Drug metabolism and inflammation related distinct miRNA signature of colchicine resistant familial Mediterranean fever patients.

OBJECTIVE

Colchicine is the primary treatment for familial Mediterranean fever (FMF). Although colchicine is safe and effective in FMF patients, around 5-10% of patients show resistance to the drug. This study investigates the possibility of a link between colchicine resistance and the distinct miRNA profiles in colchicine resistant FMF patients.

METHODS

Differentially expressed miRNAs in colchicine resistant FMF patients were detected by Affymetrix 4.0 miRNA array analysis. These miRNAs were then categorized based on the role of their target genes in drug metabolism and inflammation related pathways. qRT-PCR was used to validate candidate miRNAs selected by Enrichr, a gene enrichment analysis system based on the relevance of possible target genes in drug metabolism pathways. Expression levels of these miRNAs' potential target genes were investigated by qRT-PCR. Then, a colchicine resistant hepatoblastoma cell line (HEPG2) was established, and the differentially expressed miRNAs and genes identified in patients were also analyzed in this colchicine-resistant cell line.

RESULTS

25 differentially expressed miRNAs were detected in colchicine resistant FMF patients. miR-183-5p, miR-15b-5p, miR-505-5p, and miR-125a-5p were identified to be associated with drug resistance and inflammatory pathways and thus chosen for further validation. miR-183-5p, miR-15b-5p, miR-505-5p miRNAs showed significantly differential expression in qRT-PCR. NFKB1, NR3C1, PPARα - drug absorption, distribution, metabolism, and excretion (ADME) genes were predicted to be targeted by these miRNAs. Among these targets, NFKB1 and NR3C1 were differentially over expressed in colchicine resistant FMF patients. These findings were validated in the colchicine resistant hepatoblastoma cell line (HEPG2).

CONCLUSION

This is the first study evaluating the role of miRNAs in colchicine resistant patients with FMF. Their differential expression may result in resistance to standard colchicine treatment by affecting the expression of genes that take place in drug absorption, distribution, metabolism, and excretion (ADME) or nuclear receptors that regulate ADME genes, thus potentially playing a role in both drug metabolism and inflammation.