Increased Expression of Plasma-Induced ABCC1 mRNA in Cystic Fibrosis

Abstract

The <i>ABCC1</i> gene is structurally and functionally related to the cystic fibrosis transmembrane conductance regulator gene (<i>CFTR</i>). Upregulation of <i>ABCC1</i> is thought to improve lung function in patients with cystic fibrosis (CF); the mechanism underlying this effect is unknown. We analyzed the <i>ABCC1</i> promoter single nucleotide polymorphism (SNP rs504348), plasma-induced <i>ABCC1</i> mRNA expression levels, and <i>ABCC1</i> methylation status and their correlation with clinical variables among CF subjects with differing <i>CFTR</i> mutations. We assigned 93 CF subjects into disease severity groups and genotyped SNP rs504348. For 23 CF subjects and 7 healthy controls, donor peripheral blood mononuclear cells (PBMCs) stimulated with plasma underwent gene expression analysis via qRT-PCR. <i>ABCC1</i> promoter methylation was analyzed in the same 23 CF subjects. No significant correlation was observed between rs504348 genotypes and CF disease severity, but pancreatic insufficient CF subjects showed increased colonization with any form of <i>Pseudomonas aeruginosa</i> (OR = 3.125, 95% CI: 1.192-8.190) and mucoid <i>P. aeruginosa</i> (OR = 5.075, 95% CI: 1.307-28.620) compared to the pancreatic sufficient group. A significantly higher expression of <i>ABCC1</i> mRNA was induced by CF plasma compared to healthy control plasma (<i>p</i> < 0.001). CF subjects with rs504348 (CC/CG) also had higher mRNA expression compared to those with the ancestral GG genotype (<i>p</i> < 0.005). <i>ABCC1</i> promoter was completely unmethylated; therefore, we did not detect any association between methylation and CF disease severity. In silico predictions suggested that histone modifications are crucial for regulating <i>ABCC1</i> expression in PBMCs. Our results suggest that <i>ABCC1</i> expression has a role in <i>CFTR</i> activity thereby increasing our understanding of the molecular underpinnings of the clinical heterogeneity in CF.