中国北方群体中强直性脊柱炎的候选基因关联研究DA2B的病因学研究
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摘要
AS是一种常见的慢性炎症性疾病。病变主要累及骶髂关节,引起脊柱强直,部分患者伴有不同程度的髋关节、眼、肺、心血管、肾等多器官损害,目前为止,AS的发病原因仍不清楚。
既往研究表明AS与HLA-627强关联。全基因组连锁和关联分析结果显示在染色体1p、2q、6q、6p、9q、10q、16q以及19q存在AS连锁区段。近年来多个群体报道2q14的Interleukin 1基因簇与AS关联。这些结果为研究非B27基因提供了线索和证据。
论文一采用候选基因关联研究,在中国北方人群中定位AS的易感基因,并深入研究-850T变异对TNFa启动子转录活性的影响。
本论文的第一部分旨在以HLAⅢ类基因区的TNFa启动子-850T变异作为AS的遗传标记,在其侧翼各60kb的范围内定位AS的易感基因。我们挑选了11个SNPs,在中国北方吉林群体中进行病例对照关联研究。结果显示,TNF(rs1799724)在中国北方吉林人群中与AS关联(P=0.021),携带T等位基因增强了疾病的发病风险(OR=1.95,95%CI:1.10-3.45)。通过连锁不平衡分析,将AS可能的易感基因定位在58kb的范围内。
为了进一步寻找AS的易感基因,我们从58kb区段内的7个与免疫疾病相关基因中挑选出29个SNP进行精细定位。结果尚未发现与AS关联的SNP。
为了进一步研究-850T变异对TNFa基因启动子转录活性的影响,我们利用定点突变技术分别构建突变型T和野生型C两种荧光素酶报告基因载体,瞬时转染人HepG2细胞系,检测突变型T对TNFa启动子活性的影响。结果显示-850突变型T等位基因较野生型C增强了TNFa启动子活性,1.05-1.33倍。独立样本t检验未见统计学意义(t=1.645,P=0.102)。提示-850T变异可能仅作为遗传标记连锁AS的易感基因。
结论:我们在HLAⅢ基因区将AS的易感基因定位于58kb的范围,-850T未能增强TNFa启动子的转录活性,其周围紧密连锁有AS的易感基因。
本论文的第二部分从免疫应答和免疫调节网络入手,采用候选基因关联研究策略寻找AS的易感基因。
首先通过文献检索,挑选与抗原呈递,T细胞活化,细胞免疫和体液免疫应答,免疫调节等方面的节点基因,初步作为AS研究的候选基因。经PubMed和遗传关联数据库(GAD)筛选,保留14个与三个或三个以上的免疫学疾病关联基因作为候鸦颉Ｆ浯未?4个基因中挑选出19个与三个或三个以上的免疫学疾病关联,同时显著性大于0.001的SNP作为遗传标记,分别在45个中国吉林AS患者与HapMap数据库中提供的中国北京地区正常群体中进行关联研究,保留显著性小于0.01的两个SNP rs10489629和rs1024611,在整个中国吉林AS群体中复制关联结果。其中IL23R SNPrs10489629与AS关联。最后在其周围挑选7个SNP进行病例对照关联研究。结果显示SNP rs10736406和rs10889677与AS关联。
结论:我们基于免疫应答和免疫调节网络,采用候选基因关联研究策略,研究AS的易感基因。结果显示IL23基因与AS关联。
DA2B是一种先天性遗传病,主要表现为2个或2个以上关节的挛缩畸形,并且不包括由神经和肌肉病变所导致的关节畸形。远端关节弯曲2B型是DA中最常见的类型之一。其有明显的遗传异质性,目前发现TNNI2,TNNT3和MYH3的突变导致了疾病的发生。
论文二旨在制造携带R156X和del175K两种突变的Knock-in小鼠模型,并用其来研究DA2B的发病机理。
首先我们利用定点突变技术构建打靶载体,并通过基因打靶技术获得携带TNNI2~(del175K)突变基因的ES细胞,经囊胚注射和假孕移植产生嵌合体小鼠,筛选F1和F2代小鼠,鉴定出TNNI2~(del175K/del175K)纯合小鼠。
表型分析发现:1)部分TNNI2~(del175K/+)和全部TNNI2~(del175K/del175K)小鼠在哺乳期死亡。2)TNNI2~(del175K/+)和TNNI2~(del175K/del175K)小鼠在哺乳期内发育迟缓。
结论:1.TNNI2~(del175K)纯合突变致死。
2.TNNI2~(del175K)变导致小鼠发育迟缓。
Ankylosing Spondylitis(AS) is a common chronic inflammatory disorder,characterized by vertebral ankylosing,accompanying impairment of eye,lung,Cardiovascular system and kidney.However,the pathogenesis of AS is unknown.
Lot of studies indicated that HLA-B27 is significantly associated with AS.The results from genome wide linkage and association analysis demonstrated linkage with AS on chromosome 1p,2q,6q,6p,9q,10q,16q and 19q.The association between AS and interleukin 1 gene cluster,on chromosome 2q14 were reported by several studies in past years.All of these studies suggest that non HLA-B27 genes are susceptible to AS. In this study,we tried to position the susceptible genes to AS with candidate gene -association method in Chinese north population and exploit the effect of-850T variant on transcription of TNFαgene promoter.
In the first part of the study,we wanted to position possible susceptible genes to AS in a 120kb candidate area on HLAⅢregion.11 common SNPs were selected for case-control association study in China-Jilin population.The results showed that SNP rs1799724 was associated with AS in the China-Jilin population(P=0.021) and the T allele carried increased the risk of AS(OR=1.95,95%c.i:1.10-3.45).We position the possible susceptible genes of AS in a 58kb segment on the HLAⅢgene region by linkage disequilibrium measure.
In order to further seek the disposition genes to AS within the 58kb area,we re-selected 29 common SNPs from 7 genes which relate with immune diseases on this block. Nevertheless no association was observed in these 29 common SNPs.
To study whether the -850T variant impacted on the transcriptional activation of TNFαgene promoter,we constructed two type of luciferase report vectors,-850T and -850C,by site-directed mutagenesis technique,transiently transfected them into HepG2 cell line, respectively and detected the activation of TNFαpromoter by dual-luciferase reporter assay system.The results indicated that -850T variant appeared to increase the transcript from 1.05 to 1.33 fold than wild type C allele,however these is no statistical difference by Independent Sample t-test(t=1.645,P=0.102).
Conclusion:1) We positioned the susceptible genes to AS in a 58kb segment on HLAⅢ gene region.2)-850 T failed to affect the transcriptional activation of TNFαpromoter and it may be closely linked with true disposition genes to AS.
The second of our study is to position susceptible genes to AS by association study with a group of candidate genes which play key role in immune response and immune regulation.
Firstly,we selected genes from several sides of antigen presentation,T cell activation, cell immune response,humoral immune response and immune regulation to build a database.Screening the database with a principle of association with three different immune disorders that can be searched out from PubMed and Genetic Association Database,we retained 14 genes for candidate association study.
Secondly,we selected 19 common SNPs from these 14 candidate genes according to two rules.One is association with three or more immune diseases and the other is that significant level is more than 0.001.There were two SNPs,rs10489629 and rs1024611 demonstrated association with AS between 45 case from China Jilin population and 45 health control from China Beijing offered by Hapmap database.We replicated the association results in the whole case-control population of China Jilin.The SNP rs rs10489629 on IL23 gene was remained as a genetic mark which possibly linkages with susceptible genes to AS for the association result being replication.
