska et al. (2013) study analysis showed an association of the ADAM33 gene with COPD pathophysiology and showed that carriers of minor alleles of SNPs Q-1, S1, S2, and T2 have higher mortality due to COPD [19]. Overproduction of ADAM33 leads to the release of inflammatory mediators and growth factors inducing pathological changes. In the current study, S2 SNP is shown to be associated with COPD. S1 and S2 SNPs are located in exon S, but is involved in the modification of the structure of the protein. The ADAM33 SNP, in particular, is related to a greater decline in FEV1 in general population samples. In the current study, the S2 (rs528557) SNP is associated with COPD and has a higher frequency of major allele frequency in patients suffering from COPD than controls. It was observed that ADAM33 multidomain gene polymorphism is a susceptibility gene for COPD, which is line with the previous studies [12, 15, 18, 20, 21]. Yuan et al. (2017) demonstrated that 88 smokers were genotyped for 25 ADAM33 single nucleotide polymorphisms [22]. The current study, as compared to the above, shows a more significant relation of ADAM33 gene polymorphisms of SNP S2 with COPD.

The study has several limitations. Only S2 was included. The inclusion of other S1 could have improved the finding of this study. The results of the current study are diverse compared to previous research might be due to different ethnicities. Moreover, the sample size is limited in our study. More comprehensive data should be obtained for in-depth mechanisms and making clear interpretations regarding the current association. Other polymorphisms of ADAM33 can also be included in this potential panel of SNPs so that patients at risk of COPD may be identified in the future. However, despite this, the findings of this study provide useful insight into the association of SNP i.e., S2 (rs528557) with COPD.