痛风与高尿酸血症的研究进展参考幻灯片课件.ppt

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1、痛风与高尿酸血症的研究进展,镰,谷直之,东京女子医科大学,医学博士,日本痛风病基金会会长,风湿病协会客座教授,1,发生在第一跖趾关节部位的痛风,2,严重病情,(,可见尿酸盐晶体,),3,耳部痛风石,4,偏振光显微镜下观察到的尿酸盐晶体,5,白细胞中的尿酸结晶,6,多发性痛风石,外翘性穿凿样骨破坏,为典型特征,7,1.,痛风,-,高尿酸血症使尿酸盐晶体沉积导致的疾病,2.,受遗传因素与环境因素共同影响,3.,20,岁以上男性为痛风好发人群,4.,痛风的病程进展：无症状高尿酸血症期急性关节炎间断发,作在未经治疗的情况下逐步进展为痛风石、尿石症、肾功,能衰竭和冠心病等,5.,促尿酸排泄药物：丙磺舒与

2、苯溴马隆,6.,别嘌呤醇：抑制黄嘌呤氧化酶活性药物，现新增非布索坦和,topiroxostat,高尿酸血症与痛风,8,1.,日本痛风病基金会成立于,1984,年,a.,每年逾,10,个研究团队获得痛风及核酸代谢性疾病领域的科研基金,b.,组织“痛风与高尿酸血症的治疗”研讨年会,2.JSGNM(,日本痛风与核酸代谢性疾病学会,)-,成立于,1999,年,a.2002,年发布高尿酸血症与痛风治疗指南,b.,举办学术年会,3.,非凡的研究成果,4.,本国多家制药公司研发痛风治疗药物,a.,非布索坦,-,帝人制药株式会社,.,b.Topiroxosta-,富士制药株式会社,.,c.,苯溴马隆仍应用于临

3、床,日本痛风与高尿酸血症相关活动,9,1.,JSGNM,(,日本痛风与核酸代谢病学会,),高尿酸血症和痛风治疗指南,2.EULAR,(,欧洲抗风湿病联盟,),痛风循证医学,3.ACR,(,美国风湿病学会,),痛风治疗指南,痛风诊疗指南,本国指南时间最早,10,高尿酸血症和痛风治疗指南,JSGNM(,日本痛风与核酸代谢病学会,),第二版,11,高尿酸血症患者比例的变化,(7 mg/dl),P,r,o,p,o,r,t,i,o,n,o,f,h,y,p,e,r,u,r,i,c,e,m,i,a,Year,female,male,12,日本痛风病年门诊量,N,u,m,b,e,r,o,f,o,u,t,p,a

4、,t,i,e,n,t,s,d,i,a,g,n,o,s,e,d,a,s,g,o,u,t,100,万,Total,Male,Female,Year,13,痛风发病率随血尿酸水平上升,100,70,50,30,0,5.0,5.5,9.0,9.510.0,尿酸,(mg/dL),8.5,8.0,7.5,7.0,6.0,6.5,90,80,60,40,20,10,Shoji A,Yamanaka H,Kamatani,N:Arthritis Rheum 51:321-325,2004,Subjects:,267 patients whose first visit for a gouty attack w

5、as at least 1 year prior to the study,Method:,Analysis of the relationship between serum urate levels and the%of patients with recurrence in 91 patients with recurrence of gouty attack.,Results:,Lower serum urate levels resulted in lower recurrence rates.The mean serum urate level of patients(N=69)w

6、ho continued to have gouty attacks,despite receiving ULT was 7.01mg/dL,but recurrence in patients(N=81)receiving ULT whose serum urate level was 6.0mg/dL was 14%.,I,n,c,i,d,e,n,c,e,o,f,r,e,c,u,r,r,e,n,t,g,o,u,t,y,a,t,t,a,c,k,s,m,o,r,e,t,h,a,n,1,y,e,a,r,a,f,t,e,r,e,a,c,h,p,a,t,i,e,n,t,s,f,i,r,s,t,v,i

7、,s,i,t,(,%,),日本,14,高尿酸血症,(,血尿酸,7.0 mg/dL),痛风性关节炎或痛风石,yes,no,血尿酸,8.0 mg/dL,血尿酸,=8.0 mg/dL,伴发疾病,*,yes,no,血尿酸,9.0 mg/dL,血尿酸,=9.0 mg/dL,药物治疗,药物治疗,调整生活方式,伴发疾病包括肾脏损害，尿石症，高血压，缺血性心脏病和代谢综合征（除前两者外其余证,据仍不足）,图示：高尿酸血症和痛风诊疗步骤,15,1.,生活方式调整包括限制饮酒（尤其是啤酒），控制体重，多饮水，减少肉,类和某些海产品食用量。,2.,痛风发作时应予以秋水仙碱和,NSAIDs,药物治疗。秋水仙碱可用于预

