宋金方，趙懿清，王 濤，印曉星

·綜述·

口服降糖藥的藥物基因組學(xué)研究進(jìn)展

宋金方1,2，趙懿清1，王 濤3，印曉星2*

2型糖尿病的藥物治療中，由于個(gè)體差異，常導(dǎo)致療效及不良反應(yīng)多樣。藥物基因組學(xué)的研究表明，藥物代謝酶、轉(zhuǎn)運(yùn)蛋白、受體以及與2型糖尿病發(fā)病機(jī)制有關(guān)的易感基因的多態(tài)性都是引起藥物效應(yīng)和不良反應(yīng)多樣性的重要原因。與口服降糖藥療效相關(guān)的基因可以分為四大類：與藥物代謝和轉(zhuǎn)運(yùn)相關(guān)基因，編碼藥物作用靶點(diǎn)和受體的基因，T2DM發(fā)病相關(guān)基因以及其他影響藥物療效的基因。本文總結(jié)了與口服降糖藥療效相關(guān)的基因多態(tài)性位點(diǎn)，以期借助這些研究成果促進(jìn)糖尿病個(gè)體化治療，提高療效，減少不良反應(yīng)。

口服降糖藥；基因多態(tài)性；藥物基因組學(xué)；個(gè)體化治療

0 引言

2型糖尿病(Type 2 diabetes mellitus,T2DM)的治療以藥物治療為主，飲食、運(yùn)動(dòng)為輔[1-2]。臨床實(shí)踐發(fā)現(xiàn)，應(yīng)用相同藥物治療方案的患者其療效卻有明顯的個(gè)體差異。藥物基因組學(xué)主要研究基因多態(tài)性與藥物效應(yīng)變異性之間的關(guān)系，其分子基礎(chǔ)是以單核苷酸多態(tài)性(SNPs)為代表的基因多態(tài)性[3]。藥物基因組學(xué)的主要研究方法已經(jīng)從候選基于策略的關(guān)聯(lián)研究轉(zhuǎn)變?yōu)槿蚪M關(guān)聯(lián)研究(GWAS)，并正轉(zhuǎn)向能夠測(cè)定所有類型突變及其頻率的新一代測(cè)序方法[4]?？诜堤撬幍乃幬锘蚪M學(xué)研究可以指導(dǎo)個(gè)體化治療，改善療效，減少低血糖、肝損害等不良反應(yīng)，已經(jīng)成為研究熱點(diǎn)[2]。本文對(duì)可能影響T2DM患者對(duì)降糖藥物反應(yīng)性的SNPs進(jìn)行綜述，以指導(dǎo)T2DM患者的個(gè)體化治療。

1 與藥物代謝和轉(zhuǎn)運(yùn)相關(guān)的基因

1.1 細(xì)胞色素P450超家族 藥物代謝的個(gè)體差異是造成個(gè)體在使用相同劑量的藥物后體內(nèi)動(dòng)力學(xué)過程不同的主要原因，細(xì)胞色素氧化酶P450(CYP450)是藥物代謝的主要酶系，CYP家族至少有17個(gè)亞家族；其中CYP1、CYP2和CYP3亞家族負(fù)責(zé)約96%的外源性化學(xué)物質(zhì)代謝[5]。

磺酰脲類降糖藥主要通過肝臟的CYP2C9代謝，CYP2C9基因具有多態(tài)性[6]。多個(gè)研究表明，CYP2C9*3(rs1057910A/C，Ile359Leu)和CYP2C9*2(rs1799853C/T，Arg144Cys)突變可以使機(jī)體對(duì)格列本脲、格列吡嗪和格列美脲等磺酰脲藥物的清除減慢從而增強(qiáng)降糖作用，增加低血糖風(fēng)險(xiǎn)[7-8]。然而在日本人群中進(jìn)行的研究并未發(fā)現(xiàn)這兩個(gè)突變對(duì)格列美脲的體內(nèi)過程和不良反應(yīng)產(chǎn)生影響[9]。有研究發(fā)現(xiàn)，CYP2C9*3多態(tài)性對(duì)那格列奈的藥動(dòng)學(xué)過程有影響，但在后續(xù)研究中并未得到驗(yàn)證[10]。瑞格列奈和羅格列酮由肝臟CYP2C8代謝，CYP2C8基因也具有多態(tài)性[11]。研究表明，CYP2C8基因多態(tài)性可以影響瑞格列奈和羅格列酮的藥時(shí)曲線下面積(AUC)，但是對(duì)降糖作用沒有明顯影響[10]。

