Faculty Collaboration Database

Increased Expression of Plasma-Induced ABCC1 mRNA in Cystic Fibrosis. Int J Mol Sci 2017 Aug 11;18(8)

Date

08/12/2017

Pubmed ID

28800122

Pubmed Central ID

PMC5578142

DOI

10.3390/ijms18081752

Scopus ID

2-s2.0-85027284750 (requires institutional sign-in at Scopus site)   8 Citations

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.

Author List

Ideozu JE, Zhang X, Pan A, Ashrafi Z, Woods KJ, Hessner MJ, Simpson P, Levy H

Authors

Martin J. Hessner PhD Professor in the Pediatrics department at Medical College of Wisconsin
Amy Y. Pan PhD Associate Professor in the Pediatrics department at Medical College of Wisconsin
Pippa M. Simpson PhD Adjunct Professor in the Pediatrics department at Medical College of Wisconsin
Katherine Woods in the CTSI department at Medical College of Wisconsin - CTSI

MESH terms used to index this publication - Major topics in bold

Adolescent
Adult
Case-Control Studies
Cells, Cultured
Child
Cystic Fibrosis
DNA Methylation
Female
Histone Code
Humans
Male
Monocytes
Multidrug Resistance-Associated Proteins
Polymorphism, Single Nucleotide
Promoter Regions, Genetic
RNA, Messenger