Genomewide association study of tenofovir pharmacokinetics and creatinine clearance in AIDS Clinical Trials Group protocol A5202.
Genomewide association study of tenofovir pharmacokinetics and creatinine clearance in AIDS Clinical Trials Group protocol A5202.
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DOI：
10.1097/fpc.0000000000000156
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发表时间：
2015-09
影响因子：
2.6
通讯作者：
Shepherd BE
中科院分区：
文献类型：
--
作者：
Wanga V;Venuto C;Morse GD;Acosta EP;Daar ES;Haas DW;Li C;Shepherd BE
替诺福韦富马酸二异丙酯(TDF)在一些患者中会引起肾脏毒性。我们进行了全基因组分析，以确定在艾滋病临床试验小组协议A5202中随机接受TDF/恩曲他滨方案的受试者开始治疗后的前6个月内，与血浆替诺福韦清除量和肌酐清除量(CrCl)变化的相关性。药物动力学分析涉及501名随机服用替诺福韦的受试者。CRCL分析涉及1096名受试者，其中548名对照受试者被随机分配到含有阿巴卡韦的方案中。所有患者均随机接受阿扎那韦/利托那韦或伊法韦仑治疗。多变量线性回归和广义最小二乘模型检验了多态与替诺福韦清除量和CrCl变化之间的关联，并进行了Bonferroni校正。计划中的子分析考虑了候选基因和多态。基线时CrCl值的中位数为116ml/分钟(四分位数范围99.8至135.5)。6个月后，替诺福韦组和阿巴卡韦组CrCl值的中位数分别为−0.5ml/min(−10.7~+10.8)和2.2(IQR−9.9~+13.2)。在全基因组分析中，SLC17A1rs12662869与替诺福韦清除量增加相关(P=7.1x10−9)。在替诺福韦清除量的候选基因分析中，大多数被评估的多态发生在ABCC4。在ABCC4区，CLDN10rs12866697的p值最低(P=1.4x10−3)。在非裔美国人中，SLC22A2rs3127573与校正多次比较后6个月替诺福韦组的CrCl值增加更大相关(P=3.3x10−5)。在A5202中随机接受TDF/恩曲他滨治疗的受试者中，没有全基因组范围内与CrCl变化显著相关。这项研究没有复制先前与替诺福韦相关的肾损伤有关的基因多态性。
Tenofovir disoproxil fumarate (TDF) causes kidney toxicity in some patients. We performed genome-wide analyses to identify associations with plasma tenofovir clearance and change in creatinine clearance (CrCl) during the first 6 months after initiating therapy among subjects randomized to TDF/emtricitabine-containing regimens in AIDS Clinical Trials Group protocol A5202. Pharmacokinetic analyses involved 501 subjects randomized to the tenofovir arm. The CrCl analyses involved 1096 subjects, including 548 control subjects randomized to abacavir-containing regimens. All had been randomized to also receive atazanavir/ritonavir or efavirenz. Multivariable linear regression and generalized least squares models tested for associations between polymorphisms and tenofovir clearance and CrCl change, with Bonferroni correction. Planned sub-analyses considered candidate genes and polymorphisms. Median CrCl at baseline was 116 ml/min (interquartile range [IQR] 99.8 to 135.5). Median change in CrCl after 6 months was −0.5 ml/min (−10.7 to +10.8) and 2.2 (IQR −9.9 to +13.2) in tenofovir and abacavir arms, respectively. In genome-wide analyses SLC17A1 rs12662869 was associated with an increase in tenofovir clearance (P = 7.1x10−9). In candidate gene analysis for tenofovir clearance, most polymorphisms evaluated were in ABCC4. In the ABCC4 region, the lowest p-value was for CLDN10 rs12866697 (P=1.4x10−3). Among African Americans, SLC22A2 rs3127573 was associated with a greater 6-month CrCl increase in the tenofovir arm after correcting for multiple comparisons (P = 3.3x10−5). Among subjects randomized to receive TDF/emtricitabine in A5202, there were no genome-wide significant associations with change in CrCl. This study did not replicate polymorphisms previously implicated in tenofovir-associated renal injury.