Abstract
Purpose
Different mutations in coding and non-coding sequences of the SERPINA1 gene have been implicated in the pathogenesis of COPD. However, − 10T/C mutation in the hepatocyte-directed promoter region has not been associated with COPD pathogenesis so far. Here, we report an increased frequency of − 10C genotype that is associated with decreased levels of serum alpha1-antitrypsin (α1AT) in COPD patients.
Methods
The quantification of serum α1AT was done by ELISA, the phenol–chloroform method was used for DNA extraction, PCR products were directly sequenced. The IBM SPSS Statistics v21 software was used for statistical analyses of the data.
Results
The mean serum α1AT level was found to be 1.203+0.239 and 3.162+0.160 g/L in COPD cases and in control, respectively. The − 10C allele is associated with an increased risk of COPD [OR, 3.50 (95%CI, 1.86-6.58); p < 0.001]. The combined variant genotype (TT+CC) was significantly found associated with an increased risk of COPD [OR, 3.20 (95% CI, 1.47-6.96); p = 0.003]. A significant association of the family history with COPD (overall p value= 0.0331) suggests that genetics may play an important role in the pathogenesis of COPD.
Conclusion
The polymorphism associated with hepatocyte-specific promoter region (− 10T/C) is likely to be associated with the pathogenesis of COPD. It is quite possible that the change of the base in the hepatocyte-specific promoter of the SERPINA1 gene can modulate its strength, thereby driving the reduced expression of α1AT.
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Acknowledgements
The financial support provided by grants from the Department of Biotechnology (DBT), New Delhi to Khalid Majid Fazili and Arif Bashir (No. BT/PR7240/MED/30/915/2012) is acknowledged. We would also like to acknowledge the financial support provided bygrants from the Department of Science and Technology (No. SB/SO/ AS-126/2012), FIST (No. SR/FST/LSI-384/2008), SAP and UGC (No. F.3–26/2011(SAP-II)) and the facilities extended by University of Kashmir, Srinagar-190006, India. The authors would also like to thank all the COPD patients and control subjects who took part in this study and cooperated during the interview and sample collection. We also acknowledge the support and cooperation from the technical staff of the Government Chest Disease Hospital, Srinagar, Jammu and Kashmir-India.
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All authors have made substantial contributions: (1) The concept and design of the study was done by AB, YMH, KMF, and NNS (2) the article was drafted critically for important intellectual content by Dr. KMF, Dr. NNS and AB (3) Dr. MKI, NH, MB, SB and MB prepared reagents for DNA extraction, (4) Statistical analysis was done by Dr. TRJ, and (5) Pulmonary function assistance by SSF and (6) final approval of the version by KMF, NNS, and AB.
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All authors declared that they have no competing interests.
Ethical Approval
This study is approved by the Ethics Committee of the Government Medical College Srinagar-India.
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Bashir, A., Hazari, Y.M., Bashir, S. et al. SERPINA1 Hepatocyte-Specific Promoter Polymorphism Associate with Chronic Obstructive Pulmonary Disease in a Study of Kashmiri Ancestry Individuals. Lung 196, 447–454 (2018). https://doi.org/10.1007/s00408-018-0124-8
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DOI: https://doi.org/10.1007/s00408-018-0124-8