Department of Biostatistics, Shelley's Cottage, University of Liverpool, Liverpool, United Kingdom.
PLoS One. 2012;7(8):e44064. doi: 10.1371/journal.pone.0044064. Epub 2012 Aug 29.
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.
华法林是一种非常有效的抗凝剂，但其疗效依赖于将 INR 维持在治疗范围内。由于个体间的变异性很大，因此很难找到正确的剂量。两个基因，CYP2C9 和 VKORC1，与这种变异性有关，导致华法林标签中的基因型指导剂量表。尽管如此，目前尚不清楚如何在实践中使用基因型信息。由于患者种族、研究设计和方法学严谨性等方面存在显著差异，因此，确定基因型如何影响特定患者的华法林反应的文献错综复杂。我们进行了系统评价，以便能够公平、准确地解释哪些变体影响哪些结果、哪些患者以及影响程度。
方法/主要发现：应用全面的搜索策略，共纳入 117 项研究。主要结局为稳定剂量、达到稳定剂量的时间和出血事件。使用 Jorgensen 和 Williamson 的标准评估方法学质量，并使用高级方法进行荟萃分析综合数据。在大多数种族中，CYP2C9*3 和稳定剂量（需要 1.1（0.7-1.5）和 2.3（1.6-3.0）mg/天的突变型）以及 VKORC1 和稳定剂量的汇总效应估计值具有统计学意义。尽管亚洲人和非亚洲人之间的方向不同（亚洲人需要增加 0.8（0.4-1.3）和 1.5（1.1-1.8）mg/天，而非亚洲人需要减少 1.5（0.7-2.2）和 3.1（2.7-3.6）mg/天），但在大多数种族中，VKORC1 和稳定剂量的效应估计值也具有统计学意义。由于数据报告不足，排除了几项研究。评估研究质量突出了方法学严谨性的显著差异。值得注意的是，存在显著的选择性报告、结局和分析方法的证据。
结论/意义：华法林反应的遗传相关性在不同种族之间存在差异。为了在不同人群中获得无偏估计，必须保持高水平的方法学严谨性，并且研究应报告足够的数据，以便能够进行荟萃分析。我们提出了最低报告要求，提出了方法学指南，并就减少选择性报告的风险提出了建议。