1.2 有機(jī)陰離子轉(zhuǎn)運(yùn)多肽超家族 由SLCO1B1基因編碼的OATP1B1屬于有機(jī)陰離子轉(zhuǎn)運(yùn)多肽家族(OATPs)，是藥物攝取性轉(zhuǎn)運(yùn)體，表達(dá)于肝、腎、腦和腸，負(fù)責(zé)轉(zhuǎn)運(yùn)多種內(nèi)源性以及外源性化合物[11]。SLCO1B1 rs2306283A/G(Asn130Asp)和rs4149056C/T (Val174Ala)突變是該基因的最常見的突變[12]。有研究表明，SLCO1B1 Val174Ala多態(tài)性對(duì)瑞格列奈的藥動(dòng)學(xué)過程有明顯影響，但對(duì)羅格列酮和吡格列酮雖有親和力改變卻不影響藥動(dòng)學(xué)過程[13-14]。SLCO1B1 Val174Ala多態(tài)性對(duì)那格列奈的藥代動(dòng)力學(xué)也有顯著影響[15]，該突變導(dǎo)致OATP1B1轉(zhuǎn)運(yùn)活性下降，減慢代謝和排泄，增強(qiáng)降糖作用[16]。

1.3 有機(jī)陽離子轉(zhuǎn)運(yùn)體家族 有機(jī)陽離子轉(zhuǎn)運(yùn)體(Organic cation transporters，OCTs)可以介導(dǎo)藥物被肝臟攝取以及腸道轉(zhuǎn)運(yùn)(OCT1)、腎臟分泌(OCT1和OCT2)、透過胎盤(OCT3)[17]。二甲雙胍是廣泛使用的口服降糖藥，通過減少肝糖輸出和改善胰島素敏感性起作用。二甲雙胍的體內(nèi)過程與OCT1和OCT2密切相關(guān)，編碼OCT1的SLC22A1基因和編碼OCT2 的SLC22A2基因的多個(gè)突變均能影響二甲雙胍藥動(dòng)學(xué)過程，但對(duì)藥效的影響有待進(jìn)一步研究[14,18]。有報(bào)道，二甲雙胍也是OCT家族其他兩個(gè)成員多藥物和毒素排出轉(zhuǎn)運(yùn)蛋白1(MATE1)[SLC47A1]和多藥物和毒素排出轉(zhuǎn)運(yùn)蛋白2-K(MATE2-K)[SLC47A2]的良好底物，其多態(tài)性使得二甲雙胍的轉(zhuǎn)運(yùn)減少，清除減慢，降糖作用增強(qiáng)[19-21]。

1.4 其他轉(zhuǎn)運(yùn)體 SLC29A4基因編碼的質(zhì)膜單胺轉(zhuǎn)運(yùn)體(PMAT)是一種最近已經(jīng)被克隆的質(zhì)子活化的OCT，其底物范圍與OCTs有很大的重疊，對(duì)二甲雙胍具有良好親和力[20]。SLC29A4內(nèi)含子rs2685753A/G、rs3889348C/T、rs4720572C/T和rs4299914A/G突變以及3′非翻譯區(qū)rs6971788A/T突變均能影響二甲雙胍的藥動(dòng)學(xué)參數(shù)，但SLC29A4基因多態(tài)性對(duì)二甲雙胍藥效的影響尚未得到證實(shí)[22]。

