SCGB1A1 rs3741240 variant downregulates CC16: A molecular insight into COPD pathogenesis in Indian population

Nasima Sultana¹Himani Adhikari¹Achintya Mohan Goswami²Amalesh Mondal³INDRANIL GANAI¹Himani Biswas⁴Asif Iqbal⁵Aratrika Das⁵Saibal Moitra⁵Sanjoy Podder^1*

• ¹University of Burdwan, Bardhaman, India
• ²Krishnagar Government College, Krishnanagar, India
• ³katwa college, Burdwan, India
• ⁴Lady Brabourne College, Kolkata, India
• ⁵Apollo Multispeciality Hospitals Kolkata, Kolkata, India

Background: Chronic Obstructive Pulmonary Disease (COPD) is a progressive inflammatory lung disorder influenced by environmental and genetic factors. rs3741240 polymorphism in SCGB1A1 gene, which encodes anti-inflammatory protein CC16, has been considered as a genetic marker for COPD susceptibility. Objective: This study aimed to investigate the functional significance of SCGB1A1 rs3741240 polymorphism among 224 COPD patients and 194 controls in West Bengal population, India. Methods: Genotyping of rs3741240 was performed using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP). SCGB1A1 mRNA levels were quantified in healthy controls and among different genotypes using Real-Time PCR. Protein expression was assessed by western blot. In-silico analyses identified miRNAs and transcription factors that target the SCGB1A1 promoter using miRDB, RNA22 v2 and hTFtarget web servers. Structural modeling and docking studies were conducted to analyse miRNA-mRNA-AGO2 and TF-promoter interactions using I-TASSER, SWISS-MODEL, GalaxyGemini, RNAfold, RNA COMPOSER, HDOCK and DNAproDB web servers. Results: Genotype and allele frequencies of 38AA risk genotype were more prevalent in COPD patients than controls (P=0.01 and 0.03 respectively). Patients 38AA genotypes exhibited significantly lower FEV1 and FEV1/FVC (P<0.0001). SCGB1A1 mRNA and protein expression were significantly reduced in patients bearing 38AA genotype compared to GA and GG genotypes. Bioinformatics analyses suggested that reduced CC16 expression for rs3741240 might be mediated by miRNA hsa-miR-11181-3p and transcription factors SMAD1, HAND1, and HAND2. Conclusion: This study first reports in an Indian population SCGB1A1 rs3741240 linked to COPD via CC16 downregulation, revealing a key pathogenic mechanism and potential for precision medicine in management.