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A novel ABCC6 haplotype is associated with azathioprine drug response in myasthenia gravis

Colleoni, Lara; Galbardi, Barbara; Barzago, Claudia; Bonanno, Silvia; Franzi, Sara; Frangiamore, Rita; Camera, Giorgia; Foti, Maria; Biancolini, Donatella; Canioni, Eleonora; Maggi, Lorenzo; Antozzi, Carlo; Mantegazza, Renato; Bernasconi, Pia; Kapetis, Dimos

doi: 10.1097/FPC.0000000000000257

Objective We investigated the association of single nucleotide polymorphisms (SNPs) in drug-metabolizing enzymes and transporters (DMETs) with the response to azathioprine (AZA) in patients affected by myasthenia gravis (MG) to determine possible genotype–phenotype correlations.

Patients and methods Genomic DNA from 180 AZA-treated MG patients was screened through the Affymetrix DMET platform, which characterizes 1931 SNPs in 225 genes. The significant SNPs, identified to be involved in AZA response, were subsequently validated by allelic discrimination and direct sequencing. SNP analysis was carried out using the SNPassoc R package and the haploblocks were determined using haploview software.

Results We studied 127 patients in the discovery phase and 53 patients in the validation phase. We showed that two SNPs (rs8058694 and rs8058696) found in ATP-binding cassette subfamily C member 6, a subfamily member of ATP-binding cassette genes, constituted a new haplotype associated with AZA response in MG patients in the discovery cohort (P=0.011; odds ratio: 0.40; 95% confidence interval: 0.20–0.83) and in the combined cohort (P=0.04; odds ratio: 1.58).

Conclusion These findings highlight the role that the ATP-binding cassette subfamily C member 6 haplotype may play in AZA drug response. In view of the significant effects and AZA intolerance, these novel SNPs should be taken into consideration in pharmacogenetic profiling for AZA.

Supplemental Digital Content is available in the text.

aNeurology IV – Neuroimmunology and Neuromuscular Diseases Unit

bBioinformatics Unit, IRCCS Foundation Neurological Institute ‘Carlo Besta’

cGenopolis Consortium, Department of Biotechnology and Bioscience, University of Milano-Bicocca, Milan, Italy

Correspondence to Pia Bernasconi, PhD, Neurology IV – Neuroimmunology and Neuromuscular Diseases Unit, IRCCS Foundation Neurological Institute ‘Carlo Besta’, Via Celoria 11, Milan 20133, Italy Tel: +39 02 2394 2369; fax: +39 02 7063 3874; e-mail:

Received May 19, 2016

Accepted November 9, 2016

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