基因检测与糖尿病PPT培训课件.ppt

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,基因检测与糖尿病,2,WHO,:,控制糖尿病,刻不容缓,糖尿病,(T2D,),是四大非传染病之一,是仅次于心脑血管疾病和癌症的第三位死亡原因,;,全球每,9,秒钟就有,1,人死于糖尿病,每年约死亡,400,万人,失明约,1500,万人,;,使心脏病与脑卒中增加,34,倍,(US,CDC 2007);,仅,2010,年全球为此支出,3,780,亿美元,占全球支出的,12%!,钱荣立 中国糖尿病杂志,2010;18:881882,2010,联合国糖尿病日,;,中国蓝光行动,3,糖尿病严重威胁人类健康,Source:WHO and IDF,流行性日益加剧,2000,2030,死亡,3+million,截肢,1+million,肾衰,500,000+,失明,300,000+,医疗开支,USD 156+,billion,糖尿病每年给全球带来的巨大损失,全球糖尿病患者（百万）,4,中国糖尿病患者居全球之首,“Prevalence of Diabetes among Men and Women in China”,中国成年人中糖尿病发病率为,9.7%(,远高于全球平均患病率,6.4%),现有患者,9,240,万例,约占全球糖尿病患者,1/3,居全球之首,第二位为印度,5080,万例,;,Wenying Yang etal.N Engl J Med 2010;362:1090-1101,CDS,与,IDF,联合调研结果指出,:,我国糖尿病治疗费用每年高达,1,734,亿元,(,约,250,亿美元,),是非糖尿病人的,34,倍,;,占全国医疗总支出的,13%!,2010,11,14,第,4,个联合国糖尿病日,IDF,主席,Mbanya,报告,5,全球现有十一大类抗糖尿病药,1,胰岛素及其衍生物,;,2,磺脲类,;,3,双胍类,;,4,噻唑烷二酮类,;,5,-,糖苷酶抑制剂,;,6,格列奈类胰岛素促泌剂,(Meglitinides);,7,胰岛淀粉样肽,(Amylin analogues);,普兰林肽注射液,8,肠促胰岛素激素拟似药,(Incretin hormone mimetics);,艾塞那肽注射液,9,二肽基肽酶,抑制剂,(DPP4-I);,西他列汀,10,胰高血糖素样肽受体激动剂,(GLP-1);,利拉鲁肽,11,钠,-,葡萄糖共同转运体抑制剂,(Sodium-Glucose Co-Transport Inhibitors;,SGLTs-I,),。,注,:,黄色标记药物系目前认为与基因多态性密切相关者,6,当前,T2D,的控制率仅约,40%,而,T2D,却占全部糖尿病患者的,90%95%!,Presented by,Trudy N.Griffith BSc.Pharm(Hons),13 August 2010,7,服用降糖药的患者,40%,未能达标尤其是单一药物,!,过去的,10,年,约,40%T2D,患者的,糖化血红蛋白,(glycosylated hemoglobin,HbA1c),未能达到,Val,突变病人的有效率降低,罗格列酮,PPAR,PPAR,Pro12Ala,突变者疗效更佳,易发生药源性水肿,瑞格列奈,OATP1B1,SLCO1B1 T521C,AUC,增高,CYP2C8,CYP2C8*3,AUC,和,Cmax,降低,40%,那格列奈,OATP1B1,SLCO1B1 T521C,Cmax,和,AUC,增高,CYP2C9,CYP2C9*3,血浆清除率下降,发生低血糖的机率增高,涉及降糖药的,PGx,21,为什么有些人应用二甲双胍无效,?,FDA;1995,22,二甲双胍是治疗,T2D,的一线药物,减少肝糖的输出,增加胰岛素敏感,降低,LDL,和,TG,降低,C,反应蛋白,减轻体重或保持,不引发低血糖风险,可引发恶心痉挛及腹泻,罕见乳酸中毒,禁忌证,:CHF,肾功不良,80,岁老人,!,23,在服用二甲双胍的患者中,有,35-40%,禁食血糖水平未达标,!,Diabet.Care 1994,17,1100-1109,Diabet.Med.1994,11,953-960,Metformin is not without adverse events such as diarrhea and nausea that occur in,about 30%of patients;or a more serious,but very rare side effect,lactic acidosis.Despite an exceptional efficacy and safety profile,several T2Ds(about 38%)still fail,to reach glycemic goals in metformin therapy,.,Pharmacogenomics and Personalized Medicine 2009:2 7991,24,临床证明单用二甲双胍易出现继,发性,失效,Secondary Failure of Metformin Monotherapy in Clinical Practice,作者报告,在,20042006,年间,用二甲双胍共治疗,T2D,患者,1,799,例,以,7%!,注,:,继发性失效定义,1,需加用或换用第二种降糖药,;,2,随后的,HbA1C7.5%,。