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首页> 外文期刊>PLoS Genetics >A Genome-Wide Association Study Confirms VKORC1 , CYP2C9 , and CYP4F2 as Principal Genetic Determinants of Warfarin Dose
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A Genome-Wide Association Study Confirms VKORC1 , CYP2C9 , and CYP4F2 as Principal Genetic Determinants of Warfarin Dose

机译：全基因组关联研究确认VKORC1，CYP2C9和CYP4F2是华法林剂量的主要遗传决定因素

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We report the first genome-wide association study (GWAS) whose sample size (1,053 Swedish subjects) is sufficiently powered to detect genome-wide significance (p?7) for polymorphisms that modestly alter therapeutic warfarin dose. The anticoagulant drug warfarin is widely prescribed for reducing the risk of stroke, thrombosis, pulmonary embolism, and coronary malfunction. However, Caucasians vary widely (20-fold) in the dose needed for therapeutic anticoagulation, and hence prescribed doses may be too low (risking serious illness) or too high (risking severe bleeding). Prior work established that ～30% of the dose variance is explained by single nucleotide polymorphisms (SNPs) in the warfarin drug target VKORC1 and another ～12% by two non-synonymous SNPs (*2, *3) in the cytochrome P450 warfarin-metabolizing gene CYP2C9. We initially tested each of 325,997 GWAS SNPs for association with warfarin dose by univariate regression and found the strongest statistical signals (p?78) at SNPs clustering near VKORC1 and the second lowest p-values (p?31) emanating from CYP2C9. No other SNPs approached genome-wide significance. To enhance detection of weaker effects, we conducted multiple regression adjusting for known influences on warfarin dose (VKORC1, CYP2C9, age, gender) and identified a single SNP (rs2108622) with genome-wide significance (p?=?8.3×10?10) that alters protein coding of the CYP4F2 gene. We confirmed this result in 588 additional Swedish patients (p<0.0029) and, during our investigation, a second group provided independent confirmation from a scan of warfarin-metabolizing genes. We also thoroughly investigated copy number variations, haplotypes, and imputed SNPs, but found no additional highly significant warfarin associations. We present power analysis of our GWAS that is generalizable to other studies, and conclude we had 80% power to detect genome-wide significance for common causative variants or markers explaining at least 1.5% of dose variance. These GWAS results provide further impetus for conducting large-scale trials assessing patient benefit from genotype-based forecasting of warfarin dose.
机译：我们报告了第一个全基因组关联研究（GWAS），其样本量（1,053瑞典受试者）足以检测适度改变华法林治疗剂量的多态性的全基因组意义（p？7）。抗凝药物华法林被广泛地处方用于降低中风，血栓形成，肺栓塞和冠状动脉疾病的风险。但是，高加索人治疗抗凝所需的剂量差异很大（20倍），因此处方剂量可能太低（导致严重疾病）或太高（导致严重出血）。先前的工作表明，华法林药物靶标VKORC1中的单核苷酸多态性（SNP）可以解释约30％的剂量差异，而细胞色素P450中的两个非同义SNP（* 2，* 3）可以解释约12％的剂量差异。华法林代谢基因CYP2C9。我们最初通过单变量回归测试了325,997个GWAS SNP与华法林剂量的相关性，发现在VKORC1附近聚集的SNP处最强的统计信号（p？78）和从CYP2C9产生的第二低p值（p？31）。没有其他SNP达到全基因组意义。为了增强对较弱作用的检测，我们对华法林剂量（VKORC1，CYP2C9，年龄，性别）的已知影响进行了多元回归调整，并鉴定了具有全基因组意义的单个SNP（rs2108622）（p？=？8.3×10？10） ）会改变CYP4F2基因的蛋白质编码。我们在另外588名瑞典患者中证实了这一结果（p <0.0029），在我们的研究中，第二组从华法林代谢基因扫描中获得了独立的证实。我们还彻底研究了拷贝数变异，单倍型和推定的SNP，但没有发现其他高度重要的华法林相关性。我们介绍了可用于其他研究的GWAS的功效分析，并得出结论，我们有80％的功效可以检测出至少有1.5％的剂量差异的常见致病变异或标记的全基因组意义。这些GWAS结果为进行大规模试验评估患者从基于基因型的华法林剂量预测中获益提供了进一步的动力。

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