Iwuchukwu Otito F, Ramirez Andrea H, Shi Yaping, Bowton Erica A, Kawai Vivian K, Schildcrout Jonathan S, Roden Dan M, Denny Joshua C, Stein C Michael
aDepartment of Medicine, Division of Clinical Pharmacology Departments of bBiostatistics cMedical Bioinformatics dMedicine and Pharmacology eVanderbilt Institute for Clinical & Translational Research, Vanderbilt University School of Medicine, Nashville, Tennessee fDivision of Pharmaceutical Sciences, Fairleigh Dickinson University School of Pharmacy, Florham Park, New Jersey gMedical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
Pharmacogenet Genomics. 2016 Nov;26(11):510-516. doi: 10.1097/FPC.0000000000000244.
Genetic factors contribute considerably toward variability in warfarin dose requirements and are important in the dose-titration phase; their effects on the stability of anticoagulation later in therapy are not known.
Using deidentified electronic medical records linked to a DNA-biobank, we studied 140 African-Americans and 943 European-Americans after the warfarin dose-titration phase. We genotyped 12 single nucleotide polymorphisms in genes (CYP2C9, VKORC1, CYP4F2, GGCX, EPHX1, CALU) associated with altered warfarin dose requirements and tested their associations with international normalized ratio variability (INRVAR) and percent time in therapeutic range in European-Americans and African-Americans.
One allele copy of rs2108622 in CYP4F2 was associated with a 15% [95% confidence interval (CI): 1-26, P=0.03] decrease in the median INRVAR in European-Americans. In African-Americans, GGCX variants rs11676382 and rs699664 were associated with 4.16-fold (95% CI: 1.45-11.97, P=0.009) and 1.50-fold (95% CI: 1.07-2.08, P=0.02) changes in the median INRVAR per variant allele copy, respectively; rs11676382 was also significantly associated with a 23.19% (95% CI: 5.89-40.48, P=0.01) decrease in time in therapeutic range. The total variation in INRVAR explained by both clinical factors and rs2108622 was 5.2% for European-Americans. In African-Americans, the inclusion of GGCX variants rs11676382 and rs699664, and the CYP2C9*8 variant rs7900194 explained ∼29% of the variation in INRVAR.
The stability of anticoagulation after the warfarin dose-titration phase is differentially affected by variants in CYP4F2 in European-Americans and GGCX loci in African-Americans.
遗传因素在华法林剂量需求的变异性中起重要作用，在剂量滴定阶段很关键；但它们对治疗后期抗凝稳定性的影响尚不清楚。
利用与DNA生物样本库相关联的匿名电子病历，我们在华法林剂量滴定阶段后研究了140名非裔美国人及943名欧裔美国人。我们对与华法林剂量需求改变相关的基因（CYP2C9、VKORC1、CYP4F2、GGCX、EPHX1、CALU）中的12个单核苷酸多态性进行基因分型，并测试它们与欧裔美国人和非裔美国人的国际标准化比值变异性（INRVAR）以及治疗范围内时间百分比的关联。
CYP4F2中rs2108622的一个等位基因拷贝与欧裔美国人的中位INRVAR降低15%[95%置信区间（CI）：1 - 26，P = 0.03]相关。在非裔美国人中，GGCX变体rs11676382和rs699664分别与每个变体等位基因拷贝的中位INRVAR变化4.16倍（95%CI：1.45 - 11.97，P = 0.009）和1.50倍（95%CI：1.07 - 2.08，P = 0.02）相关；rs11676382还与治疗范围内时间显著降低23.19%（95%CI：5.89 - 40.48，P = 0.01）相关。临床因素和rs2108622共同解释的欧裔美国人INRVAR总变异为5.2%。在非裔美国人中，纳入GGCX变体rs11676382和rs699664以及CYP2C9*8变体rs7900194可解释约29%的INRVAR变异。
华法林剂量滴定阶段后抗凝的稳定性在欧裔美国人中受CYP4F2变体影响，在非裔美国人中受GGCX基因座变体影响，存在差异。