,Diabetes Care 2010;33:501506,25,二甲双胍在体内的转运,二甲双胍为一亲水性有机阳离子,(pKa 12.4),是有机阳离子转运体,(organic cation transporters;OCTs),包括,OCT1,OCT2,的底物,OCT1,主要在肝细胞表达,OCT2,则在肾细胞中表达,二者分別将二甲双胍转运至肝细胞内和肾脏上皮细胞内,.,Pharmaceuticals,2010;,3:,2610-2646,26,二甲双胍的摄取及其作用机制,LKB,alias of serine-threonine kinase 11(STK11);,PGC-1,peroxisome proliferator activated receptor coactivator 1;,TORC2,target of rapamycin complex 2.,J.Clin.Invest 2007:17:1422-1431,27,涉及二甲双胍的,PGx,转运体,基因多态性,OCTs,:Organic cation transporter gene,(,有机阳离子,转运体基因,),OCT 1,:,由,SLC22A1,编码,承载肝摄取,;,OCT 2,:,由,SLC22A2,编码,承载肾排泄,;,MATE,:,Multidrug and toxin extrusion gene,(,多药与毒素外排基因,),MATE1,:,由,SLC47A1,编码,承载从肝细胞转运至胆汁,;,MATE2,:,由,SLC47A2,编码,承载肾排泄,.,Acta Pharm 60;387406,28,OCTs,的表达及其基因多态性,OCT1,主要在肝细胞和肠上皮细胞表达,介导二甲双胍在这些细胞的摄取,;,OCT2,主要在远端肾小管细胞表达,介导、促进包括二甲双胍在内的许多生物异源性物质在尿中的排泄,OCT1,的变异已知有,12,个,:,S14F,R61C,F160L,S189L,G220V,P341L,R342H,G401S,V408M,420del,G465R,R488M,其中标记为,兰色者为功能降低的转运体,。,Pharmacogenomics and Personalized Medicine 2009:2 7991,29,为什么二甲双胍必需个体化给药,?,应用最广泛,;,在美国处方量排名前,15,位,!,治疗指数窄,;,为多因素病,;,疗效差异大,;,有的有效,有的无效,有的甚至发生乳酸中毒,!,(MALA range from,three to nine cases per 100,000,patient-years)once it develops,it has been associated with a 50%to 75%mortality rate.,N Engl J Med.1998;338:265-6.Letter;,Diabetes Care.1999;22:925-7.,Ellenhorns medical toxicology:,1997;728-731,.,在肝脏起效,;,转运体或肝功能影响很大,主经肾排泄,;,转运体或肾功能影响很大,30,OCT1,等位基因对二甲双胍摄取的影响,*,P 180 mg/dl),高达,34%,而罗格列酮为,15%;,二甲双胍为,21%;,UKPDS,试验表明,每年约有,1%,服用磺脲类的患者发生严重低血糖,!,.,N.Engl.J.Med.2006;355(23):24272443,38,磺脲类降糖机制,Schematic Representation of the Pancreatic Beta Cell,Illustrating the Role of the,ATP-Sensitive Potassium(K,ATP,)Channel,in Insulin Secretion.,N Engl J Med 2004;350:1838-49.,39,影响磺脲类作用的基因多态性,Acta Pharm.60(2010)387406,transcription factor 1(TCF1,transcription factor 2(TCF2),40,涉及磺脲类的基因多态性,Kir6.2,pore,:,为,K,ATP,channels,的亚单位,由,KCNJ11,gene,编码,系,SU,的靶点,;,SUR1,subunits,:,为,K,ATP,channels,的亚单位由,ABCC8,gene,编码,系,SU,的靶点,;,Inactivating mutations cause the channel to be closed and thus the,-cells to over-secrete insulin,causing hyperinsulinaemic,hypoglycaemia.Activating mutations cause the,-cell to be unresponsive