口服降糖药的药物基因组学研究进展

宋金方，赵懿清，王 涛，印晓星

·综述·

口服降糖药的药物基因组学研究进展

宋金方1,2，赵懿清1，王 涛3，印晓星2*

2型糖尿病的药物治疗中，由于个体差异，常导致疗效及不良反应多样。药物基因组学的研究表明，药物代谢酶、转运蛋白、受体以及与2型糖尿病发病机制有关的易感基因的多态性都是引起药物效应和不良反应多样性的重要原因。与口服降糖药疗效相关的基因可以分为四大类：与药物代谢和转运相关基因，编码药物作用靶点和受体的基因，T2DM发病相关基因以及其他影响药物疗效的基因。本文总结了与口服降糖药疗效相关的基因多态性位点，以期借助这些研究成果促进糖尿病个体化治疗，提高疗效，减少不良反应。

口服降糖药；基因多态性；药物基因组学；个体化治疗

0 引言

2型糖尿病(Type 2 diabetes mellitus,T2DM)的治疗以药物治疗为主，饮食、运动为辅[1-2]。临床实践发现，应用相同药物治疗方案的患者其疗效却有明显的个体差异。药物基因组学主要研究基因多态性与药物效应变异性之间的关系，其分子基础是以单核苷酸多态性(SNPs)为代表的基因多态性[3]。药物基因组学的主要研究方法已经从候选基于策略的关联研究转变为全基因组关联研究(GWAS)，并正转向能够测定所有类型突变及其频率的新一代测序方法[4]。口服降糖药的药物基因组学研究可以指导个体化治疗，改善疗效，减少低血糖、肝损害等不良反应，已经成为研究热点[2]。本文对可能影响T2DM患者对降糖药物反应性的SNPs进行综述，以指导T2DM患者的个体化治疗。

1 与药物代谢和转运相关的基因

1.1 细胞色素P450超家族 药物代谢的个体差异是造成个体在使用相同剂量的药物后体内动力学过程不同的主要原因，细胞色素氧化酶P450(CYP450)是药物代谢的主要酶系，CYP家族至少有17个亚家族；其中CYP1、CYP2和CYP3亚家族负责约96%的外源性化学物质代谢[5]。

磺酰脲类降糖药主要通过肝脏的CYP2C9代谢，CYP2C9基因具有多态性[6]。多个研究表明，CYP2C9*3(rs1057910A/C，Ile359Leu)和CYP2C9*2(rs1799853C/T，Arg144Cys)突变可以使机体对格列本脲、格列吡嗪和格列美脲等磺酰脲药物的清除减慢从而增强降糖作用，增加低血糖风险[7-8]。然而在日本人群中进行的研究并未发现这两个突变对格列美脲的体内过程和不良反应产生影响[9]。有研究发现，CYP2C9*3多态性对那格列奈的药动学过程有影响，但在后续研究中并未得到验证[10]。瑞格列奈和罗格列酮由肝脏CYP2C8代谢，CYP2C8基因也具有多态性[11]。研究表明，CYP2C8基因多态性可以影响瑞格列奈和罗格列酮的药时曲线下面积(AUC)，但是对降糖作用没有明显影响[10]。

1.2 有机阴离子转运多肽超家族 由SLCO1B1基因编码的OATP1B1属于有机阴离子转运多肽家族(OATPs)，是药物摄取性转运体，表达于肝、肾、脑和肠，负责转运多种内源性以及外源性化合物[11]。SLCO1B1 rs2306283A/G(Asn130Asp)和rs4149056C/T (Val174Ala)突变是该基因的最常见的突变[12]。有研究表明，SLCO1B1 Val174Ala多态性对瑞格列奈的药动学过程有明显影响，但对罗格列酮和吡格列酮虽有亲和力改变却不影响药动学过程[13-14]。SLCO1B1 Val174Ala多态性对那格列奈的药代动力学也有显著影响[15]，该突变导致OATP1B1转运活性下降，减慢代谢和排泄，增强降糖作用[16]。

