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Int. J. Mol. Sci. 2017, 18(8), 1752; doi:10.3390/ijms18081752

Increased Expression of Plasma-Induced ABCC1 mRNA in Cystic Fibrosis

1
Division of Pulmonary Medicine, Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago, 225 E Chicago Ave., Chicago, IL 60611, USA
2
Human Molecular Genetics Program, Stanley Manne Children’s Research Institute, Chicago, IL 60614, USA
3
Department of Pediatrics, Division of Quantitative Health Sciences, Medical College of Wisconsin, Milwaukee, WI 53226, USA
4
Department of Pediatrics, Division of Critical Care, Medical College of Wisconsin, Milwaukee, WI 53226, USA
5
Department of Pediatrics, Max McGee National Research Center for Juvenile Diabetes, Medical College of Wisconsin, Milwaukee, WI 53226, USA
6
Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
*
Author to whom correspondence should be addressed.
Received: 6 June 2017 / Revised: 1 August 2017 / Accepted: 8 August 2017 / Published: 11 August 2017
(This article belongs to the Special Issue Physiological and Pathological Roles of ABC Transporters)
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Abstract

The ABCC1 gene is structurally and functionally related to the cystic fibrosis transmembrane conductance regulator gene (CFTR). Upregulation of ABCC1 is thought to improve lung function in patients with cystic fibrosis (CF); the mechanism underlying this effect is unknown. We analyzed the ABCC1 promoter single nucleotide polymorphism (SNP rs504348), plasma-induced ABCC1 mRNA expression levels, and ABCC1 methylation status and their correlation with clinical variables among CF subjects with differing CFTR 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. ABCC1 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 Pseudomonas aeruginosa (OR = 3.125, 95% CI: 1.192–8.190) and mucoid P. aeruginosa (OR = 5.075, 95% CI: 1.307–28.620) compared to the pancreatic sufficient group. A significantly higher expression of ABCC1 mRNA was induced by CF plasma compared to healthy control plasma (p < 0.001). CF subjects with rs504348 (CC/CG) also had higher mRNA expression compared to those with the ancestral GG genotype (p < 0.005). ABCC1 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 ABCC1 expression in PBMCs. Our results suggest that ABCC1 expression has a role in CFTR activity thereby increasing our understanding of the molecular underpinnings of the clinical heterogeneity in CF. View Full-Text
Keywords: ABCC1; cystic fibrosis; DNA methylation; polymorphism ABCC1; cystic fibrosis; DNA methylation; polymorphism
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Ideozu, J.E.; Zhang, X.; Pan, A.; Ashrafi, Z.; Woods, K.J.; Hessner, M.J.; Simpson, P.; Levy, H. Increased Expression of Plasma-Induced ABCC1 mRNA in Cystic Fibrosis. Int. J. Mol. Sci. 2017, 18, 1752.

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