For fine-mapping whether IL23 gene is susceptible to AS,we continually did a case-control association study with 7 common SNPs selected from IL23 gene in the population of China Jilin.The results exhibited that two of 7 SNPs,rs10736406 and rs 10889677 were associated with AS.
Conclusion:we researched susceptible genes to AS with candidate-gene method on the base of immune response and regulation network in the population of China Jilin.Our result indicated that IL23 gene is associated with AS and possibly contributed susceptibility to AS.
Distal arthrogryposis type 2B,one of most common types of DAs,is a multiple congenital contracture disorder characterized by contractures of the distal joints of limbs without neurological and skeletal muscle defect.DA2B has obvious genetic heterogeneity.Several reports showed mutations in TNNI2,TNNT3 and MYH3 responsible to DA2B.
The partⅡof my study is to generate two types of knock-in mice carrying with mutations of R156X and del175K in TNNI2 and study the pathogenesis of this disorder on these models.
Firstly,we constructed targeting vectors using site-directed mutagenesis and obtained the positive ES cell clones with two mutations by gene targeting technique,produced chimeras through microinjecting ES cell into blastocysts and transferring them into uterus of pseudopregnant recipient,and got the homogenous TNNI2~(del175K/del175K) mice by detecting the mutant gene of F1 and F2 generations.
We found:1) parts of TNNI2~(del175K/+) and all of TNNI2~(del175K/del175K) pups died within 20 days.2) Almost TNNI2~(del175K/+) and all of TNNI2~(del175K/del175K) pups were growth retardation during suckling.
Conclusion:The homogenous del175K mutation of TNNI2 is lethal.The del175K mutation of TNNI2 causes growth failure of mouse.
既往研究表明AS与HLA-627强关联。全基因组连锁和关联分析结果显示在染色体1p、2q、6q、6p、9q、10q、16q以及19q存在AS连锁区段。近年来多个群体报道2q14的Interleukin 1基因簇与AS关联。这些结果为研究非B27基因提供了线索和证据。
论文一采用候选基因关联研究,在中国北方人群中定位AS的易感基因,并深入研究-850T变异对TNFa启动子转录活性的影响。
本论文的第一部分旨在以HLAⅢ类基因区的TNFa启动子-850T变异作为AS的遗传标记,在其侧翼各60kb的范围内定位AS的易感基因。我们挑选了11个SNPs,在中国北方吉林群体中进行病例对照关联研究。结果显示,TNF(rs1799724)在中国北方吉林人群中与AS关联(P=0.021),携带T等位基因增强了疾病的发病风险(OR=1.95,95%CI:1.10-3.45)。通过连锁不平衡分析,将AS可能的易感基因定位在58kb的范围内。
为了进一步寻找AS的易感基因,我们从58kb区段内的7个与免疫疾病相关基因中挑选出29个SNP进行精细定位。结果尚未发现与AS关联的SNP。
为了进一步研究-850T变异对TNFa基因启动子转录活性的影响,我们利用定点突变技术分别构建突变型T和野生型C两种荧光素酶报告基因载体,瞬时转染人HepG2细胞系,检测突变型T对TNFa启动子活性的影响。结果显示-850突变型T等位基因较野生型C增强了TNFa启动子活性,1.05-1.33倍。独立样本t检验未见统计学意义(t=1.645,P=0.102)。提示-850T变异可能仅作为遗传标记连锁AS的易感基因。
结论:我们在HLAⅢ基因区将AS的易感基因定位于58kb的范围,-850T未能增强TNFa启动子的转录活性,其周围紧密连锁有AS的易感基因。
本论文的第二部分从免疫应答和免疫调节网络入手,采用候选基因关联研究策略寻找AS的易感基因。
首先通过文献检索,挑选与抗原呈递,T细胞活化,细胞免疫和体液免疫应答,免疫调节等方面的节点基因,初步作为AS研究的候选基因。经PubMed和遗传关联数据库(GAD)筛选,保留14个与三个或三个以上的免疫学疾病关联基因作为候鸦颉Ｆ浯未?4个基因中挑选出19个与三个或三个以上的免疫学疾病关联,同时显著性大于0.001的SNP作为遗传标记,分别在45个中国吉林AS患者与HapMap数据库中提供的中国北京地区正常群体中进行关联研究,保留显著性小于0.01的两个SNP rs10489629和rs1024611,在整个中国吉林AS群体中复制关联结果。其中IL23R SNPrs10489629与AS关联。最后在其周围挑选7个SNP进行病例对照关联研究。结果显示SNP rs10736406和rs10889677与AS关联。
结论:我们基于免疫应答和免疫调节网络,采用候选基因关联研究策略,研究AS的易感基因。结果显示IL23基因与AS关联。
DA2B是一种先天性遗传病,主要表现为2个或2个以上关节的挛缩畸形,并且不包括由神经和肌肉病变所导致的关节畸形。远端关节弯曲2B型是DA中最常见的类型之一。其有明显的遗传异质性,目前发现TNNI2,TNNT3和MYH3的突变导致了疾病的发生。
论文二旨在制造携带R156X和del175K两种突变的Knock-in小鼠模型,并用其来研究DA2B的发病机理。
首先我们利用定点突变技术构建打靶载体,并通过基因打靶技术获得携带TNNI2~(del175K)突变基因的ES细胞,经囊胚注射和假孕移植产生嵌合体小鼠,筛选F1和F2代小鼠,鉴定出TNNI2~(del175K/del175K)纯合小鼠。
表型分析发现:1)部分TNNI2~(del175K/+)和全部TNNI2~(del175K/del175K)小鼠在哺乳期死亡。2)TNNI2~(del175K/+)和TNNI2~(del175K/del175K)小鼠在哺乳期内发育迟缓。
结论:1.TNNI2~(del175K)纯合突变致死。
2.TNNI2~(del175K)变导致小鼠发育迟缓。
Ankylosing Spondylitis(AS) is a common chronic inflammatory disorder,characterized by vertebral ankylosing,accompanying impairment of eye,lung,Cardiovascular system and kidney.However,the pathogenesis of AS is unknown.
Lot of studies indicated that HLA-B27 is significantly associated with AS.The results from genome wide linkage and association analysis demonstrated linkage with AS on chromosome 1p,2q,6q,6p,9q,10q,16q and 19q.The association between AS and interleukin 1 gene cluster,on chromosome 2q14 were reported by several studies in past years.All of these studies suggest that non HLA-B27 genes are susceptible to AS. In this study,we tried to position the susceptible genes to AS with candidate gene -association method in Chinese north population and exploit the effect of-850T variant on transcription of TNFαgene promoter.
In the first part of the study,we wanted to position possible susceptible genes to AS in a 120kb candidate area on HLAⅢregion.11 common SNPs were selected for case-control association study in China-Jilin population.The results showed that SNP rs1799724 was associated with AS in the China-Jilin population(P=0.021) and the T allele carried increased the risk of AS(OR=1.95,95%c.i:1.10-3.45).We position the possible susceptible genes of AS in a 58kb segment on the HLAⅢgene region by linkage disequilibrium measure.
In order to further seek the disposition genes to AS within the 58kb area,we re-selected 29 common SNPs from 7 genes which relate with immune diseases on this block. Nevertheless no association was observed in these 29 common SNPs.
