title: Pharmacogenetics of cyclophosphamide and CYP2C19 polymorphism in Thai systemic lupus erythematosus.
abstract: To assess whether the CYP2C19 polymorphism modified the effect of cyclophosphamide on ovarian toxicity in Thai patients with SLE. We performed a case-control study of female patients with SLE who were treated with cyclophosphamide at Ramathibodi Hospital, Bangkok, Thailand. Cases were patient who had ovarian toxicity (sustained amenorrhoea >12 months or lack of menstruation for >4 months). CYP2C19 polymorphism was genotyped using PCR-RFLP method. Logistic regression was applied to assess CYP2C19 polymorphism as an effect modifier of cyclophosphamide. Seventy-one patients with SLE were enrolled, of which 36 (59.7%) had ovarian toxicity. CYP2C19*2 allele frequencies were 27.8 and 21.4% in the ovarian and non-ovarian toxicity groups. Patients with CYP2C19*1/*1 genotype and higher cumulative dose of cyclophosphamide (>23.75 g) had the highest odds of ovarian toxicity, i.e. 11.0 (95% CI: 1.2-99.1) times higher than patients with the CYP2C19*1/*2 or *2/*2 genotypes who received less cyclophosphamide (<23.75 g). After adjusting for age at start of treatment, this risk increased to 13.6 (95% CI: 1.1-162.2). Our results suggest that a cumulative cyclophosphamide dose of 23.75 g or higher carries a twofold higher risk of ovarian toxicity and the CYP2C19*1/*1 genotype increases the risk of toxicity a further fivefold.
authors.affiliation: Allergy Immunology and Rheumatology Division, Department of Medicine, Ramathibodi Hospital, Mahidol University, Rachatevi, Bangkok, 10400, Thailand. rapnj@mucc.mahidol.ac.th
authors.forename: Pintip
authors.initials: P
authors.lastname: Ngamjanyaporn
authors.forename: Ammarin
authors.initials: A
authors.lastname: Thakkinstian
authors.forename: Oravan
authors.initials: O
authors.lastname: Verasertniyom
authors.forename: Porntip
authors.initials: P
authors.lastname: Chatchaipun
authors.forename: Monchand
authors.initials: M
authors.lastname: Vanichapuntu
authors.forename: Kanokrat
authors.initials: K
authors.lastname: Nantiruj
authors.forename: Kitti
authors.initials: K
authors.lastname: Totemchokchyakarn
authors.forename: John
authors.initials: J
authors.lastname: Attia
authors.forename: Suchela
authors.initials: S
authors.lastname: Janwityanujit
mesh_terms: D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D016022:Case-Control Studies; D003520:Cyclophosphamide / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D065731:Cytochrome P-450 CYP2C19; D005260:Female; D005787:Gene Frequency; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy*; D010049:Ovarian Diseases / Q000139:chemically induced* / Q000235:genetics*; D011110:Polymorphism, Genetic; D013785:Thailand / Q000453:epidemiology; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D003520:Cyclophosphamide; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19