2 藥物作用靶點(diǎn)和受體的基因

2.1 過氧化物酶體增殖物激活受體γ PPARG基因編碼過氧化物酶體增殖物激活受體γ(PPARγ)，是噻唑烷二酮類藥物作用的靶點(diǎn)，并且PPARG rs1801282C/G(Pro12Ala)與T2DM發(fā)病的關(guān)聯(lián)在多項(xiàng)研究中得到驗(yàn)證[23-24]。在韓國(guó)人群中進(jìn)行的一項(xiàng)研究證實(shí)，PPARG Pro12Ala突變是影響羅格列酮療效的重要遺傳因素，攜帶該突變的T2DM患者對(duì)羅格列酮治療的反應(yīng)性較好[25]。近年來，PPAR家族的另一成員PPARδ因其在代謝過程中的重要作用也正被越來越多的學(xué)者在T2DM相關(guān)領(lǐng)域中進(jìn)行研究，有研究表明，PPARD基因多態(tài)性與胰島素抵抗有關(guān)[26]，激活PPARδ在增加胰島素敏感性的同時(shí)，還可以改善db/db小鼠的胰島功能[27]。開展PPARD基因多態(tài)性對(duì)降糖藥物療效影響的相關(guān)研究，并進(jìn)一步進(jìn)行機(jī)制研究對(duì)促進(jìn)T2DM患者個(gè)體化治療具有重要意義。

2.2 ATP敏感性鉀通道 磺脲類藥物的作用靶點(diǎn)是ATP敏感性鉀通道(KATP)，由調(diào)節(jié)亞基磺脲類藥物受體1(SUR1)和核心亞基內(nèi)向整流鉀通道(Kir6.2)組成，SUR1由ABCC8基因編碼，Kir6.2由KCNJ11基因編碼[28]。ABCC8 Ser1369Ala基因多態(tài)性與磺脲類藥物的敏感性密切相關(guān)，攜帶Ala等位基因的患者對(duì)磺脲類藥物反應(yīng)較敏感，用藥后空腹血糖和糖化血紅蛋白下降更加明顯[29]。

KCNJ11 rs5219A/G(Lys23Glu)突變與T2DM易感性以及胰島素分泌減少有關(guān)[30]，對(duì)磺脲類藥物療效的影響在不同人群中表現(xiàn)為增強(qiáng)和減弱兩種情況[24,31]。格列奈類降糖藥也需要通過抑制KATP刺激胰島B細(xì)胞分泌胰島素[32]。KCNJ11 Lys23Glu突變和ABCC8內(nèi)含子rs1799854C/T突變與瑞格列奈反應(yīng)性有關(guān)聯(lián)[27]。雖然KATP并非二甲雙胍的作用靶點(diǎn)，但有研究表明，二甲雙胍的療效與KCNJ11 Lys23Glu突變有關(guān)，其具體機(jī)制尚未闡明[15]。

2.3 腸促胰島素受體 葡萄糖依賴性促胰島素多肽(GIP)和胰高血糖素樣肽1(GLP1)統(tǒng)稱為腸促胰島素，除能刺激胰島素分泌外，尚有抑制餐后胰高血糖素的分泌、延緩腸排空、抑制食欲、增強(qiáng)胰島素敏感性等作用[33]。這兩種激素分別通過結(jié)合主要分布于胰島B細(xì)胞表面的GIP受體(GIPR)和GLP1受體(GLP1R)，改善葡萄糖依賴的胰島素分泌[34]。GIPR基因多態(tài)性，可以明顯減弱針對(duì)腸胰島軸的治療效果，但是確切機(jī)制尚未闡明[34]。GLP1R基因多態(tài)性可能降低外源性或內(nèi)源性GLP1和GLP1R激動(dòng)劑的療效[35]。最近一項(xiàng)在美國(guó)健康人群中進(jìn)行的臨床研究表明，通過測(cè)定GLP1R rs6923761A/G(Gly168Ser)和rs3765467C/T(Arg131Gln)基因多態(tài)性可以預(yù)測(cè)腸促胰島素干預(yù)治療的效果[36]。