To study whether the -850T variant impacted on the transcriptional activation of TNFαgene promoter,we constructed two type of luciferase report vectors,-850T and -850C,by site-directed mutagenesis technique,transiently transfected them into HepG2 cell line, respectively and detected the activation of TNFαpromoter by dual-luciferase reporter assay system.The results indicated that -850T variant appeared to increase the transcript from 1.05 to 1.33 fold than wild type C allele,however these is no statistical difference by Independent Sample t-test(t=1.645,P=0.102).
Conclusion:1) We positioned the susceptible genes to AS in a 58kb segment on HLAⅢ gene region.2)-850 T failed to affect the transcriptional activation of TNFαpromoter and it may be closely linked with true disposition genes to AS.
The second of our study is to position susceptible genes to AS by association study with a group of candidate genes which play key role in immune response and immune regulation.
Firstly,we selected genes from several sides of antigen presentation,T cell activation, cell immune response,humoral immune response and immune regulation to build a database.Screening the database with a principle of association with three different immune disorders that can be searched out from PubMed and Genetic Association Database,we retained 14 genes for candidate association study.
Secondly,we selected 19 common SNPs from these 14 candidate genes according to two rules.One is association with three or more immune diseases and the other is that significant level is more than 0.001.There were two SNPs,rs10489629 and rs1024611 demonstrated association with AS between 45 case from China Jilin population and 45 health control from China Beijing offered by Hapmap database.We replicated the association results in the whole case-control population of China Jilin.The SNP rs rs10489629 on IL23 gene was remained as a genetic mark which possibly linkages with susceptible genes to AS for the association result being replication.
For fine-mapping whether IL23 gene is susceptible to AS,we continually did a case-control association study with 7 common SNPs selected from IL23 gene in the population of China Jilin.The results exhibited that two of 7 SNPs,rs10736406 and rs 10889677 were associated with AS.
Conclusion:we researched susceptible genes to AS with candidate-gene method on the base of immune response and regulation network in the population of China Jilin.Our result indicated that IL23 gene is associated with AS and possibly contributed susceptibility to AS.
Distal arthrogryposis type 2B,one of most common types of DAs,is a multiple congenital contracture disorder characterized by contractures of the distal joints of limbs without neurological and skeletal muscle defect.DA2B has obvious genetic heterogeneity.Several reports showed mutations in TNNI2,TNNT3 and MYH3 responsible to DA2B.
The partⅡof my study is to generate two types of knock-in mice carrying with mutations of R156X and del175K in TNNI2 and study the pathogenesis of this disorder on these models.
Firstly,we constructed targeting vectors using site-directed mutagenesis and obtained the positive ES cell clones with two mutations by gene targeting technique,produced chimeras through microinjecting ES cell into blastocysts and transferring them into uterus of pseudopregnant recipient,and got the homogenous TNNI2~(del175K/del175K) mice by detecting the mutant gene of F1 and F2 generations.
We found:1) parts of TNNI2~(del175K/+) and all of TNNI2~(del175K/del175K) pups died within 20 days.2) Almost TNNI2~(del175K/+) and all of TNNI2~(del175K/del175K) pups were growth retardation during suckling.
Conclusion:The homogenous del175K mutation of TNNI2 is lethal.The del175K mutation of TNNI2 causes growth failure of mouse.
引文
1.Brown,M.A.,et al.,A genome-wide screen for susceptibility loci in ankylosing spondyfitis.:Arthritis Rheum,1998.41(4):p.588-95.
2.Burton,P.R.,et al.,Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants.:Nat Genet,2007.39(11):p.1329-37.
3.Gu,M.M.,et al.,[A genomewide scan for the susceptibility gene loci to ankylosing spondylitis in Chinese Han population].:Yi Chuan Xue Bao,2004.31(3):p.217-20.
4.Laval,S.H.,et al.,Whole-genome screening in ankylosing spondylitis:evidence of non-MHC genetic-susceptibility loci.:Am J Hum Genet,2001.68(4):p.918-26.
5.Kim,T.J.,et al.,Interleukin 1 polymorphisms in patients with ankylosing spondyfitis in Korea.:J Rheumatol,2008.35(8):p.1603-8.
6.Maksymowych,W.P.,et al.,Association of the IL1 gene cluster with susceptibility to ankylosing spondylitis:an analysis of three Canadian populations.:Arthritis Rheum,2006.54(3):p.974-85.
7.Maksymowych,W.P.et al.,High-throughput single-nucleotide polymorphism analysis of the IL1RN locus in patients with ankylosing spondylitis by matrix-assisted laser desorption ionization-time-of-flight mass spectrometry.:Arthritis Rheum,2003.48(7):p.2011-8.
8.Jimenez-Balderas,F.J.and G.Mintz,Ankylosing spondylitis:clinical course in women and men.:J Rheumatol,1993.20(12):p.2069-72.
9.Seurynck,K.and L.A.Baxter-Lowe,Novel polymorphism detected in exon 1 of HLA-B~*2713.:Tissue Antigens,1998.52(2):p.187-9.
10.Brown,M.A.,et al.,HLA class I associations of ankylosing spondylitis in the white population in the United Kingdom:Ann Rheum Dis,1996.55(4):p.268-70.
11.Lopez de Castro,J.A.,The pathogenetic role of HLA-B27 in chronic arthritis.:Curr Opin Immunol,1998.10(1):p.59-66.
12.Breban,M.A.,R.E.Hammer,and J.D.Taurog,[Transgenic rats for HLA-B27 and human beta 2microglobulin:a model of spondyloarthritis].:Rev Rhum Ed Fr,1993.60(3):p.181-6.
13.Rath,H.C.,Role of commensal bacteria in chronic experimental colitis:lessons from the HLA-B27transgenic rat.:Pathobiology,2002.70(3):p.131-8.
14.Rauner,M.,et al.,The HLA-B27 transgenic rat,a model of spondyloarthritis,has decreased bone mineral density and increased RANKL to osteoprotegerin mRNA ratio.:J Rheumatol,2009.36(1):p.120-6.
15.Wei,J.C.,et al.,HLA-B60 and B61 are strongly associated with ankylosing spondylitis in HLA-B27-negative Taiwan Chinese patients.:Rheumatology(Oxford),2004.43(7):p.839-42.
16.Perez-Guijo,V.,et al.,Distribution of HLA-DRB1 genes in patients with sporadic ankylosing spondylitis in the south of Spain.:Joint Bone Spine,2002.69(5):p.458-62.
17.Orchard,T.R.,et al.,Clinical phenotype is related to HLA genotype in the peripheral arthropathies of inflammatory bowel disease.:Gastroenterology,2000.118(2):p.274-8.
18.Kaijzel,E.L.,et al.,Polymorphism within the tumor necrosis factor alpha(TNF) promoter region in patients with ankylosing spondylitis:Hum Immunol,1999.60(2):p.140-4.
19.Verjans,G.M.,et al.,Polymorphism of tumour necrosis factor-alpha(TNF-alpha) at position-308in relation to ankylosing spondylitis.:Clin Exp Immunol,1994.97(1):p.45-7.
20.Chou,C.T.,et al.,Replication of association of IL1 gene complex members with ankylosing spondylitis in Taiwanese Chinese.:Ann Rheum Dis,2006.65(8):p.1106-9.