to glucose and therefore are a cause of neonatal,diabetes mellitus(NDM),TCF7L2,:,直接影响,SU,的疗效,;,CYP2C9,CYP2C19,:SU,的代谢,;,HNF1,&HNF1,:,直接影响,SU,的疗效,;,IRS1:,直接影响,SU,的疗效,;,NOS1AP,:,降低,SU,的疗效,.,Acta Pharm 2010;60:387406,41,两种最重要的,CYP2C9,基因多态性,CYP2C9*2:,是单核苷酸中的外显子,3,位由,C T),其活性仅是正常功能者的,40%,左右,;,CYP2C9*3:,是单核苷酸中的外显子,7,位由,A C),其活性仅是正常功能者的,10%,左右,;,42,CYP2C9,基因多态性显著降低磺脲类的疗效,A recent population-based study of incident sulfonylurea users found that Type 2 diabetes patients with,CYP2C9,*,2,/*,2,*,2,/*,3,or*,3,/*,3,genotypes were 3.4-times,more likely to achieve a treatment HbA1c of less than 7%compared with,CYP2C9,wild-type,homozygotes.Furthermore,patients with at least one copy of the,CYP2C9,*,2,or*,3,allele were less likely to experience sulfonylurea monotherapy,treatment failure,Clin.Pharmacol.Ther.2009;87(1):5256,43,CYP2C9,基因多态性显著增加磺脲类的,ADR,CYP2C9 polymorphisms may also serve as useful predictors of adverse effects.For example,a different study showed that sulfonylurea-treated patients who possessed the,CYP2C9*3/*3 or*2/*3 genotype had 5.2-times the odds,of a,severe hypoglycemic,event than the other CYP2C9 genotype groups,.,Br.J.Clin.Pharmacol.2005;60(1):103106.,44,CYP2C9,基因多态性影响磺脲类的疗效,携带杂合子,CYP2C9*1/*2,的患者可轻度减少格列本脲,的肾清除,较携带纯合子,CYP2C9*2/*2,者降低,10%;,携带杂合子,CYP2C9*1/*3,和,CYP2C9*2/*3,的患者可减少甲苯磺丁脲,肾清除率,50%;,携带纯合子,CYP2C9*3/*3,的患者可显著减少格列本脲,的肾清除。,Acta Pharm 2010;60:387406,45,携带杂合子,CYP2C9*1/*2,和 纯合子,CYP2C9*3/*3,的患者,与携带野生型,CYP2C9*1/*1,的患者相比,可分别减少,甲苯磺丁脲、格列本脲以及格列吡嗪,的肾清除率,16%,、,50%,和,20%,携带纯合子,CYP2C9*2/*2,的患者,与携带野生型,CYP2C9*1/*1,的患者相比,可分别减少,甲苯磺丁脲、格列本脲,的肾清除率,75%,和,90%,。,CYP2C9,基因多态性影响磺脲类的疗效,46,为什么有些国人应用磺脲类易发生,ADR?,Br.J.Clin.Pharmacol.,2007,64,67-74,.,因为亚洲人的,PM,占,10-25%,而白人仅有,2-6%,。如携带,CYP2C19,PM,的中国男性患者,服用格列齐特后的,AUC,与携带野生型,CYP2C9*1/*1,的患者相比增加,3.4-fold,95%CI 2.5,4.7;,P,0.01,;,其半衰期也从,15.1h,延长至,44.5 h,(,P,0.01);,相似的差别,在多剂量研究时也同样存在,携带,CYP2C19,PM,的患者与携带野生型,CYP2C9*1/*1,的患者相比,AUCss,AUC0 and,C,max,分别增加,3.4,倍,(95%CI 2.9,4.0),、,4.5,倍,(95%CI 3.8,5.4),和,2.9,倍,(95%CI 2.4,3.4),(,P,0.01),其,半衰期也从,13.5 h,延长至,24.6h(,P,1/2,依此给患者调整剂量极为重要。,Acta Pharm.2010;60:387406,近期,Zeller,等提岀将,格列苯脲,淘汰岀局,因显著增加,AMI,死亡率。