8、防痛风,发作或急性发作前的先兆期。,3.,高尿酸血症的治疗应始于痛风发作后一段时期。,4.,丙磺舒和苯溴马隆均为促尿酸排泄药。,5.,别嘌呤醇曾作为唯一的黄嘌呤氧化酶抑制剂，但在携带,HLA-B*5801,阳性基,因的患者中可能发生,Stevens-,Johsons综合征和,TEN(,中毒性表皮坏死松,解症,),。,6.,在日本，非布索坦即将应用于临床，,topiroxosta,已经开始应用,。,治,疗,16,高尿酸血症和痛风领域研究的飞速进展,17,环境因素,遗传因素,遗传与环境因素,(20,年前的观点,),交通意外,遗传性疾病,HPRT,缺陷,PRPP,合成,酶,活性,过强,18,HPRT

9、,缺陷,Seegmiller,JE et al.Science 155:1682-1684,1967.,PRPP,活性,过强,Sperling,O.et al.Biochem.Med.6:310-316,1972.,先天性高尿酸血症,/,痛风,酶的异常与痛风发病相关,Courtesy of Dr.Miyaji,19,20,探索疾病相关基因,方法学的重大改变,(,以前,),候选基因法,(,生化学，分子生物学,),全组基因法,（遗传学，统计学，信息学）,连锁分析,分析多数孟德尔性状,GWAS,分析多数复杂性状,钓竿钓鱼,拖网捕鱼,海图,(,即全基因组序列,),什么是连锁分析,?,21,遗传,定律,

10、基因分型,Lod score,测,序,连锁分析,分析多数孟德尔性状,22,Family 1,I,II,III,IV,V,VI,1,2,1,2,3,4,5,1,2,1,2,3,4,5,6,1,2,3,4,6,5,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,无症状性高尿酸血症,痛,风,肾,功能不全,尿酸排泄障碍,病情不明,家族性青少年期高尿酸肾病,(FJHN),遗传性肾功能不全伴高,尿酸血症的致病基因尚,

11、不清楚,提取多数家族成员,DNA,并对,500,多个,marker,进行基因分型,23,-4,-3,-2,-1,0,1,2,3,4,5,6,7,0,5,10,15,D,1,6,S,4,9,9,D,1,6,S,5,0,1,D,1,6,S,3,0,5,6,D,1,6,S,4,1,0,#,1,1,8,#,2,3,8,D,1,6,S,3,0,4,1,D,1,6,S,3,0,3,6,#,1,2,3,D,1,6,S,7,7,3,D,1,6,S,3,0,4,6,D,1,6,S,7,7,2,D,1,6,S,3,0,4,5,D,1,6,S,4,1,2,D,1,6,S,3,1,1,3,D,1,6,S,4,0,1,

12、D,1,6,S,3,1,3,3,D,1,6,S,3,1,1,6,染色体图距,(cM),L,O,D,s,c,o,r,e,D,1,6,S,4,1,7,a,c,0,0,2,3,0,2,a,4,a,c,0,0,2,2,9,9,a,3,a,c,0,0,2,2,9,9,a,4,D,1,6,S,4,2,0,D,1,6,S,5,3,7,D,1,6,S,3,1,3,1,连锁,分析,软,件分析基因型数据,通,过,定位克隆，找出致病位点,尿,调节,素基因,24,Family 1,I,II,III,IV,V,VI,1,2,1,2,3,4,5,1,2,1,2,3,4,5,6,1,2,3,4,6,5,7,8,9,10,1

13、1,12,13,14,15,16,17,18,19,20,21,22,1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,T,TGGCACGCATCCGTCCAGCGACGA,Pro236Leu,尿调节素基因,发生突变,UMOD,突变基因与,FJHN,发病相关,25,什么是,GWAS,?,26,病例,对,照,DNA,SNP,分型,统计,分析,LD map,Manhattan plot,什么是,GWAS,?-,全基因组关联研究,500,000 SNPs,多种统计学方法,.,需,100,000 mar

14、ker,Associated loci,复杂性状的研究曾经令人感到头疼,GWAS,改变了这一现状,.,27,GWAS,生物医疗领域的革命性创新,GWAS,相关,报,道由,RIKEN,的,Yusuke Nakamura,团队,首,发,2005 2006 2007 2008 2009,28,年度,疾病,/,性状,文章数量,2002,心肌梗死,1,2003,风,湿性关,节,炎,2,2004,心肌梗死,1,2005,风,湿性关,节,炎，骨性关,节,炎,3,2006,心肌梗死,1,2007,骨性关,节,炎，,脑,梗死,2,2008,风,湿性关,节,炎，糖尿病，骨性关,节,炎，川崎病，胃癌，直,肠,癌,6

