Sun Boguang, Wen Ya-Feng, Culhane-Pera Kathleen A, Lo Muaj, Xiong Txia, Lee Koobmeej, Peng Kerui, Thyagarajan Bharat, Bishop Jeffrey R, Zierhut Heather, Straka Robert J
Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, USA.
Minnesota Community Care, St. Paul, Minnesota, USA.
Pharmacotherapy. 2021 Mar;41(3):265-276. doi: 10.1002/phar.2487. Epub 2020 Dec 21.
Warfarin's narrow therapeutic index and high variability in dosage requirements make dosage selection critical. Genetic factors are known to impact warfarin dosage selection. The Hmong are a unique Asian subpopulation numbering over 278,000 in the United States whose participation in genetics-based research is virtually nonexistent. The translational significance of early reports of warfarin pharmacogene differences in Hmong has not been evaluated.
(i) To validate previously identified allele frequency differences relevant to warfarin dosing in Hmong versus East Asians and (ii) to compare predicted warfarin sensitivity and maintenance doses between a Hmong population and an East Asian cohort.
DNA collected from two independent cohorts (n=236 and n=198) of Hmong adults were genotyped for CYP2C9 (*2, *3), VKORC1 (G-1639A), and CYP4F2 (*3). Allele frequencies between the combined Hmong cohort (n=433) and East Asians (n=1165) from the 2009 International Warfarin Pharmacogenetics Consortium (IWPC) study were compared using a χ test. Percentages of Hmong and East Asian participants predicted to be very sensitive to warfarin were compared using a χ test, and the predicted mean warfarin maintenance dose was compared with a t test.
The allele frequencies of CYP2C93 in the combined Hmong cohort and CYP4F23 in the VIP-Hmong cohort are significantly different from those in East Asians (18.9% vs 3.0%, p<0.001 and 9.8% vs 22.1%, p<0.001, respectively). Comparing the combined Hmong cohort to the East Asian cohort, the percentage of participants predicted to be very sensitive to warfarin was significantly higher (28% vs 5%, p<0.01) and the mean predicted warfarin maintenance dose was significantly lower (19.8 vs 21.3 mg/week, p<0.001), respectively.
The unique allele frequencies related to warfarin when combined with nongenetic factors observed in the Hmong translate into clinically relevant differences in predicted maintenance dose requirements for Hmong versus East Asians.
华法林的治疗指数狭窄，剂量需求个体差异大，因此剂量选择至关重要。已知遗传因素会影响华法林的剂量选择。苗族是美国一个独特的亚洲亚群，人数超过27.8万，但几乎没有参与基于遗传学的研究。苗族人群中华法林药物基因差异早期报告的转化意义尚未得到评估。
（i）验证先前确定的与苗族和东亚人群华法林给药相关的等位基因频率差异；（ii）比较苗族人群和东亚队列之间预测的华法林敏感性和维持剂量。
对从两个独立的苗族成年人队列（n = 236和n = 198）收集的DNA进行CYP2C9（*2，*3）、VKORC1（G-1639A）和CYP4F2（*3）基因分型。使用χ检验比较合并的苗族队列（n = 433）和来自2009年国际华法林药物遗传学联盟（IWPC）研究的东亚人群（n = 1165）之间的等位基因频率。使用χ检验比较预测对华法林非常敏感的苗族和东亚参与者的百分比，并使用t检验比较预测的平均华法林维持剂量。
合并的苗族队列中CYP2C93的等位基因频率和VIP-苗族队列中CYP4F23的等位基因频率与东亚人群有显著差异（分别为18.9%对3.0%，p<0.001和9.8%对22.1%，p<0.001）。将合并的苗族队列与东亚队列进行比较，预测对华法林非常敏感的参与者百分比显著更高（28%对5%，p<0.01），预测的平均华法林维持剂量显著更低（19.8对21.3毫克/周，p<0.001）。
与华法林相关的独特等位基因频率，结合在苗族中观察到的非遗传因素，转化为苗族和东亚人群在预测维持剂量需求方面的临床相关差异。