1.3 有机阳离子转运体家族 有机阳离子转运体(Organic cation transporters，OCTs)可以介导药物被肝脏摄取以及肠道转运(OCT1)、肾脏分泌(OCT1和OCT2)、透过胎盘(OCT3)[17]。二甲双胍是广泛使用的口服降糖药，通过减少肝糖输出和改善胰岛素敏感性起作用。二甲双胍的体内过程与OCT1和OCT2密切相关，编码OCT1的SLC22A1基因和编码OCT2 的SLC22A2基因的多个突变均能影响二甲双胍药动学过程，但对药效的影响有待进一步研究[14,18]。有报道，二甲双胍也是OCT家族其他两个成员多药物和毒素排出转运蛋白1(MATE1)[SLC47A1]和多药物和毒素排出转运蛋白2-K(MATE2-K)[SLC47A2]的良好底物，其多态性使得二甲双胍的转运减少，清除减慢，降糖作用增强[19-21]。

1.4 其他转运体 SLC29A4基因编码的质膜单胺转运体(PMAT)是一种最近已经被克隆的质子活化的OCT，其底物范围与OCTs有很大的重叠，对二甲双胍具有良好亲和力[20]。SLC29A4内含子rs2685753A/G、rs3889348C/T、rs4720572C/T和rs4299914A/G突变以及3′非翻译区rs6971788A/T突变均能影响二甲双胍的药动学参数，但SLC29A4基因多态性对二甲双胍药效的影响尚未得到证实[22]。

2 药物作用靶点和受体的基因

2.1 过氧化物酶体增殖物激活受体γ PPARG基因编码过氧化物酶体增殖物激活受体γ(PPARγ)，是噻唑烷二酮类药物作用的靶点，并且PPARG rs1801282C/G(Pro12Ala)与T2DM发病的关联在多项研究中得到验证[23-24]。在韩国人群中进行的一项研究证实，PPARG Pro12Ala突变是影响罗格列酮疗效的重要遗传因素，携带该突变的T2DM患者对罗格列酮治疗的反应性较好[25]。近年来，PPAR家族的另一成员PPARδ因其在代谢过程中的重要作用也正被越来越多的学者在T2DM相关领域中进行研究，有研究表明，PPARD基因多态性与胰岛素抵抗有关[26]，激活PPARδ在增加胰岛素敏感性的同时，还可以改善db/db小鼠的胰岛功能[27]。开展PPARD基因多态性对降糖药物疗效影响的相关研究，并进一步进行机制研究对促进T2DM患者个体化治疗具有重要意义。

2.2 ATP敏感性钾通道 磺脲类药物的作用靶点是ATP敏感性钾通道(KATP)，由调节亚基磺脲类药物受体1(SUR1)和核心亚基内向整流钾通道(Kir6.2)组成，SUR1由ABCC8基因编码，Kir6.2由KCNJ11基因编码[28]。ABCC8 Ser1369Ala基因多态性与磺脲类药物的敏感性密切相关，携带Ala等位基因的患者对磺脲类药物反应较敏感，用药后空腹血糖和糖化血红蛋白下降更加明显[29]。

KCNJ11 rs5219A/G(Lys23Glu)突变与T2DM易感性以及胰岛素分泌减少有关[30]，对磺脲类药物疗效的影响在不同人群中表现为增强和减弱两种情况[24,31]。格列奈类降糖药也需要通过抑制KATP刺激胰岛B细胞分泌胰岛素[32]。KCNJ11 Lys23Glu突变和ABCC8内含子rs1799854C/T突变与瑞格列奈反应性有关联[27]。虽然KATP并非二甲双胍的作用靶点，但有研究表明，二甲双胍的疗效与KCNJ11 Lys23Glu突变有关，其具体机制尚未阐明[15]。

