title: Multidrug resistance 1 (MDR1) 3435C>T gene polymorphism influences the clinical phenotype and methotrexate-induced adverse events in South Indian Tamil rheumatoid arthritis.
abstract: OBJECTIVE
  Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease primarily targeting the synovial joints causing joint damage and significant functional impairment. Methotrexate (MTX) remains the mainstay for the treatment of RA, and approximately 10-30% of the patients fail to attain remission because of inefficacy of the drug or due to development of adverse events. Multidrug resistance 1 (MDR1) gene encodes for permeable glycoprotein (P-gp) which is an integral membrane protein for the transport of chemotherapeutic agents, immunosuppressive drugs etc. MDR1 3435C>T results in a wobble mutation in exon 26 but is associated with altered P-gp expression and reduced P-gp function. The present study was carried out to find the role of MDR1 3435C>T gene polymorphism with clinical phenotype, treatment response, and MTX adverse events in 336 RA and 329 healthy controls of South Indian Tamil ethnicity.
  
  
  METHODS
  MDR1 3435C>T gene polymorphism was analyzed by TaqMan 5' nuclease assay.
  
  
  RESULTS
  We found MDR1 3435T allele as a risk allele for contributing to high EULAR disease activity [p = 0.02, OR 1.50, 95% CI (1.06-2.13)]. Also, MDR1 3435CT genotype was associated with deforming disease [p = 0.02, OR 1.79, 95% CI (1.11-2.88)]. However, this SNP did not influence the MTX treatment response in these patients. MDR1 3435CT genotype was associated with MTX-induced adverse events [p = 0.01, OR 2.01, 95% CI (1.15-3.52)], and the 3435 TT genotype remained protective for the development of adverse events [p = 0.009, OR 0.40, 95% CI (0.21-0.78)]. Also, the heterozygous 3435 CT genotype was associated with gastrointestinal events [p = 0.02, OR 3.62, 95% CI (1.25-10.47)], and CT genotype remained protective in patients developing infection [p = 0.002, OR 0.05, 95% CI (0.006-0.460)].
  
  
  CONCLUSIONS
  MDR1 3435C>T gene polymorphism influences the clinical phenotype and adverse events to MTX in the South Indian cohort of patients with RA.
authors.affiliation: Department of Clinical Immunology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, 605 006, India.
authors.forename: Niveditha
authors.initials: N
authors.lastname: Muralidharan
authors.forename: Paul T
authors.initials: PT
authors.lastname: Antony
authors.forename: Vikramraj K
authors.initials: VK
authors.lastname: Jain
authors.forename: Christina Mary
authors.initials: CM
authors.lastname: Mariaselvam
authors.forename: Vir Singh
authors.initials: VS
authors.lastname: Negi
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000328:Adult; D018501:Antirheumatic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D007194:India; D008297:Male; D008727:Methotrexate / Q000009:adverse effects* / Q000627:therapeutic use; D010641:Phenotype; D011110:Polymorphism, Genetic; D012720:Severity of Illness Index; D044465:White People
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D018501:Antirheumatic Agents; D008727:Methotrexate