3 T2DM發(fā)病相關(guān)基因

3.1 脂肪因子 研究證實(shí)，脂肪因子基因變異可以影響血漿脂肪因子水平、T2DM進(jìn)展以及胰島素抵抗[37]。噻唑烷二酮類通過活化PPARγ調(diào)節(jié)循環(huán)中脂聯(lián)素、瘦素、腫瘤壞死因子(TNF)-α和抵抗素(RETN)的水平實(shí)現(xiàn)其降糖作用[32]。因此，推測(cè)脂肪細(xì)胞因子的基因多態(tài)性可能與噻唑烷二酮類藥物療效個(gè)體差異有關(guān)。有報(bào)道，編碼脂聯(lián)素(ADIPOQ)基因多態(tài)性、瘦素(LEP)基因rs7799039A/G突變、TNF基因rs1800629A/G突變和RETN基因rs1862513C/G突變與羅格列酮、比格列酮藥效減弱有關(guān)聯(lián)[32,38]。

3.2 轉(zhuǎn)錄因子7類似物2(TCF7L2) 當(dāng)前關(guān)于TCF7L2基因的研究較為明確，已經(jīng)證實(shí)TCF7L2基因多態(tài)性與T2DM風(fēng)險(xiǎn)增加有關(guān)[39]。蘇格蘭人群的研究表明，TCF7L2基因突變與磺脲類療效降低有關(guān)，該結(jié)果在德國(guó)人群中得到了驗(yàn)證[34,40]。有報(bào)道，TCF7L2基因第三內(nèi)含子rs290487C/T突變影響瑞格列奈中國(guó)2型糖尿病患者的療效[41]。

3.3 胰島素受體底物1(IRS1) IRS1是胰島素信號(hào)轉(zhuǎn)導(dǎo)的關(guān)鍵蛋白，可以調(diào)節(jié)胰島素的作用，IRS1基因多態(tài)性與T2DM和胰島素抵抗有關(guān)聯(lián)[42]。有研究報(bào)道，攜帶IRS1 Gly972Arg突變的T2DM患者對(duì)磺脲類藥物發(fā)生繼發(fā)性失效的可能性顯著高于純合子的T2DM患者[37]。有研究證實(shí)，IRS1 Gly972Arg多態(tài)性也能減弱格列奈類降低糖化血紅蛋白的效果[43]。

3.4 一氧化氮合酶1轉(zhuǎn)接蛋白(NOS1AP) NOS1AP基因表達(dá)產(chǎn)物NOS1AP主要分布于線粒體和細(xì)胞質(zhì)，其結(jié)合并抑制一氧化氮合酶1(NOS1)[44]。NOS1AP基因多態(tài)性在T2DM發(fā)病中的意義較為明確，以中國(guó)上海地區(qū)人群為研究對(duì)象，發(fā)現(xiàn)NOS1AP rs12742393與T2DM關(guān)聯(lián)性最強(qiáng)[45-46]。有研究報(bào)道，NOS1AP基因多態(tài)性對(duì)格列美脲及瑞格列奈的療效有影響[45-46]。

3.5 鋅轉(zhuǎn)運(yùn)蛋白-8 SLC30A8基因表達(dá)產(chǎn)物鋅轉(zhuǎn)運(yùn)蛋白-8主要分布于胰島B細(xì)胞。SLC30A8 rs13266634C/T(Arg325Trp)突變和T2DM的關(guān)聯(lián)以及該突變對(duì)藥物治療反應(yīng)性的影響存在爭(zhēng)議[47]。攜帶有保護(hù)性T等位基因的患者對(duì)8周的瑞格列奈治療反應(yīng)性較好[42]，但瑞格列奈治療1年后，這種關(guān)聯(lián)性消失[48]。

3.6 解偶聯(lián)蛋白2(UCP2) UCP2基因編碼的UCP2是一種線粒體陰離子轉(zhuǎn)運(yùn)蛋白，是胰島B細(xì)胞能量代謝的重要調(diào)節(jié)器，也是代謝疾病的重要候選易感基因[49]。一項(xiàng)以日本T2DM患者為對(duì)象的病例對(duì)照研究表明，UCP2 rs659366A等位基因攜帶者病情進(jìn)展較快[44]。以中國(guó)T2DM患者為對(duì)象的研究表明，UCP2 rs659366A等位基因攜帶者羅格列酮療效更明顯[50]，但對(duì)瑞格列奈治療反應(yīng)較差[51]。