21.Sung,I.H.,et al.,IL-23R Polymorphisms in Patients with Ankylosing Spondyfitis in Korea.:J Rheumatol,2009.
22.Frankel,W.N.and N.J.Schork,Who's afraid of epistasis?:Nat Genet,1996.14(4):p.371-3.
23.Spielman,R.S.,R.E.McGinnis,and W.J.Ewens,Transmission test for linkage disequilibrium:the insulin gene region and insulin-dependent diabetes mellitus(IDDM).:Am J Hum Genet,1993.52(3):p.506-16.
24.Barroso,I.,et al.,Candidate gene association study in type 2 diabetes indicates a role for genes involved in beta-cell function as well as insufin action.:PLoS Biol,2003.1(1):p.E20.
25.Continuous ambulatory peritoneal dialysis(CAPD) peritonitis and exit-site infections:challenges for the future.:Perit Dial Int,1989.9(4):p.239-40.
26.Hamilton,G.,et al.,Candidate gene association study of insulin signaling genes and Alzheimer's disease:evidence for SOS2,PCK1,and PPARgamma as susceptibility loci.:Am J Med Genet B Neuropsychiatr Genet,2007.144B(4):p.508-16.
27.Smithies,O.and N.Maeda,Gene targeting approaches to complex genetic diseases:atherosclerosis and essential hypertension.:Proc Natl Acad Sci U S A,1995.92(12):p.5266-72.
28.Tremblay,K.,et al.,Genes to diseases(G2D) computational method to identify asthma candidate genes.:PLoS ONE,2008.3(8):p.e2907.
29.Sladek,R.,et al.,A genome-wide association study identifies novel risk loci for type 2 diabetes.:Nature,2007.445(7130):p.881-5.
30.Fellay,J.,et al.,A whole-genome association study of major determinants for host control of HIV-1.:Science,2007.317(5840):p.944-7.
31.Salonen,J.T.,et al.,Type 2 diabetes whole-genome association study in four populations:the DiaGen consortium.:Am J Hum Genet,2007.81(2):p.338-45.
1.Shichi,D.,et al.,The haplotype block,NFKBIL1-ATP6V1G2-BAT1-MICB-MICA,within the class Ⅲ-class 1 boundary region of the human major histocompatibility complex may control susceptibility to hepatitis C virus-associated dilated cardiomyopathy.:Tissue Antigens,2005.66(3):p.200-8.
2.Delahaye,N.F.,et al.,Association analyses of NCR3 polymorphisms with P.falciparum mild malaria.:Microbes Infect 2007.9(2):p.160-6.
3.Koch,W.,et al.,Association of variants in the BAT1-NFKBIL1-LTA genomic region with protection against myocardial infarction in Europeans.:Hum Mol Genet,2007.16(15):p.1821-7.
4.Hensel,G.,et al.,PMA-responsive 5' flanking sequences of the human TNF gene.:Lymphokine Res,1989.8(3):p.347-51.
5.Demeter,J.,G.Messer,and H.Schrezenmeier,Clinical relevance of the TNF-alpha promoter/enhancer polymorphism in patients with aplastic anemia.:Ann Hematol,2002.83.(10):p.566-9.
6.Gonzalez,S.,et al.,TNF-238A promoter polymorphism contributes to susceptibility to ankylosing spondylitis in HLA-B27 negative patients.:J Rheumatol,2001.28(6):p.1288-93.
7.Kaijzel,E.L.,et al.,Polymorphism within the tumor necrosis factor alpha(TNF) promoter region in patients with ankylosing spandylitis.:Hum Immunol,1999.60(2):p.140-4.
8.Milicic,A.,et al.,Interethnic studies of TNF polymorphisms confirm the likely presence of a second MHC susceptibility locus in ankylosing spondylitis.:Genes Immun,2000.1(7):p.418-22.
9.Lange,U.,J.Teichmann,and H.Stracke,Correlation between plasma TNF-alpha,IGF-1, biochemical markers of bone metabolism,markers of inflammation/disease activity,and clinical manifestations in ankylosing spondylitis.:Eur J Med Res,2000.5(12):p.507-11.
10.Gratacos,J.,et al.,Serum cytokines (IL-6,TNF-alpha,IL-1 beta and IFN-gamma)in ankylosing spondylitis:a close correlation between serum IL-6 and disease activity and severity.:Br J Rheumatol,1994.33(10):p.927-31.
11.Okamoto,K.,et al.,Identification of I kappa BL as the second major histocompatibility complex-linked susceptibility locus for rheumatoid arthritis.:Am J Hum Genet,2003.72(2):p.303-12.
12.Ozaki,K.,et a I.,Functional SNPs in the lymphotoxin-alpha gene that are associated with susceptibility to myocardial infarction.:Nat Genet,2002.32(4):p.650-4.
13.Schlosstein,L,et al.,High association of an HL-A antigen,W27,with ankylosing spondylitis.:N Engl J Med,1973.288(14):p.704-6.
14.Brewerton,D.A.,et al.,Ankylosing spondylitis and HL-A 27:Lancet,1973.1(7809):p.904-7.
15.Brown,M.A.,et al..Susceptibility to ankylosing spondylitis in twins:the role of genes,HLA,and the environment.:Arthritis Rheum,1997.40(10):p.1823-8.
16.Malik,ST.,Tumour necrosis factor:roles in cancer pathophysiology.:Semin Cancer Biol,1992.3(1):p.27-33.
17.Verjans,G.M.,et al.,Restriction fragment length polymorphism of the tumor necrosis factor region in patients with ankylosing spondylitis.:Arthritis Rheum,1991.34(4):p.486-9.
18.McGarry,F.,et al.,The-308.1 polymorphism in the promoter region of the tumor necrosis factor gene is associated with ankylosing spondylitis independent of HLA-B27.:J Rheumatol,1999.26(5):p.1110-6.
1.Quinones-Lombrana,A.,et al.,BAT2 promoter polymorphism is associated with rheumatoid arthritis susceptibility.:J Rheumatol,2008.35(5):p.741-4.
2.Lin,C.H.,et al.,Inhibitors of kB-fike gene polymorphisms in rheumatoid arthritis.:Immunol Lett,2006.105(2):p.193-7.
3.Okamoto,K.,et al.,Identification of I kappa BL as the second major histocompatibility complex-linked susceptibility locus for rheumatoid arthritis.:Am J Hum Genet,2003.72(2):p.303-12.
4.Mulcahy,H.,et al.,L5T1 and NCR3 expression in autoimmune inflammation and in response to IFN-gamma,LPS end microbiol infection.:Immunogenetics,2006.57(12):p.893-903.
5.Lu,M.C.,et al.,HLA haplotype A33-B58-Cw10 may modulate rodiographic development of bamboo spine in Taiwanese patients with primary ankylosing spondylitis.:Dis Markers,2009.26(2):p.93-6.
6.Merino,E.,et al.,Disparate folding and stability of the ankylosing spondylitis-associated HLA-B~*1403 and B~*2705 proteins.:Arthritis Rheum,2008.58(12):p.3693-704.
7.Marcilla,M.and J.A.Lopez de Castro,Peptides:the cornerstone of HLA-B27 biology and pathogenetic role in spondyloarthritis.:Tissue Antigens,2008.71(6):p.495-506.
8.Cai,Q.,et al.,[Study on the association of ankylosing spondylitis with HLA-B ond HLA-DRB1].:Zhonghua Yi Xue Za Zhi,2005.85(14}:p.992-4.