15、,2009,心肌梗死，,溃疡,性,结肠,炎，乙肝,3,2010,类风,关，糖尿病，血液,检验,，子,宫,内膜异位，前列腺癌，瘢痕瘤，肺癌,7,2011,子,宫,肌瘤，病毒性肝癌，支气管哮喘，,肾,病,综,合征，血小板，代,谢,性状，眼黄斑,变,性，脊柱,侧,凸,8,2012,BMI,，前列腺癌，十二指,肠溃疡,，川崎病，,类风,关，房,颤,，,肾,功，肺,纤维,化，痛,风,10,2013,脊柱,侧,凸,1,Total,45,RIKEN,应,用,GWAS,技,术发,表的文章,（,Nature,Nature Genetics,杂,志）,RIKEN,领先,GWAS,研究领域,29,GWAS,的本质：

16、检测基因改变对表型的影响,拓展了表型的概念,Disease or,not disease,基因,mRNA,蛋白,质,细,胞,器官,人体,小分子,Only G,is stable.,30,Urate,HDL-chol,早期研究,结,果,显,示，基因,组,改,变,可影响尿酸水平,Nat Genet.2010 42:210-5,31,Okada Y et al.Nat Genet.44(8):904-9,2012.,一项针对亚洲人群尿酸相关基因的,GWAS,研究,32,尿酸相关基因,GWAS,研究的,meta,分析结果,Kottgen,A et al.Nat Genet.2013 45:145-54

17、.,33,环境因素,遗传因素,高尿酸血症与痛风的遗传与环境因素,（现有认识,),HPRT,缺陷,PRPP,活性,过强,连锁,分析,:,UMOD,相关疾病,GWAS,SLC22A12,SLC2A9,WDR1,ABCG2,SLC17A3,SLC17A1,SLC22A11,SLC16A9,GCKR,LRRC16A,near,PDZK1,LRP2,etc,34,痛风药物导致的,不良反应,35,日本国内报道的,Stevens-Johnson,综合征,/TEN,病例数,年度,2010,2009,2008,2007,别嘌呤醇,45,19,63,28,卡马西平,39,38,44,34,拉莫三嗪,31,14,3

18、,-,感冒药,25,22,16,19,扑热息痛,21,10,8,21,洛索洛芬,20,25,24,20,塞来昔布,13,11,7,4,Non-pyrime,感冒药,10,10,8,14,左氧氟沙星,14,7,8,13,唑尼沙胺,10,12,18,5,36,?,别嘌呤醇致,14,例,严重皮肤过敏反应,HLA-B*5801,Allopurinol:The most frequent,cause of Stevens-,Johnsons,syndrome and TEN,PNAS 102:4134,4139,2005,37,敏感度,Odds ratio,人群,HLA-B*5801,基因阳性率,中国汉

19、族,51/51=100%,580,20%,韩国,23/25=92%,97.8,12.6%,欧洲,19/31=61%,61,1.6%,日本,4/10=40%,54,1.2%,别嘌呤醇介导的皮肤反应与,HLA-B*5801,等位基因相关,38,别嘌呤醇上市,40,年后，非布索坦成为其替代药物,xanthine,IMP,GMP,guanine,hypoxanthine,HGPRT,guanase,uric acid,XO,Allopurinol,Febuxostat,PRPP,PRPP,39,Okamoto,Nishino,非布索坦成为继别嘌呤醇后的新型痛风药物,日本帝人制药株式会社研发,武田制药（

20、美国）销售,安斯泰来（亚洲）销售,40,痛风治疗指南,PGx,影响药物应用,非布索坦有望减少因服用导致的不良反应,41,别嘌呤醇,非布索坦,opiroxostat,痛风治疗药物的选择,HLA-B*5801,基因检测,阴性,阳性,或,42,体积小巧，精准快速的,基因分型仪器,43,44,体积小巧，精准快速的,基因分型仪器,与,RIKEN,（日本理化研究所）合作研究,产品特点,?,45,分钟内基因精准分型,用于,?,药物基因组学，遗传性疾病,44,鸣谢,1.,Former Director,Center for Genomic Medicine(CGM),RIKEN,Yusuke Nakamura

21、,2.Laboratory for Genotyping Development,Naoya,Hosono,Michiaki Kubo,3.Laboratory for Biomarker Development,Hidewaki,Nakagawa,4.Research Group for Medical Informatics,Yumi,Yamaguchi-Kabata,Yukinori Okada,Atsushi Takahashi,Tatsuhiko,Tsunoda,5.Research Group for Disease-causing Mechanisms,Many researchers,6.Human Genome Center,University of Tokyo,Yoichiro,Kamatani,Yataro,Daigo,Koichi Matsuda,Yusuke Nakamura,7.Japan Biobank,45,