是否与患者基因变异相关,?,JCEM 2010;95;49935002,48,CYP2C9,基因多态性,与磺脲类等的清除率,49,相关生物标记物的基因多态性对磺脲类作用的重要影响,There are several other,KCNJ11,variants(which include F333I,F35V,R201H,R201C,Q52R,I296L,L164P,G53S,G53R)and,ABCC8,variants(which include I182V,H1023Y,I1424Y,F132L),Pharmacogenomics and Personalized Medicine 2009:2 7991,50,CYP2C19,基因多态性,对格,列齐特,PK,的影响,(,单剂量,),Br.J.Clin.Pharmacol.2007,64,67-74,51,CYP2C19,基因多态性对,格列齐特,PK,的影响,(,多剂量,),Br.J.Clin.Pharmacol.2007,64,67-74,52,磺脲类与,TCF7L2,变异,GoDARTS,(Genetics of Diabetes Audit and Research Tayside),study,方法,:1997 July 2006,901,例口服磺脲类,945,例口服二甲双胍,研究,转录因子,7-,相似物,2,(Transcription factor 7-like 2;,TCF7L2,),的等位基因,rs,12255372,和,rs7903146,是否影响两类药物的作用,;,无效指标是用药,312,个月后,HbA1C 7%,。,Diabetes 56:21782182,2007,53,磺脲类与,TCF7L2,的变异,结果,:,携带,rs12255372 T/T,等位基因的患者与携带,rs12255372 G/G,的患者相比,无效率的,Odds ratio(OR),为,1.95(95%CI 1.233.06;,P,0.005),如以基线,HbA1C,相比,则,OR,为,2.16 95%CI 1.213.86,P=,0.009);,携带,rs,7903146,等位基因的患者其结果相似,;,在二甲双胍组未见此相关性。,Diabetes 56:21782182,2007,54,涉及,格列奈类,/,二甲双胍,/,噻唑烷二酮,的基因多态性,Acta Pharm.60(2010)387406,55,涉及格列奈类的基因多态性,CYP2C9,其基因变异有,CYP2C9*3,CYP2C8,其基因变异有,CYP2C8*3,SLCO1B1:,solute carrier organic anion transporter family,member 1B1),其基因变异有,521TT,521TC,521CC,OATP:,其基因变异有,OATP,1B1,IGF2BP2(,insulin-like growth factor 2 mRNA binding protein 2,),Pharmaceuticals(Basel).2010 August 1;3(8):26102646,Pharmacogenomics and Personalized Medicine 2009:2 7991,56,Pharmacogenomics and Personalized Medicine 2009:2 7991,转运体,/,药酶基因多态性影响格列奈类的疗效,57,2C9,基因多态性影响格列奈类的清除,研究表明,CYP2C9*3,可减少格列奈类的清除,而,CYP2C8*3,则增加格列奈类的清除。,Mol Diagn Ther.2007;11(5):291-302,58,2C9,基因多态性影响格列奈类的疗效,携带,CYP2C9*3,的患者,可显著降低那格列奈的清除率,;,而携带,CYP2C9*2,的患者,其药动学参数与携带野生型,CYP2C9*1,的患者却相似,;,携带,CYP2C9*3/*3,的患者与携带野生型,CYP2C9*1/*1,的患者相比,可增加低血糖的风险,特别是那格列奈剂量超过,120 mg,时,!,Mol Diagn Ther.2007;11(5):291-302,59,SLCO1B1,基因多态性对格列奈类的影响,SLCO1B1,有三个等位基因,:,521TT,521TC,521CC,;,携带杂合子,521TC,和纯合子,521CC,的患者与携带纯合子,521,TT,相比,可分别显著增加那格列奈的血浓度,83%,和,76%,;,半衰期延长,78%,(p=0.036),;,提示,SLCO1B1,基因多态性可显著增加那格列奈血浓度,可能是减少了肝细胞的摄取所致。,60,涉及噻唑烷二酮类的基因多态性,PPAR-gene:,过氧化物体增殖激活受体,-,基因变异有,PPAR-,heterozygous,genotype(rs1801282;Pro12Ala),和,homozygous,genotype(Pro12Pro).,lipoprotein lipase gene:,其基因变异有,S447S,和,S447X,CYP2C8 gene:,其基因变异有,CYP2C8*1/*3,CYP2C8*3/*3,ACDC gene:,adipocyte C1q and collagen domain-containing(ACDC)gene,编码,adiponectin,其基因变异有,SNP45,SNP276,SNP11377,SLCO1B1:,solute carrier