9.Perez-Guijo,V.,et al.,Distribution of HLA-DRB1 genes in patients with sporadic ankylosing spondylitis in the south of Spain.:Joint Bone Spine,2002.69(5):p.458-62.
10.Wang,Y.W.,et al.,[Mapping study of ankylosing spondylitis on HLA region in Jilin population of China].:Yi Chuan,2007.29(7):p.805-12.
1.Skoog,T.,et al.,A common functional polymorphism(C—>A substitution at position-863) in the promoter region of the tumour necrosis factor-alpha(TNF-alpha) gone associated with reduced circulating levels of TNF-alpha.:Hum Mol Genet,1999.8(8):p.1443-9.
2.Ye,J.,et al.,Inhibition of TNF-alpho gone expression and bioactivity by site-specific transcription factor-binding oligonucleotides.:Am J Physiol Lung Cell Mol Physiol,2003.2.84(2):p.L386-94.
1.Brown,M.A.,et al.,HLA class I associations of ankylosing spondylitis in the white population in the United Kingdom.:Ann Rheum Dis,1996.55(4):p.268-70.
2.Wei,J.C.,et al.,HLA-B60 and B61 are strongly associated with ankylosing spondylitis in HLA-B27-negative Taiwan Chinese patients.:Rheumatology(Oxford),2004.43(7):p.839-42.
3.Vargas-Alarcon,G.,et al.,Association study of LMP gene polymorphisms in Mexican patients with spondyloarthritis.:Hum Immunol,2004.65(12):p.1437-42.
4.Maksymowych,W.P.,et al.,LMP2 polymorphism is associated with extraspinal disease in HLA-B27negative Caucasian and Mexican Mestizo patients with ankylosing spondyfitis.:J Rheumatol,2000.27(1):p.183-9.
5.Maksymowych,W.P.,et al.,The LMP2 polymorphism is associated with susceptibility to acute anterior uveitis in HLA-B27 positive juvenile and adult Mexican subjects with ankylosing spondyfitis.:Ann Rheum Dis,1997.56(8):p.488-92.
6.Orchard,T.R.,et al.,Clinical phenotype is related to HLA genotype in the peripheral arthropathies of inflammatory bowel disease.:Gastroenterology,2000.118(2):p.274-8.
7.Ragoussis,J.,et al.,Localization of the genes for tumor necrosis factor and lymphotoxin between the HLA class Ⅰ and Ⅲ regions by field inversion gel electrophoresis:Immunogenetics,1988.27(1):p.66-9.
8.Beyeler,C.,et al.,Relationship between genotype for the cytochrome P450 CYP2D6 and susceptibility to ankylosing spondylitis and rheumatoid arthritis.:Ann Rheum Dis,1996.55(1):p.66-8.
9.Maksymowych,W.P.,et al.,High-throughput single-nucleotide polymorphism analysis of the IL1RN locus in patients with ankylosing spondyfitis by matrix-assisted laser desorption ionization-time-of-flight mass spectrometry.:Arthritis Rheum,2003.48(7):p.2011-8.
10.van der Paardt,M.,et al.,Interleukin-1beta and interleukin-1 receptor antagonist gene polymorphisms in ankylosing spondylitis.:Rheumatology(Oxford),2002.41(12):p.1419-23.
11.Redondo,M.J.and G.S.Eisenbarth,Genetic control of autoimmunity in Type Ⅰ diabetes and associated disorders.:Diabetologia,2002.45(5):p.605-22.
12.Ban,Y.and Y.Tomer,Susceptibility genes in thyroid autoimmunity.:Clin Dev Immunol,2005.12(1):p.47-58.
13.Barcellos,L.F.,et al.,HLA-DR2 dose effect on susceptibility to multiple sclerosis and influence on disease course.:Am J Hum Genet,2003.72(3):p.710-6.
14.Graham,R.R.,et al.,Visualizing human leukocyte antigen class Ⅱ risk haplotypes in human systemic lupus erythematosus.:Am J Hum Genet,2002.71(3):p.543-53.
15.Hall,F.C.,et al.,Influence of the HLA-DRB1 locus on susceptibility and severity in rheumatoid arthritis.:QJM,1996.89(11):p.821-9.
16.Bottini,N.,et al.,Role of PTPN22 in type 1 diabetes and other autoimmune diseases.:Semin Immunol,2006.18(4):p.207-13.
17.Bottini,N.,et al.,A junctional variant of lymphoid tyrosine phosphatase is associated with type I diabetes.:Nat Genet,2004.36(4):p.337-8.
18.Begovich,A.B.,et al.,A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase(PTPN22) is associated with rheumatoid arthritis.:Am J Hum Genet,2004.75(2):p.330-7.
19.Kyogoku,C.,et al.,Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE.:Am J Hum Genet,2004.75(3):p.504-7.
20.Nistico,L.,et al.,The CTLA-4 gene region of chromosome 2q33 is linked to,and associated with,type 1 diabetes.Belgian Diabetes Registry.:Hum Mol Genet,1996.5(7):p.1075-80.
21.Ueda,H.,et al.,Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease.:Nature,2003.423(6939):p.506-11.
22.Duerr,R.H.,et al.,A genome-wide association study identifies IL23R as an inflammatory bowel disease gene.:Science,2006.314(5804):p.1461-3.
23.Fisher,S.A.,et al.,Genetic determinants of ulcerative colitis include the ECM1 locus and live loci implicated in Crohn's disease.:Nat Genet,2008.40(6):p.710-2.
24.Burton,P.R.,et al.,Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants.:Nat Genet,2007.39(11):p.1329-37.
25.Kanda,N.and S.Watanabe,IL-12,IL-23,and IL-27 enhance human beta-defensin-2 production in human keratinocytes.:Eur J Immunol,2008.38(5):p.1287-96.
1.Hall,J.G.,S.D.Reed,and G.Greene,The distal arthrogryposes:delineation of new entities-review and nosologic discussion.Am J Med Genet,1982.11(2):p.185-239.
2.Bamshad,M.,L.B.Jorde,and J.C.Carey,A revised and extended classification of the distal arthrogryposes.Am J Med Genet,1996.65(4):p.277-81.
3.Bamshad,M.,et al.,A gene for distal arthrogryposis type I maps to the pericentromeric region of chromosome 9.Am J Hum Genet,1994.55(6):p.1153-8.
4.Sung,S.S.,et al.,Mutations in genes encoding fast-twitch contractile proteins cause distal arthrogryposis syndromes.Am J Hum Genet,2003.72(3):p.681-90.
5.Krakowiak,P.A.,et al.,A variant of Freeman-Sheldon syndrome maps to 11p15.5-pter.Am J Hum Genet,1997.60(2):p.426-32.
6.Sung,S.S.,et al.,Mutations in TNNT3 cause multiple congenital contractures:a second locus,for distal arthrogryposis type 2B.Am J Hum Genet,2003.73(1):p.212-4.
7.Putnam,E.A.,et al.,Fibrillin-2(FBN2) mutations result in the Marian-like disorder,congenital contractural arachnodactyly.Nat Genet,1995.11(4):p.456-8.
8.Feinberg,M.and B.J.Carroll,Biological 'markers' for endogenous depression.Effect of age,severity of illness,weight loss,and polarity.Arch Gen Psychiatry,1984.41(11):p.1080-5.
