CYP2C9, VKORC1, and CYP4F2 polymorphisms and pediatric warfarin maintenance dose: a systematic review and meta-analysis

• Published in: The pharmacogenomics journal Vol. 20; no. 2; pp. 306 - 319
• Main Authors: Takeuchi, Masanobu, Kobayashi, Tohru, Biss, Tina, Kamali, Farhad, Vear, Susan I., Ho, Richard H., Bajolle, Fanny, Loriot, Marie-Anne, Shaw, Kaitlyn, Carleton, Bruce C., Hamberg, Anna-Karin, Wadelius, Mia, Hirono, Keiichi, Taguchi, Masato, Wakamiya, Takuya, Yanagimachi, Masakatsu, Hirai, Keita, Itoh, Kunihiko, Brandão, Leonardo R., Ito, Shinya
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-04-2020; Nature Publishing Group
• Subjects: 45; 631/208/727; 692/308/2056; 692/699/75; 692/700/565; Anticoagulants - administration & dosage; Biomedical and Life Sciences; Biomedicine; Child; Children; Cross-Sectional Studies - methods; Cytochrome; Cytochrome P-450; Cytochrome P-450 CYP2C9 - genetics; Cytochrome P450; Cytochrome P450 Family 4 - genetics; Drug metabolism; Gene Expression; Genetic aspects; Genetic polymorphisms; Health aspects; Human Genetics; Humans; Maintenance Chemotherapy - methods; Meta-analysis; Methadone; Observational Studies as Topic - methods; Oncology; Patient outcomes; Pharmacotherapy; Polymorphism, Single Nucleotide - genetics; Psychopharmacology; Reductase; Sensitivity analysis; Systematic review; Vitamin K; Vitamin K Epoxide Reductases - genetics; Warfarin; Warfarin - administration & dosage; Canada
• ISSN: 1470-269X; 1473-1150; 1473-1150
• DOI: 10.1038/s41397-019-0117-x

Studies on the effect of cytochrome P450 2C9 (
CYP2C9
), vitamin K epoxide reductase complex subunit 1 (
VKORC1
), and cytochrome P450 4F2 (
CYP4F2
) polymorphisms on warfarin maintenance dose in children are conflicting. We conducted a systematic review and meta-analysis to evaluate the effect of these polymorphisms on warfarin maintenance dose in children. We searched relevant literature using the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trial libraries without any language restrictions from their inception to 23 July 2017. Dose differences are expressed as standardized mean difference (SMD) or mean difference (MD) with 95% confidence intervals (CI). This review was registered in the PROSPERO prospective register of systematic reviews (CRD42015016172). We included a total of nine studies (745 participants) in the meta-analysis. Patients with
CYP2C9
*1/*2, *1/*3, *2/*2, *2/*3, or *3/*3 required a lower warfarin maintenance dose compared with patients with
CYP2C9
*1/*1 (SMD = −0.610, 95% CI: −0.802 to −0.419,
I
2
 = 0%). Patients with
VKORC1
-1639GA or AA required a lower warfarin maintenance dose compared with patients with
VKORC1
-1639GG (SMD = −0.666, 95% CI: −0.887 to −0.445,
I
2
 = 33%). However, no associations were observed between
CYP4F2
polymorphisms and warfarin maintenance dose (MD = 0.005 mg/kg/day, 95% CI: −0.006 to 0.015,
I
2
 = 0%). These results were not affected by a sensitivity analysis. Our meta-analysis provides evidence that
CYP2C9
and
VKORC1
variant statuses affect warfarin maintenance dose in children, but not CYP4F2.