SERPINA1 Hepatocyte-Specific Promoter Polymorphism Associate with Chronic Obstructive Pulmonary Disease in a Study of Kashmiri Ancestry Individuals

Bashir, Aadil; Hazari, Younis; Bashir, Samirul; Hilal, Nazia; Banday, Mariam; Iqbal, Mir Khurshid; Jan, Tariq Rashid; Farooq, Syed Suraiya; Shah, Naveed Nazir; Fazili, Khalid Majid

doi:10.1007/s00408-018-0124-8

Cited by 4 publications

(2 citation statements)

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“…In our previous study, the mean serum α1AT level in COPD cases carrying M3 variant on a promoter hepatocyte background (composite heterozygote) was found to be 1.20 ± 0.24 and 3.16 ± 0.16 g/L in cases and controls, respectively. The serum α1AT level in COPD cases was found to be 2.6 times less than the control group 13 . In this investigation, we explored this association further in context of M3-α1AT being largely considered as a normal variant of α1AT.…”

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confidence: 67%

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Aggregation of M3 (E376D) variant of alpha1- antitrypsin

Bashir

Hazari

Pal

et al. 2020

Sci Rep

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Alpha1-antitrypsin (α1AT) is an abundant serine-protease inhibitor in circulation. It has an important role in neutralizing the neutrophil elastase activity. Different pathogenic point mutations like Z(E342K)-α1AT have been implicated in the development of liver cirrhosis and Chronic Obstructive Pulmonary Disease (COPD), the latter being a cluster of progressive lung diseases including chronic bronchitis and emphysema. M3-α1AT (376Glu > Asp) is another variant of α1AT which so far is largely being considered as normal though increased frequency of the variant has been reported in many human diseases including COPD. We also observed increased frequency of M3-α1AT in COPD cases in Kashmiri population. The frequency of heterozygous (AC) genotype in cases and controls was 58.57% and 27.61% (odds-ratio 6.53 (2.27–15.21); p < 0.0001) respectively, while homozygous CC genotype was found to be 21.42% and 6.66% (odds-ratio 10.56 (3.63–18.64); p < 0.0001) respectively. Comparative in vitro investigations that include trypsin‒antitrypsin assay, Circular Dichroism spectroscopy and dynamic light scattering performed on wild-type (M-α1AT), M3-α1AT, and Z-α1AT proteins along with the molecular dynamics simulations revealed that M3-α1AT has properties similar to Z-α1AT capable of forming aggregates of varied size. Our maiden observations suggest that M3-α1AT may contribute to the pathogenesis of COPD and other disorders by mechanisms that warrant further investigations.

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confidence: 67%

“…Approximately, 2 mL of the venous blood sample was drawn from each participant in accordance to our established protocol 13 . The blood was collected in ethylene diamine-tetra-acetic acid-coated vials.…”

Section: Genomic Dna Extractionmentioning

confidence: 99%