9.Jiang,M.,et al.,A novel deletion in TNNI2 causes distal arthrogryposis in a large Chinese family with marked variability of expression.Hum Genet,2006.120(2):p.238-42.
10.Robinson,P.,et al.,Mutations in fast skeletal troponin I,troponin T,and beta-tropomyosin that cause distal arthrogryposis all increase contractile,function.FASEB J,2007.21(3):p.896-905.
11.Toydemir,R.M.,et al.,Mutations in embryonic myosin heavy chain(MYH3) cause Freeman-Sheldon syndrome and Sheldon-Hall syndrome.Nat Genet,2006.38(5):p.561-5.
12.Malnic,B.,C.S.Farah,and F.C.Reinach,Regulatory properties of the NH2-and COOH-terminal domains of troponin T.ATPase activation and binding to troponin I and troponin C.J Biol Chem,1998.273(17):p.10594-601.
13.Jha,P.K.,P.C.Leavis,and S.Sarkar,Interaction of deletion mutants of troponins I and T:COOH-terminal truncation of troponin T abolishes troponin I binding and reduces Ca2+ sensitivity of the reconstituted regulatory system.Biochemistry,1996.35(51):p.16573-80.
14.Vinogradova,M.V.,et al.,Ca(2+)-regulated structural changes in troponin.Proc Natl Acad Sci U S A,2005.102(14):p.5038-43.
15.Sever,L.E.,Use of folic acid supplementation in the periconceptional period provides great promise for the primary prevention of the neural tube defects(NTDs),anencephaly,and spina bifida.J Nurse Midwifery,1992.37(5):p.350.
16.Ramos,C.H.,Mapping subdomains in the C-terminal region of troponin I involved in its binding to troponin C and to thin filament.J Biol Chem,1999.274(26):p.18189-95.
2.Burton,P.R.,et al.,Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants.:Nat Genet,2007.39(11):p.1329-37.
3.Gu,M.M.,et al.,[A genomewide scan for the susceptibility gene loci to ankylosing spondylitis in Chinese Han population].:Yi Chuan Xue Bao,2004.31(3):p.217-20.
4.Laval,S.H.,et al.,Whole-genome screening in ankylosing spondylitis:evidence of non-MHC genetic-susceptibility loci.:Am J Hum Genet,2001.68(4):p.918-26.
5.Kim,T.J.,et al.,Interleukin 1 polymorphisms in patients with ankylosing spondyfitis in Korea.:J Rheumatol,2008.35(8):p.1603-8.
6.Maksymowych,W.P.,et al.,Association of the IL1 gene cluster with susceptibility to ankylosing spondylitis:an analysis of three Canadian populations.:Arthritis Rheum,2006.54(3):p.974-85.
7.Maksymowych,W.P.et al.,High-throughput single-nucleotide polymorphism analysis of the IL1RN locus in patients with ankylosing spondylitis by matrix-assisted laser desorption ionization-time-of-flight mass spectrometry.:Arthritis Rheum,2003.48(7):p.2011-8.
8.Jimenez-Balderas,F.J.and G.Mintz,Ankylosing spondylitis:clinical course in women and men.:J Rheumatol,1993.20(12):p.2069-72.
9.Seurynck,K.and L.A.Baxter-Lowe,Novel polymorphism detected in exon 1 of HLA-B~*2713.:Tissue Antigens,1998.52(2):p.187-9.
10.Brown,M.A.,et al.,HLA class I associations of ankylosing spondylitis in the white population in the United Kingdom:Ann Rheum Dis,1996.55(4):p.268-70.
11.Lopez de Castro,J.A.,The pathogenetic role of HLA-B27 in chronic arthritis.:Curr Opin Immunol,1998.10(1):p.59-66.
12.Breban,M.A.,R.E.Hammer,and J.D.Taurog,[Transgenic rats for HLA-B27 and human beta 2microglobulin:a model of spondyloarthritis].:Rev Rhum Ed Fr,1993.60(3):p.181-6.
13.Rath,H.C.,Role of commensal bacteria in chronic experimental colitis:lessons from the HLA-B27transgenic rat.:Pathobiology,2002.70(3):p.131-8.
14.Rauner,M.,et al.,The HLA-B27 transgenic rat,a model of spondyloarthritis,has decreased bone mineral density and increased RANKL to osteoprotegerin mRNA ratio.:J Rheumatol,2009.36(1):p.120-6.
15.Wei,J.C.,et al.,HLA-B60 and B61 are strongly associated with ankylosing spondylitis in HLA-B27-negative Taiwan Chinese patients.:Rheumatology(Oxford),2004.43(7):p.839-42.
16.Perez-Guijo,V.,et al.,Distribution of HLA-DRB1 genes in patients with sporadic ankylosing spondylitis in the south of Spain.:Joint Bone Spine,2002.69(5):p.458-62.
17.Orchard,T.R.,et al.,Clinical phenotype is related to HLA genotype in the peripheral arthropathies of inflammatory bowel disease.:Gastroenterology,2000.118(2):p.274-8.
18.Kaijzel,E.L.,et al.,Polymorphism within the tumor necrosis factor alpha(TNF) promoter region in patients with ankylosing spondylitis:Hum Immunol,1999.60(2):p.140-4.
19.Verjans,G.M.,et al.,Polymorphism of tumour necrosis factor-alpha(TNF-alpha) at position-308in relation to ankylosing spondylitis.:Clin Exp Immunol,1994.97(1):p.45-7.
20.Chou,C.T.,et al.,Replication of association of IL1 gene complex members with ankylosing spondylitis in Taiwanese Chinese.:Ann Rheum Dis,2006.65(8):p.1106-9.
21.Sung,I.H.,et al.,IL-23R Polymorphisms in Patients with Ankylosing Spondyfitis in Korea.:J Rheumatol,2009.
22.Frankel,W.N.and N.J.Schork,Who's afraid of epistasis?:Nat Genet,1996.14(4):p.371-3.
23.Spielman,R.S.,R.E.McGinnis,and W.J.Ewens,Transmission test for linkage disequilibrium:the insulin gene region and insulin-dependent diabetes mellitus(IDDM).:Am J Hum Genet,1993.52(3):p.506-16.
24.Barroso,I.,et al.,Candidate gene association study in type 2 diabetes indicates a role for genes involved in beta-cell function as well as insufin action.:PLoS Biol,2003.1(1):p.E20.
25.Continuous ambulatory peritoneal dialysis(CAPD) peritonitis and exit-site infections:challenges for the future.:Perit Dial Int,1989.9(4):p.239-40.
26.Hamilton,G.,et al.,Candidate gene association study of insulin signaling genes and Alzheimer's disease:evidence for SOS2,PCK1,and PPARgamma as susceptibility loci.:Am J Med Genet B Neuropsychiatr Genet,2007.144B(4):p.508-16.
27.Smithies,O.and N.Maeda,Gene targeting approaches to complex genetic diseases:atherosclerosis and essential hypertension.:Proc Natl Acad Sci U S A,1995.92(12):p.5266-72.
28.Tremblay,K.,et al.,Genes to diseases(G2D) computational method to identify asthma candidate genes.:PLoS ONE,2008.3(8):p.e2907.
29.Sladek,R.,et al.,A genome-wide association study identifies novel risk loci for type 2 diabetes.:Nature,2007.445(7130):p.881-5.
30.Fellay,J.,et al.,A whole-genome association study of major determinants for host control of HIV-1.:Science,2007.317(5840):p.944-7.
