BACKGROUND: Warfarin is a highly effective anticoagulant however its 
effectiveness relies on maintaining INR in therapeutic range. Finding the 
correct dose is difficult due to large inter-individual variability. Two genes, 
CYP2C9 and VKORC1, have been associated with this variability, leading to 
genotype-guided dosing tables in warfarin labeling. Nonetheless, it remains 
unclear how genotypic information should be used in practice. Navigating the 
literature to determine how genotype will influence warfarin response in a 
particular patient is difficult, due to significant variation in patient 
ethnicity, outcomes investigated, study design, and methodological rigor. Our 
systematic review was conducted to enable fair and accurate interpretation of 
which variants affect which outcomes, in which patients, and to what extent.
METHODOLOGY/PRINCIPAL FINDINGS: A comprehensive search strategy was applied and 
117 studies included. Primary outcomes were stable dose, time to stable dose and 
bleeding events. Methodological quality was assessed using criteria of Jorgensen 
and Williamson and data synthesized in meta-analyses using advanced methods. 
Pooled effect estimates were significant in most ethnic groups for CYP2C9*3 and 
stable dose (mutant types requiring between 1.1(0.7-1.5) and 2.3 
(1.6-3.0)mg/day). Effect estimates were also significant for VKORC1 and stable 
dose for most ethnicities, although direction differed between asians and 
non-asians (mutant types requiring between 0.8(0.4-1.3) and 1.5(1.1-1.8)mg/day 
more in asians and between 1.5(0.7-2.2) and 3.1(2.7-3.6)mg/day less in 
non-asians). Several studies were excluded due to inadequate data reporting. 
Assessing study quality highlighted significant variability in methodological 
rigor. Notably, there was significant evidence of selective reporting, of 
outcomes and analysis approaches.
CONCLUSIONS/SIGNIFICANCE: Genetic associations with warfarin response vary 
between ethnicities. In order to achieve unbiased estimates in different 
populations, a high level of methodological rigor must be maintained and studies 
should report sufficient data to enable inclusion in meta-analyses. We propose 
minimum reporting requirements, suggest methodological guidelines and provide 
recommendations for reducing the risk of selective reporting.