title: A novel ABCC6 haplotype is associated with azathioprine drug response in myasthenia gravis.
abstract: 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.
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.
authors.affiliation: 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.
authors.forename: Lara
authors.initials: L
authors.lastname: Colleoni
authors.forename: Barbara
authors.initials: B
authors.lastname: Galbardi
authors.forename: Claudia
authors.initials: C
authors.lastname: Barzago
authors.forename: Silvia
authors.initials: S
authors.lastname: Bonanno
authors.forename: Sara
authors.initials: S
authors.lastname: Franzi
authors.forename: Rita
authors.initials: R
authors.lastname: Frangiamore
authors.forename: Giorgia
authors.initials: G
authors.lastname: Camera
authors.forename: Maria
authors.initials: M
authors.lastname: Foti
authors.forename: Donatella
authors.initials: D
authors.lastname: Biancolini
authors.forename: Eleonora
authors.initials: E
authors.lastname: Canioni
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Maggi
authors.forename: Carlo
authors.initials: C
authors.lastname: Antozzi
authors.forename: Renato
authors.initials: R
authors.lastname: Mantegazza
authors.forename: Pia
authors.initials: P
authors.lastname: Bernasconi
authors.forename: Dimos
authors.initials: D
authors.lastname: Kapetis
mesh_terms: D000328:Adult; D000368:Aged; D001379:Azathioprine / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005260:Female; D056726:Genetic Association Studies / Q000379:methods*; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D009157:Myasthenia Gravis / Q000188:drug therapy* / Q000235:genetics; D000071184:Pharmacogenomic Variants; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA
chemical_list: D001379:Azathioprine; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C102029:ABCC6 protein, human