31.Salonen,J.T.,et al.,Type 2 diabetes whole-genome association study in four populations:the DiaGen consortium.:Am J Hum Genet,2007.81(2):p.338-45.
1.Shichi,D.,et al.,The haplotype block,NFKBIL1-ATP6V1G2-BAT1-MICB-MICA,within the class Ⅲ-class 1 boundary region of the human major histocompatibility complex may control susceptibility to hepatitis C virus-associated dilated cardiomyopathy.:Tissue Antigens,2005.66(3):p.200-8.
2.Delahaye,N.F.,et al.,Association analyses of NCR3 polymorphisms with P.falciparum mild malaria.:Microbes Infect 2007.9(2):p.160-6.
3.Koch,W.,et al.,Association of variants in the BAT1-NFKBIL1-LTA genomic region with protection against myocardial infarction in Europeans.:Hum Mol Genet,2007.16(15):p.1821-7.
4.Hensel,G.,et al.,PMA-responsive 5' flanking sequences of the human TNF gene.:Lymphokine Res,1989.8(3):p.347-51.
5.Demeter,J.,G.Messer,and H.Schrezenmeier,Clinical relevance of the TNF-alpha promoter/enhancer polymorphism in patients with aplastic anemia.:Ann Hematol,2002.83.(10):p.566-9.
6.Gonzalez,S.,et al.,TNF-238A promoter polymorphism contributes to susceptibility to ankylosing spondylitis in HLA-B27 negative patients.:J Rheumatol,2001.28(6):p.1288-93.
7.Kaijzel,E.L.,et al.,Polymorphism within the tumor necrosis factor alpha(TNF) promoter region in patients with ankylosing spandylitis.:Hum Immunol,1999.60(2):p.140-4.
8.Milicic,A.,et al.,Interethnic studies of TNF polymorphisms confirm the likely presence of a second MHC susceptibility locus in ankylosing spondylitis.:Genes Immun,2000.1(7):p.418-22.
9.Lange,U.,J.Teichmann,and H.Stracke,Correlation between plasma TNF-alpha,IGF-1, biochemical markers of bone metabolism,markers of inflammation/disease activity,and clinical manifestations in ankylosing spondylitis.:Eur J Med Res,2000.5(12):p.507-11.
10.Gratacos,J.,et al.,Serum cytokines (IL-6,TNF-alpha,IL-1 beta and IFN-gamma)in ankylosing spondylitis:a close correlation between serum IL-6 and disease activity and severity.:Br J Rheumatol,1994.33(10):p.927-31.
11.Okamoto,K.,et al.,Identification of I kappa BL as the second major histocompatibility complex-linked susceptibility locus for rheumatoid arthritis.:Am J Hum Genet,2003.72(2):p.303-12.
12.Ozaki,K.,et a I.,Functional SNPs in the lymphotoxin-alpha gene that are associated with susceptibility to myocardial infarction.:Nat Genet,2002.32(4):p.650-4.
13.Schlosstein,L,et al.,High association of an HL-A antigen,W27,with ankylosing spondylitis.:N Engl J Med,1973.288(14):p.704-6.
14.Brewerton,D.A.,et al.,Ankylosing spondylitis and HL-A 27:Lancet,1973.1(7809):p.904-7.
15.Brown,M.A.,et al..Susceptibility to ankylosing spondylitis in twins:the role of genes,HLA,and the environment.:Arthritis Rheum,1997.40(10):p.1823-8.
16.Malik,ST.,Tumour necrosis factor:roles in cancer pathophysiology.:Semin Cancer Biol,1992.3(1):p.27-33.
17.Verjans,G.M.,et al.,Restriction fragment length polymorphism of the tumor necrosis factor region in patients with ankylosing spondylitis.:Arthritis Rheum,1991.34(4):p.486-9.
18.McGarry,F.,et al.,The-308.1 polymorphism in the promoter region of the tumor necrosis factor gene is associated with ankylosing spondylitis independent of HLA-B27.:J Rheumatol,1999.26(5):p.1110-6.
1.Quinones-Lombrana,A.,et al.,BAT2 promoter polymorphism is associated with rheumatoid arthritis susceptibility.:J Rheumatol,2008.35(5):p.741-4.
2.Lin,C.H.,et al.,Inhibitors of kB-fike gene polymorphisms in rheumatoid arthritis.:Immunol Lett,2006.105(2):p.193-7.
3.Okamoto,K.,et al.,Identification of I kappa BL as the second major histocompatibility complex-linked susceptibility locus for rheumatoid arthritis.:Am J Hum Genet,2003.72(2):p.303-12.
4.Mulcahy,H.,et al.,L5T1 and NCR3 expression in autoimmune inflammation and in response to IFN-gamma,LPS end microbiol infection.:Immunogenetics,2006.57(12):p.893-903.
5.Lu,M.C.,et al.,HLA haplotype A33-B58-Cw10 may modulate rodiographic development of bamboo spine in Taiwanese patients with primary ankylosing spondylitis.:Dis Markers,2009.26(2):p.93-6.
6.Merino,E.,et al.,Disparate folding and stability of the ankylosing spondylitis-associated HLA-B~*1403 and B~*2705 proteins.:Arthritis Rheum,2008.58(12):p.3693-704.
7.Marcilla,M.and J.A.Lopez de Castro,Peptides:the cornerstone of HLA-B27 biology and pathogenetic role in spondyloarthritis.:Tissue Antigens,2008.71(6):p.495-506.
8.Cai,Q.,et al.,[Study on the association of ankylosing spondylitis with HLA-B ond HLA-DRB1].:Zhonghua Yi Xue Za Zhi,2005.85(14}:p.992-4.
9.Perez-Guijo,V.,et al.,Distribution of HLA-DRB1 genes in patients with sporadic ankylosing spondylitis in the south of Spain.:Joint Bone Spine,2002.69(5):p.458-62.
10.Wang,Y.W.,et al.,[Mapping study of ankylosing spondylitis on HLA region in Jilin population of China].:Yi Chuan,2007.29(7):p.805-12.
1.Skoog,T.,et al.,A common functional polymorphism(C—>A substitution at position-863) in the promoter region of the tumour necrosis factor-alpha(TNF-alpha) gone associated with reduced circulating levels of TNF-alpha.:Hum Mol Genet,1999.8(8):p.1443-9.
2.Ye,J.,et al.,Inhibition of TNF-alpho gone expression and bioactivity by site-specific transcription factor-binding oligonucleotides.:Am J Physiol Lung Cell Mol Physiol,2003.2.84(2):p.L386-94.
1.Brown,M.A.,et al.,HLA class I associations of ankylosing spondylitis in the white population in the United Kingdom.:Ann Rheum Dis,1996.55(4):p.268-70.
2.Wei,J.C.,et al.,HLA-B60 and B61 are strongly associated with ankylosing spondylitis in HLA-B27-negative Taiwan Chinese patients.:Rheumatology(Oxford),2004.43(7):p.839-42.
3.Vargas-Alarcon,G.,et al.,Association study of LMP gene polymorphisms in Mexican patients with spondyloarthritis.:Hum Immunol,2004.65(12):p.1437-42.
4.Maksymowych,W.P.,et al.,LMP2 polymorphism is associated with extraspinal disease in HLA-B27negative Caucasian and Mexican Mestizo patients with ankylosing spondyfitis.:J Rheumatol,2000.27(1):p.183-9.