2.3 肠促胰岛素受体 葡萄糖依赖性促胰岛素多肽(GIP)和胰高血糖素样肽1(GLP1)统称为肠促胰岛素，除能刺激胰岛素分泌外，尚有抑制餐后胰高血糖素的分泌、延缓肠排空、抑制食欲、增强胰岛素敏感性等作用[33]。这两种激素分别通过结合主要分布于胰岛B细胞表面的GIP受体(GIPR)和GLP1受体(GLP1R)，改善葡萄糖依赖的胰岛素分泌[34]。GIPR基因多态性，可以明显减弱针对肠胰岛轴的治疗效果，但是确切机制尚未阐明[34]。GLP1R基因多态性可能降低外源性或内源性GLP1和GLP1R激动剂的疗效[35]。最近一项在美国健康人群中进行的临床研究表明，通过测定GLP1R rs6923761A/G(Gly168Ser)和rs3765467C/T(Arg131Gln)基因多态性可以预测肠促胰岛素干预治疗的效果[36]。

3 T2DM发病相关基因

3.1 脂肪因子 研究证实，脂肪因子基因变异可以影响血浆脂肪因子水平、T2DM进展以及胰岛素抵抗[37]。噻唑烷二酮类通过活化PPARγ调节循环中脂联素、瘦素、肿瘤坏死因子(TNF)-α和抵抗素(RETN)的水平实现其降糖作用[32]。因此，推测脂肪细胞因子的基因多态性可能与噻唑烷二酮类药物疗效个体差异有关。有报道，编码脂联素(ADIPOQ)基因多态性、瘦素(LEP)基因rs7799039A/G突变、TNF基因rs1800629A/G突变和RETN基因rs1862513C/G突变与罗格列酮、比格列酮药效减弱有关联[32,38]。

3.2 转录因子7类似物2(TCF7L2) 当前关于TCF7L2基因的研究较为明确，已经证实TCF7L2基因多态性与T2DM风险增加有关[39]。苏格兰人群的研究表明，TCF7L2基因突变与磺脲类疗效降低有关，该结果在德国人群中得到了验证[34,40]。有报道，TCF7L2基因第三内含子rs290487C/T突变影响瑞格列奈中国2型糖尿病患者的疗效[41]。

3.3 胰岛素受体底物1(IRS1) IRS1是胰岛素信号转导的关键蛋白，可以调节胰岛素的作用，IRS1基因多态性与T2DM和胰岛素抵抗有关联[42]。有研究报道，携带IRS1 Gly972Arg突变的T2DM患者对磺脲类药物发生继发性失效的可能性显著高于纯合子的T2DM患者[37]。有研究证实，IRS1 Gly972Arg多态性也能减弱格列奈类降低糖化血红蛋白的效果[43]。

3.4 一氧化氮合酶1转接蛋白(NOS1AP) NOS1AP基因表达产物NOS1AP主要分布于线粒体和细胞质，其结合并抑制一氧化氮合酶1(NOS1)[44]。NOS1AP基因多态性在T2DM发病中的意义较为明确，以中国上海地区人群为研究对象，发现NOS1AP rs12742393与T2DM关联性最强[45-46]。有研究报道，NOS1AP基因多态性对格列美脲及瑞格列奈的疗效有影响[45-46]。

3.5 锌转运蛋白-8 SLC30A8基因表达产物锌转运蛋白-8主要分布于胰岛B细胞。SLC30A8 rs13266634C/T(Arg325Trp)突变和T2DM的关联以及该突变对药物治疗反应性的影响存在争议[47]。携带有保护性T等位基因的患者对8周的瑞格列奈治疗反应性较好[42]，但瑞格列奈治疗1年后，这种关联性消失[48]。

3.6 解偶联蛋白2(UCP2) UCP2基因编码的UCP2是一种线粒体阴离子转运蛋白，是胰岛B细胞能量代谢的重要调节器，也是代谢疾病的重要候选易感基因[49]。一项以日本T2DM患者为对象的病例对照研究表明，UCP2 rs659366A等位基因携带者病情进展较快[44]。以中国T2DM患者为对象的研究表明，UCP2 rs659366A等位基因携带者罗格列酮疗效更明显[50]，但对瑞格列奈治疗反应较差[51]。

