Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota.
Department of Pharmacy Practice, Faculty of Pharmacy, Helwan University, Cairo, Egypt.
Am J Transplant. 2019 Oct;19(10):2795-2804. doi: 10.1111/ajt.15385. Epub 2019 May 13.
Tacrolimus trough and dose requirements vary dramatically between individuals of European and African American ancestry. These differences are less well described in other populations. We conducted an observational, prospective, multicenter study from which 2595 kidney transplant recipients of European, African, Native American, and Asian ancestry were studied for tacrolimus trough, doses, and genetic determinants of metabolism. We studied the well-known variants and conducted a CYP3A4/5 gene-wide analysis to identify new variants. Daily doses, and dose-normalized troughs were significantly different between the four groups (P < .001). CYP3A53 (rs776746) was associated with higher dose-normalized tacrolimus troughs in all groups but occurred at different allele frequencies and had differing effect sizes. The CYP3A56 (rs10264272) and 7 (rs413003343) variants were only present in African Americans. CYP3A422 (rs35599367) was not found in any of the Asian ancestry samples. We identified seven suggestive variants in the CYP3A4/5 genes associated with dose-normalized troughs in Native Americans (P = 1.1 × 10 -8.8 × 10 ) and one suggestive variant in Asian Americans (P = 5.6 × 10 ). Tacrolimus daily doses and dose-normalized troughs vary significantly among different ancestry groups. We identified potential new variants important in Asians and Native Americans. Studies with larger populations should be conducted to assess the importance of the identified suggestive variants.
他克莫司谷值和剂量需求在欧洲和非裔美国人种个体之间差异显著。这些差异在其他人群中描述得较少。我们进行了一项观察性、前瞻性、多中心研究，研究了 2595 名欧洲、非洲、北美和亚洲血统的肾移植受者的他克莫司谷值、剂量和代谢的遗传决定因素。我们研究了众所周知的变体，并进行了 CYP3A4/5 全基因分析以鉴定新变体。四个组之间的每日剂量和剂量标准化谷值差异具有统计学意义（P<.001）。CYP3A53（rs776746）在所有组中均与较高的剂量标准化他克莫司谷值相关，但等位基因频率不同，且效应大小不同。CYP3A56（rs10264272）和7（rs413003343）变体仅存在于非裔美国人中。CYP3A422（rs35599367）在任何亚洲血统样本中均未发现。我们在北美人群中鉴定出与剂量标准化谷值相关的 CYP3A4/5 基因中的七个提示性变体（P=1.1×10-8至 8.8×10-8），在亚裔美国人中鉴定出一个提示性变体（P=5.6×10-7）。不同种族群体之间他克莫司的日剂量和剂量标准化谷值差异显著。我们确定了在亚洲人和北美人群中重要的潜在新变体。应进行更大人群的研究以评估所鉴定的提示性变体的重要性。