5.Maksymowych,W.P.,et al.,The LMP2 polymorphism is associated with susceptibility to acute anterior uveitis in HLA-B27 positive juvenile and adult Mexican subjects with ankylosing spondyfitis.:Ann Rheum Dis,1997.56(8):p.488-92.
6.Orchard,T.R.,et al.,Clinical phenotype is related to HLA genotype in the peripheral arthropathies of inflammatory bowel disease.:Gastroenterology,2000.118(2):p.274-8.
7.Ragoussis,J.,et al.,Localization of the genes for tumor necrosis factor and lymphotoxin between the HLA class Ⅰ and Ⅲ regions by field inversion gel electrophoresis:Immunogenetics,1988.27(1):p.66-9.
8.Beyeler,C.,et al.,Relationship between genotype for the cytochrome P450 CYP2D6 and susceptibility to ankylosing spondylitis and rheumatoid arthritis.:Ann Rheum Dis,1996.55(1):p.66-8.
9.Maksymowych,W.P.,et al.,High-throughput single-nucleotide polymorphism analysis of the IL1RN locus in patients with ankylosing spondyfitis by matrix-assisted laser desorption ionization-time-of-flight mass spectrometry.:Arthritis Rheum,2003.48(7):p.2011-8.
10.van der Paardt,M.,et al.,Interleukin-1beta and interleukin-1 receptor antagonist gene polymorphisms in ankylosing spondylitis.:Rheumatology(Oxford),2002.41(12):p.1419-23.
11.Redondo,M.J.and G.S.Eisenbarth,Genetic control of autoimmunity in Type Ⅰ diabetes and associated disorders.:Diabetologia,2002.45(5):p.605-22.
12.Ban,Y.and Y.Tomer,Susceptibility genes in thyroid autoimmunity.:Clin Dev Immunol,2005.12(1):p.47-58.
13.Barcellos,L.F.,et al.,HLA-DR2 dose effect on susceptibility to multiple sclerosis and influence on disease course.:Am J Hum Genet,2003.72(3):p.710-6.
14.Graham,R.R.,et al.,Visualizing human leukocyte antigen class Ⅱ risk haplotypes in human systemic lupus erythematosus.:Am J Hum Genet,2002.71(3):p.543-53.
15.Hall,F.C.,et al.,Influence of the HLA-DRB1 locus on susceptibility and severity in rheumatoid arthritis.:QJM,1996.89(11):p.821-9.
16.Bottini,N.,et al.,Role of PTPN22 in type 1 diabetes and other autoimmune diseases.:Semin Immunol,2006.18(4):p.207-13.
17.Bottini,N.,et al.,A junctional variant of lymphoid tyrosine phosphatase is associated with type I diabetes.:Nat Genet,2004.36(4):p.337-8.
18.Begovich,A.B.,et al.,A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase(PTPN22) is associated with rheumatoid arthritis.:Am J Hum Genet,2004.75(2):p.330-7.
19.Kyogoku,C.,et al.,Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE.:Am J Hum Genet,2004.75(3):p.504-7.
20.Nistico,L.,et al.,The CTLA-4 gene region of chromosome 2q33 is linked to,and associated with,type 1 diabetes.Belgian Diabetes Registry.:Hum Mol Genet,1996.5(7):p.1075-80.
21.Ueda,H.,et al.,Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease.:Nature,2003.423(6939):p.506-11.
22.Duerr,R.H.,et al.,A genome-wide association study identifies IL23R as an inflammatory bowel disease gene.:Science,2006.314(5804):p.1461-3.
23.Fisher,S.A.,et al.,Genetic determinants of ulcerative colitis include the ECM1 locus and live loci implicated in Crohn's disease.:Nat Genet,2008.40(6):p.710-2.
24.Burton,P.R.,et al.,Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants.:Nat Genet,2007.39(11):p.1329-37.
25.Kanda,N.and S.Watanabe,IL-12,IL-23,and IL-27 enhance human beta-defensin-2 production in human keratinocytes.:Eur J Immunol,2008.38(5):p.1287-96.
1.Hall,J.G.,S.D.Reed,and G.Greene,The distal arthrogryposes:delineation of new entities-review and nosologic discussion.Am J Med Genet,1982.11(2):p.185-239.
2.Bamshad,M.,L.B.Jorde,and J.C.Carey,A revised and extended classification of the distal arthrogryposes.Am J Med Genet,1996.65(4):p.277-81.
3.Bamshad,M.,et al.,A gene for distal arthrogryposis type I maps to the pericentromeric region of chromosome 9.Am J Hum Genet,1994.55(6):p.1153-8.
4.Sung,S.S.,et al.,Mutations in genes encoding fast-twitch contractile proteins cause distal arthrogryposis syndromes.Am J Hum Genet,2003.72(3):p.681-90.
5.Krakowiak,P.A.,et al.,A variant of Freeman-Sheldon syndrome maps to 11p15.5-pter.Am J Hum Genet,1997.60(2):p.426-32.
6.Sung,S.S.,et al.,Mutations in TNNT3 cause multiple congenital contractures:a second locus,for distal arthrogryposis type 2B.Am J Hum Genet,2003.73(1):p.212-4.
7.Putnam,E.A.,et al.,Fibrillin-2(FBN2) mutations result in the Marian-like disorder,congenital contractural arachnodactyly.Nat Genet,1995.11(4):p.456-8.
8.Feinberg,M.and B.J.Carroll,Biological 'markers' for endogenous depression.Effect of age,severity of illness,weight loss,and polarity.Arch Gen Psychiatry,1984.41(11):p.1080-5.
9.Jiang,M.,et al.,A novel deletion in TNNI2 causes distal arthrogryposis in a large Chinese family with marked variability of expression.Hum Genet,2006.120(2):p.238-42.
10.Robinson,P.,et al.,Mutations in fast skeletal troponin I,troponin T,and beta-tropomyosin that cause distal arthrogryposis all increase contractile,function.FASEB J,2007.21(3):p.896-905.
11.Toydemir,R.M.,et al.,Mutations in embryonic myosin heavy chain(MYH3) cause Freeman-Sheldon syndrome and Sheldon-Hall syndrome.Nat Genet,2006.38(5):p.561-5.
12.Malnic,B.,C.S.Farah,and F.C.Reinach,Regulatory properties of the NH2-and COOH-terminal domains of troponin T.ATPase activation and binding to troponin I and troponin C.J Biol Chem,1998.273(17):p.10594-601.
13.Jha,P.K.,P.C.Leavis,and S.Sarkar,Interaction of deletion mutants of troponins I and T:COOH-terminal truncation of troponin T abolishes troponin I binding and reduces Ca2+ sensitivity of the reconstituted regulatory system.Biochemistry,1996.35(51):p.16573-80.
14.Vinogradova,M.V.,et al.,Ca(2+)-regulated structural changes in troponin.Proc Natl Acad Sci U S A,2005.102(14):p.5038-43.
15.Sever,L.E.,Use of folic acid supplementation in the periconceptional period provides great promise for the primary prevention of the neural tube defects(NTDs),anencephaly,and spina bifida.J Nurse Midwifery,1992.37(5):p.350.
16.Ramos,C.H.,Mapping subdomains in the C-terminal region of troponin I involved in its binding to troponin C and to thin filament.J Biol Chem,1999.274(26):p.18189-95.