Pharmacogenetics of cyclophosphamide and CYP2C19 polymorphism in Thai systemic lupus erythematosus.
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.
Ngamjanyaporn
Pintip
P
Allergy Immunology and Rheumatology Division, Department of Medicine, Ramathibodi Hospital, Mahidol University, Rachatevi, Bangkok, 10400, Thailand. rapnj@mucc.mahidol.ac.th
Thakkinstian
Ammarin
A
Verasertniyom
Oravan
O
Chatchaipun
Porntip
P
Vanichapuntu
Monchand
M
Nantiruj
Kanokrat
K
Totemchokchyakarn
Kitti
K
Attia
John
J
Janwityanujit
Suchela
S
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
D007166:Immunosuppressive Agents; D003520:Cyclophosphamide; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19