title: Polymorphisms in the multidrug-resistance 1 gene related to glucocorticoid response in rheumatoid arthritis treatment.
abstract: A substantial proportion of rheumatoid arthritis (RA)-patients experience an insufficient response to glucocorticoids, an important therapeutic agent in RA. The multidrug-resistance 1 (MDR1) gene product P-glycoprotein (P-gp) is an efflux pump that actively transports substrates, such as glucocorticoids, out of the cell. We investigated if the variation in response might be explained by single-nucleotide polymorphisms (SNPs) in the MDR1 gene. RA-patients treated with intravenous methylprednisolone pulses (n = 18) or oral prednisone/prednisolone (n = 22) were included in a prospective cohort, and clinical response was measured after 5 and 30 days, respectively. The C1236T, G2677A/T, and C3435T SNPs were determined, and the functionality of P-gp was assessed by flow cytometry (Rhodamine efflux assay). Carriage of the G2677A/T SNP was significantly associated with response (OR = 6.18, p = 0.035), the other SNPs showed trends. Stratified for received treatment, the effect was only present in methylprednisolone treated patients. Mutant allele carriage significantly decreased functionality of P-gp in B cells, though had a smaller impact in other PBMC subtypes. Carriage of a MDR1 SNP was related to a response to methylprednisolone in this study, which his suggests that RA-patients carrying wild-type alleles might benefit from P-gp inhibition or administration of glucocorticoid analogues that are non-P-gp substrates.
authors.affiliation: Rheumatology and Clinical Immunology, University Medical Center Utrecht, F02.127, 3508 GA, Utrecht, The Netherlands. b.v.j.cuppen@umcutrecht.nl.
authors.forename: Bart V J
authors.initials: BV
authors.lastname: Cuppen
authors.affiliation: Respiratory and Inflammation iMed, AstraZeneca, Pepparedsleden 1, 431 83, Mölndal, Sweden. katerina.pardali@astrazeneca.com.
authors.forename: Katerina
authors.initials: K
authors.lastname: Pardali
authors.affiliation: Rheumatology and Clinical Immunology, University Medical Center Utrecht, F02.127, 3508 GA, Utrecht, The Netherlands.|Respiratory and Inflammation iMed, AstraZeneca, Pepparedsleden 1, 431 83, Mölndal, Sweden.
authors.forename: Maarten C
authors.initials: MC
authors.lastname: Kraan
authors.affiliation: Rheumatology and Clinical Immunology, University Medical Center Utrecht, F02.127, 3508 GA, Utrecht, The Netherlands.
authors.forename: Anne C A
authors.initials: AC
authors.lastname: Marijnissen
authors.affiliation: Respiratory and Inflammation iMed, AstraZeneca, Pepparedsleden 1, 431 83, Mölndal, Sweden.
authors.forename: Linda
authors.initials: L
authors.lastname: Yrlid
authors.affiliation: Respiratory and Inflammation iMed, AstraZeneca, Pepparedsleden 1, 431 83, Mölndal, Sweden.
authors.forename: Marita
authors.initials: M
authors.lastname: Olsson
authors.affiliation: Rheumatology and Clinical Immunology, University Medical Center Utrecht, F02.127, 3508 GA, Utrecht, The Netherlands.
authors.forename: Johannes W J
authors.initials: JW
authors.lastname: Bijlsma
authors.affiliation: Rheumatology and Clinical Immunology, University Medical Center Utrecht, F02.127, 3508 GA, Utrecht, The Netherlands.
authors.forename: Floris P J G
authors.initials: FP
authors.lastname: Lafeber
authors.affiliation: Rheumatology and Clinical Immunology, University Medical Center Utrecht, F02.127, 3508 GA, Utrecht, The Netherlands.|1st Medical Department and Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, Hanusch Hospital, Vienna, Austria.|Sigmund Freud University, Vienna, Austria.
authors.forename: Ruth D E
authors.initials: RD
authors.lastname: Fritsch-Stork
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000328:Adult; D000368:Aged; D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D005838:Genotype; D005938:Glucocorticoids / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008775:Methylprednisolone / Q000627:therapeutic use; D008875:Middle Aged; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D011239:Prednisolone / Q000627:therapeutic use; D011241:Prednisone / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005938:Glucocorticoids; D011239:Prednisolone; D011241:Prednisone; D008775:Methylprednisolone
keywords: Glucocorticoids; MDR1; Multidrug resistance; Polymorphisms; Rheumatoid Arthritis