organic anion transporter family,member 1B1),其基因变异有,521TT,521TC,521CC,ADIPOQ,:,其基因变异有,rs1501288,和,rs2241766,PGC-1,(,PPAR-coactivator):,其基因变异有,Thr394,和,Gly482,Pharmaceuticals(Basel).2010 August 1;3(8):26102646,Pharmacogenomics and Personalized Medicine 2009:2 7991,61,为什么有些患者,TZDs,无效,?,TZDs,未达标率,:,罗格列酮,(2mg/bid;26week)45.8%,罗格列酮,(4mg/bid;26week)36.1%,吡格列酮,(45 mg/d,;,26 weeks),25.0%,(,空腹血糖降低不超过,10%;12%,患者,HbA1c,仅降低,0.5%1.0%),The Journal of Clinical Endocrinology&Metabolism 2001 86:280-288,Diabetes Care 2003;26:825831,62,ACDC/S447S,基因多态性对,TZDs,的影响,Pharmacogenomics and Personalized Medicine 2009:2 7991,63,脂蛋白酯酶,(LDL),基因多态性对,TZDs,的影响,研究发现,中国,T2D,患者服用吡格列酮,如携带纯合子,S447S,其达标率较携带其他基因多态性者更高,反之如携带,S447X,则达标率较携带,S447S,患者降低,1/2,提示检测,LPL,基因多态性可预测吡格列酮的疗效。,64,脂联素,ADIPOQ,等位基因 对罗格列酮疗效的影响,Pharmaceuticals(Basel).2010 Aug 1;3(8):2610-2646.,65,PGx,与噻唑烷二酮类的疗效,首先,过氧化物体增殖激活受体,-,(,PPAR-,),基因变异有,heterozygous,genotype(rs1801282;Pro12Ala),和,homozygous,genotype(Pro12Pro).,如携带,Pro/Ala,者,较携带,Pro/Pro,者显著降低罗格列酮的禁食血糖水平和,HbA1c,水平,;,如携带,Pro12Ala,则,PPAR-,增加,7.2,倍,Mol Diagn Ther.2007;11(5):291-302,Pharmacogenomics 2007;8:917931,66,CYP2C8/SLCO1B1,基因多态性 对罗格列酮疗效的影响,研究表明携带,CYP2C8,基因多态性者,可显著改变罗格列酮的,PK,并提高疗效,而,SLCO1B1,则否,;,Human,Genomics 2008;3:716,67,小结,:PGx,与口服抗高血糖药,British Journal of Diabetes&Vascular Disease 2011 11:10,68,美国糖尿病协会,2010,年会重点研讨,PGx,与,T2D,的相关性,70th:PGx Abstracts from the American Diabetes Associations Annual Scientific Sessions,July 07,2010,investigating SNPs showing variable patient responses to commonly prescribed medications;and analyzing genetic risk for conditions that can heighten peoples chances of developing diabetes.,69,PGx&,抗高血糖药,主要,关注三个基因多态性,1,针对药物,ADME,的,OCT1,和,2C9/8/19 3A4,;,2,针对药物受体的,KCNJ11;,3,针对疾病发展的,TCF7L2,70,防治糖尿病达标,我们的目的是什么,?,如何做得更好,!,Achieving Diabetes TargetsWhere are we,and how can we do better?,Robert E.Ratner,MD,MedStar Research Institute,Georgetown University Medical School,Washington,DC,71,代结束语,Una Glamoclija professor:,Genetic polymorphisms in diabetes:Influenceon therapy with oral antidiabetics,迄今资料显示,一系列,基因,影响着口服降糖药的疗效,为此,有关糖尿病个体化治疗的成绩与日俱增,特别是关注的焦点集中在如何保证剂量准确的领域,即防止因过量或不合理用药所致的低血糖,!,PGx,的发展为改善糖尿病的预后提供了科学依据,今后将更深入研究发展。,Acta Pharm.60(2010)387406,72,根据您的基因而选用药物,!,基因身份证,73,謝谢大家参与,!,