4 其他可能與T2DM發(fā)病機(jī)制有關(guān)的基因

細(xì)胞周期素依賴性激酶5調(diào)節(jié)亞單位相關(guān)蛋白l類似物l基因(CDKAL1)、電壓門控鉀通道Q亞家族成員1基因(KCNQ1)、胰島素樣生長(zhǎng)因子2 mRNA結(jié)合蛋白基因(IGF2BP2)、煙酰胺磷酸核糖轉(zhuǎn)移酶基因(NAMPT)、配對(duì)盒4基因(PAX4)、毛細(xì)血管擴(kuò)張性共濟(jì)失調(diào)癥突變基因(ATM)和絲氨酸消旋酶基因(SRR)等基因多態(tài)性與口服降糖藥物的療效差異存在一定關(guān)聯(lián)[52-53]。其中CDKAL1基因多態(tài)性與磺脲類和格列奈類療效的關(guān)聯(lián)，KCNQ1基因多態(tài)性對(duì)瑞格列奈和羅格列酮療效的影響[54]，IGF2BP2基因多態(tài)性、NAMPT基因多態(tài)性以及PAX4基因多態(tài)性對(duì)瑞格列奈療效的影響[55-57]，ATM基因多態(tài)性和SRR基因多態(tài)性對(duì)二甲雙胍療效的影響的研究較多[58-59]，意義也較為明確，但這些基因的變異影響藥效的具體機(jī)制有待進(jìn)一步探討。

5 結(jié)語

口服降糖藥物是治療T2DM患者最常用的方法，臨床常用藥物包括：二甲雙胍、磺脲類/格列奈類、噻唑烷二酮類、α糖苷酶抑制劑、二肽基肽酶Ⅳ(DPP-4)抑制劑和GLP1類似物等[2]。隨著病情進(jìn)展，大多數(shù)患者往往需要一種以上的降糖藥物聯(lián)合治療，并且療效和不良反應(yīng)具有明顯個(gè)體差異[4]。口服降糖藥的藥物基因組學(xué)研究的最終目標(biāo)是個(gè)體化治療糖尿病患者，促進(jìn)合理用藥。本文討論了一些可能影響降糖藥物療效的基因多態(tài)性，但只有少數(shù)基因及其多態(tài)性與藥物療效的關(guān)聯(lián)是明確的，大部分結(jié)果尚需進(jìn)一步研究佐證。藥物治療的個(gè)體差異不能用單個(gè)SNP完全解釋，往往是多個(gè)遺傳因素的疊加表現(xiàn)；因此，GWAS或者相關(guān)基因的高通量測(cè)序技術(shù)已成為研究藥物治療個(gè)體差異的重要方法。藥物基因組學(xué)研究結(jié)果在不同種族中的變異性、相關(guān)的機(jī)制研究較為薄弱、社會(huì)的接受與認(rèn)可程度較低、臨床基因檢測(cè)技術(shù)不夠成熟等問題都使得將研究結(jié)果應(yīng)用于臨床實(shí)踐具有一定的局限性。當(dāng)前的研究很少有關(guān)于聯(lián)合用藥藥物相互作用與基因多態(tài)性關(guān)聯(lián)的探討，而臨床實(shí)踐中聯(lián)合用藥十分廣泛，該領(lǐng)域的研究應(yīng)引起我們足夠的重視。

本文總結(jié)了很多有意義的結(jié)果，但是只有更多的影響藥物反應(yīng)性的遺傳因素得到闡明，個(gè)體化用藥理念進(jìn)一步深入人心，個(gè)體化用藥基因檢測(cè)的臨床模式更加完善，才能將T2DM的藥物基因組學(xué)研究成果轉(zhuǎn)化為廣泛的臨床實(shí)踐。

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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.無錫市第三人民醫(yī)院，江蘇 無錫 214000；2.江蘇省新藥研究與臨床藥學(xué)重點(diǎn)實(shí)驗(yàn)室，江蘇 徐州 221000；3.徐州醫(yī)學(xué)院附屬醫(yī)院，江蘇 徐州 221000

江蘇省“六大人才高峰”資助項(xiàng)目(2011-SWYY-019)；徐州市科技計(jì)劃項(xiàng)目(XZZDY1203)

10.14053/j.cnki.ppcr.201507026

*通信作者