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. 2016 Jan 6;8(1):2.
doi: 10.1186/s13073-015-0255-y.

A multi-factorial analysis of response to warfarin in a UK prospective cohort

Stephane Bourgeois  1 , Andrea Jorgensen  2 , Eunice J Zhang  3 , Anita Hanson  4 , Matthew S Gillman  5 , Suzannah Bumpstead  6 , Cheng Hock Toh  7 , Paula Williamson  8 , Ann K Daly  9 , Farhad Kamali  10 , Panos Deloukas  11   12 , Munir Pirmohamed  13   14   15
Affiliations

A multi-factorial analysis of response to warfarin in a UK prospective cohort

Stephane Bourgeois et al. Genome Med. .

Abstract

Background: Warfarin is the most widely used oral anticoagulant worldwide, but it has a narrow therapeutic index which necessitates constant monitoring of anticoagulation response. Previous genome-wide studies have focused on identifying factors explaining variance in stable dose, but have not explored the initial patient response to warfarin, and a wider range of clinical and biochemical factors affecting both initial and stable dosing with warfarin.

Methods: A prospective cohort of 711 patients starting warfarin was followed up for 6 months with analyses focusing on both non-genetic and genetic factors. The outcome measures used were mean weekly warfarin dose (MWD), stable mean weekly dose (SMWD) and international normalised ratio (INR) > 4 during the first week. Samples were genotyped on the Illumina Human610-Quad chip. Statistical analyses were performed using Plink and R.

Results: VKORC1 and CYP2C9 were the major genetic determinants of warfarin MWD and SMWD, with CYP4F2 having a smaller effect. Age, height, weight, cigarette smoking and interacting medications accounted for less than 20 % of the variance. Our multifactorial analysis explained 57.89 % and 56.97 % of the variation for MWD and SMWD, respectively. Genotypes for VKORC1 and CYP2C9*3, age, height and weight, as well as other clinical factors such as alcohol consumption, loading dose and concomitant drugs were important for the initial INR response to warfarin. In a small subset of patients for whom data were available, levels of the coagulation factors VII and IX (highly correlated) also played a role.

Conclusion: Our multifactorial analysis in a prospectively recruited cohort has shown that multiple factors, genetic and clinical, are important in determining the response to warfarin. VKORC1 and CYP2C9 genetic polymorphisms are the most important determinants of warfarin dosing, and it is highly unlikely that other common variants of clinical importance influencing warfarin dosage will be found. Both VKORC1 and CYP2C9*3 are important determinants of the initial INR response to warfarin. Other novel variants, which did not reach genome-wide significance, were identified for the different outcome measures, but need replication.

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Figures

Fig. 1
Fig. 1
Manhattan plots for multiple regressions on MWD only adjusting for non-genetic factors (a) and adjusting for non-genetic and genetic factors (b). The vertical axis represents the common logarithm of the P value, numbers on the horizontal axis represent the chromosome. Signals below the genome-wide significance threshold of 5 × 10−08 are represented in green
Fig. 2
Fig. 2
Manhattan plots for multiple regressions on SMWD only adjusting for non-genetic factors (a) and adjusting for non-genetic and genetic factors (b). The vertical axis represents the common logarithm of the P value, numbers on the horizontal axis represent the chromosome. Signals below the genome-wide significance threshold of 5 × 10−08 are represented in green
Fig. 3
Fig. 3
Manhattan plots for multiple regressions on INR >4 during first week of treatment only adjusting for non-genetic factors (a) and adjusting for non-genetic and genetic factors (b). The vertical axis represents the common logarithm of the P value, numbers on the horizontal axis represent the chromosome. Signals below the genome-wide significance threshold of 5 × 10−08 are represented in green
See this image and copyright information in PMC

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