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Pharmacogenomics. 2016 Aug;17(13):1425-39. doi: 10.2217/pgs-2016-0061. Epub 2016 Aug 4.

Genetic determinants of warfarin maintenance dose and time in therapeutic treatment range: a RE-LY genomics substudy.

Author information

1
Uppsala Clinical Research Center & Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
2
Department Medical Sciences & Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
3
Population Health Research Institute, Hamilton Health Sciences & McMaster University, Hamilton, ON, Canada.
4
Sidney Kimmel Medical Collage at Thomas Jefferson University, Philadelphia, PA, USA.
5
Boehringer Ingelheim Pharma Inc, Ridgefield, CT, USA.
6
Department of Immunology, Genetics & Pathology & Science for Life Laboratory, Uppsala University, Uppsala, Sweden.

Abstract

AIMS:

We investigated associations between genetic variation in candidate genes and on a genome-wide scale with warfarin maintenance dose, time in therapeutic range (TTR), and risk of major bleeding.

MATERIALS & METHODS:

In total, 982 warfarin-treated patients from the RE-LY trial were studied.

RESULTS:

After adjusting for SNPs in VKORC1 and CYP2C9, SNPs in DDHD1 (rs17126068) and NEDD4 (rs2288344) were associated with dose. Adding these SNPs and CYP4F2 (rs2108622) to a base model increased R(2) by 2.9%. An SNP in ASPH (rs4379440) was associated with TTR (-6.8% per minor allele). VKORC1 was associated with time less than INR 2.0. VKORC1 and CYP2C9 were associated with time more than INR 3.0, but not with major bleeding.

CONCLUSIONS:

We identified two novel genes associated with warfarin maintenance dose and one gene associated with TTR. These genes need to be replicated in an independent cohort.

KEYWORDS:

CYP2C9; CYP4F2; VKORC1; genome-wide association study; prediction models; time in therapeutic range; warfarin; warfarin dose

PMID:
27488176
DOI:
10.2217/pgs-2016-0061
[Indexed for MEDLINE]
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