4 其他可能与T2DM发病机制有关的基因

细胞周期素依赖性激酶5调节亚单位相关蛋白l类似物l基因(CDKAL1)、电压门控钾通道Q亚家族成员1基因(KCNQ1)、胰岛素样生长因子2 mRNA结合蛋白基因(IGF2BP2)、烟酰胺磷酸核糖转移酶基因(NAMPT)、配对盒4基因(PAX4)、毛细血管扩张性共济失调症突变基因(ATM)和丝氨酸消旋酶基因(SRR)等基因多态性与口服降糖药物的疗效差异存在一定关联[52-53]。其中CDKAL1基因多态性与磺脲类和格列奈类疗效的关联，KCNQ1基因多态性对瑞格列奈和罗格列酮疗效的影响[54]，IGF2BP2基因多态性、NAMPT基因多态性以及PAX4基因多态性对瑞格列奈疗效的影响[55-57]，ATM基因多态性和SRR基因多态性对二甲双胍疗效的影响的研究较多[58-59]，意义也较为明确，但这些基因的变异影响药效的具体机制有待进一步探讨。

5 结语

口服降糖药物是治疗T2DM患者最常用的方法，临床常用药物包括：二甲双胍、磺脲类/格列奈类、噻唑烷二酮类、α糖苷酶抑制剂、二肽基肽酶Ⅳ(DPP-4)抑制剂和GLP1类似物等[2]。随着病情进展，大多数患者往往需要一种以上的降糖药物联合治疗，并且疗效和不良反应具有明显个体差异[4]。口服降糖药的药物基因组学研究的最终目标是个体化治疗糖尿病患者，促进合理用药。本文讨论了一些可能影响降糖药物疗效的基因多态性，但只有少数基因及其多态性与药物疗效的关联是明确的，大部分结果尚需进一步研究佐证。药物治疗的个体差异不能用单个SNP完全解释，往往是多个遗传因素的叠加表现；因此，GWAS或者相关基因的高通量测序技术已成为研究药物治疗个体差异的重要方法。药物基因组学研究结果在不同种族中的变异性、相关的机制研究较为薄弱、社会的接受与认可程度较低、临床基因检测技术不够成熟等问题都使得将研究结果应用于临床实践具有一定的局限性。当前的研究很少有关于联合用药药物相互作用与基因多态性关联的探讨，而临床实践中联合用药十分广泛，该领域的研究应引起我们足够的重视。

本文总结了很多有意义的结果，但是只有更多的影响药物反应性的遗传因素得到阐明，个体化用药理念进一步深入人心，个体化用药基因检测的临床模式更加完善，才能将T2DM的药物基因组学研究成果转化为广泛的临床实践。

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Study progress on pharmacogenomics of oral hypoglycemic agents

SONG Jin-fang1,2,ZHAO Yi-qing1,WANG Tao3,YIN Xiao-xing2*

(1.Wuxi Third People′s Hospital,Wuxi 214000,China; 2.Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy,Xuzhou 221000,China; 3.Affiliated Hospital of Xuzhou Medical College,Xuzhou 221000,China)

In the treatment of type 2 diabetes mellitus (T2DM),hypoglycemic drugs,due to individual differences,often result in varied efficacy and adverse reactions.Pharmacogenomics studies show that the polymorphisms of drug-metabolizing enzymes,transporters,receptors,and the pathogenesis of type 2 diabetes susceptibility genes are important impact factors.The related genes of efficacy of oral hypoglycemic agents can be divided into four categories: drug metabolism and transport-related genes,encoding drug targets and receptor genes,T2DM related genes and other genes affect drug efficacy.This article summarizes the genetic polymorphisms associated with the efficacy of oral hypoglycemic agents to promote individualized treatment of diabetes,improve efficacy and reduce adverse reactions.

Oral hypoglycemic agent; Genepolymorphism; Pharmacogenomics; Personalized treatment

2014-11-01

1.无锡市第三人民医院，江苏 无锡 214000；2.江苏省新药研究与临床药学重点实验室，江苏 徐州 221000；3.徐州医学院附属医院，江苏 徐州 221000

江苏省“六大人才高峰”资助项目(2011-SWYY-019)；徐州市科技计划项目(XZZDY1203)

10.14053/j.cnki.ppcr.201507026

*通信作者