FAMILY STUDIES OF THE GENETICS OF ANKYLOSING SPONDYLITIS

强直性脊柱炎遗传学的家庭研究

• 批准号: 6616857
• 负责人: JOHN Duffin REVEILLE
• 金额: $ 98.21万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-10 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6616857
• 关键词: MHC class II antigen; clinical research; data collection methodology /evaluation; family genetics; fluorescent dye /probe; gene expression; genetic polymorphism; genotype; human genetic material tag; human subject; linkage mapping; major histocompatibility complex; medical records; nucleic acid sequence; polymerase chain reaction; questionnaires; radiography; rheumatoid arthritis; spondylitis; statistics /biometry

Although HLA-B27 is regarded as an essential feature for the development of ankylosing spondylitis (AS, recent studies have implicated other genes and chromosomal regions, both inside and outside the major histocompatibility complex (MHC), in the pathogenesis of the disorder. The entire MHC contribution has been calculated at only 31 percent. Linkage analysis of sib pairs from the United Kingdom has shown eight chromosomal regions, including the MHC, to have moderate evidence of linkage to AS. However, many genes are contained in these regions, and which are the actual disease susceptibility genes within these regions has not been established. Thus, the specific aims of this proposal are: 1) to establish a consortium of investigators with a recent record of clinical or genetic research in AS (and hence established patient cohorts) based at 10 academic medical centers throughout North America (the North American Spondylitis Consortium-NASC) in order to identify from their cohorts families with at least two siblings fulfilling the modified New York criteria for AS; 2) from the membership of the Spondylitis Association of America (SAA), to identify similarly affected families and verify the diagnoses in both groups by questionnaire, medical record review and pelvic radiographs; 3) to collect 50 ml of blood from affected and unaffected sib pairs and, when available, both their parents in order to establish a bank of sera, genomic DNA and frozen lymphocytes from these 400 families; 4) to characterize the MHC contribution to predisposition to AS by DNA typing for HLA-B27 alleles, B60 and HLA-DRB1, DQA1 and DQB1 alleles; 5) to conduct a genome wide search using closely spaced microsatellite markers in sib pairs concordant and discordant for AS in the 400 Caucasian families; 6) to conduct microsatellite polymorphism analyses of non-MHC genes using multipoint analyses for fine mapping studies of genes linked to AS using transmission disequilibrium testing (TDT); and finally, 7) to study sequence variation of three to four candidate genes in 25 AS patients and 25 controls to identify the mutations an disease-relevant polymorphisms involved in AS.

尽管 HLA-B27 被认为是强直性脊柱炎 (AS) 发展的一个重要特征，但最近的研究表明，主要组织相容性复合体 (MHC) 内部和外部的其他基因和染色体区域与该疾病的发病机制有关。经计算，整个 MHC 的贡献仅为 31%。对英国同胞对的连锁分析显示了 8 个染色体区域，包括 MHC，有与 AS 相关的中等证据。 然而，这些区域中含有许多基因，而哪些是这些区域内真正的疾病易感基因尚未确定。 因此，该提案的具体目标是：1) 建立一个由拥有 AS 临床或基因研究最新记录（并因此建立的患者队列）的研究人员组成的联盟，该联盟以遍布北美的 10 个学术医疗中心（北美脊柱炎协会）为基础。 Consortium-NASC），以便从队列中识别出至少有两个兄弟姐妹符合纽约修订后的 AS 标准的家庭； 2) 来自美国脊柱炎协会（SAA）的会员，通过问卷调查、病历审查和盆腔X光检查来确定类似受影响的家庭并验证两组的诊断； 3) 从受影响和未受影响的同胞对以及（如果有）其父母收集 50 毫升血液，以便建立这 400 个家庭的血清、基因组 DNA 和冷冻淋巴细胞库； 4) 通过 HLA-B27 等位基因、B60 和 HLA-DRB1、DQA1 和 DQB1 等位基因的 DNA 分型来表征 MHC 对 AS 易感性的贡献； 5) 使用 400 个白人家族中 AS 一致和不一致的同胞对中间隔很近的微卫星标记进行全基因组搜索； 6) 使用多点分析对非 MHC 基因进行微卫星多态性分析，以便使用传递不平衡测试 (TDT) 对与 AS 相关的基因进行精细作图研究；最后，7) 研究 25 名 AS 患者和 25 名对照者中三到四个候选基因的序列变异，以确定与 AS 相关的突变和疾病相关多态性。

项目成果

Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci.

• DOI: 10.1038/ng.2667
• 发表时间: 2013-07
• 期刊: NATURE GENETICS
• 影响因子: 30.8
• 作者: Cortes, Adrian;Hadler, Johanna;Pointon, Jenny P.;Robinson, Philip C.;Karaderi, Tugce;Leo, Paul;Cremin, Katie;Pryce, Karena;Harris, Jessica;Lee, Seunghun;Joo, Kyung Bin;Shim, Seung-Cheol;Weisman, Michael;Ward, Michael;Zhou, Xiaodong;Garchon, Henri-Jean;Chiocchia, Gilles;Nossent, Johannes;Lie, Benedicte A.;Forre, Oystein;Tuomilehto, Jaakko;Laiho, Kari;Jiang, Lei;Liu, Yu;Wu, Xin;Bradbury, Linda A.;Elewaut, Dirk;Burgos-Vargas, Ruben;Stebbings, Simon;Appleton, Louise;Farrah, Claire;Lau, Jonathan;Kenna, Tony J.;Haroon, Nigil;Ferreira, Manuel A.;Yang, Jian;Mulero, Juan;Fernandez-Sueiro, Jose Luis;Gonzalez-Gay, Miguel A.;Lopez-Larrea, Carlos;Deloukas, Panos;Donnelly, Peter;Bowness, Paul;Gafney, Karl;Gaston, Hill;Gladman, Dafna D.;Rahman, Proton;Maksymowych, Walter P.;Xu, Huji;Crusius, J. Bart A.;van der Horst-Bruinsma, Irene E.;Chou, Chung-Tei;Valle-Onate, Raphael;Romero-Sanchez, Consuelo;Hansen, Inger Myrnes;Pimentel-Santos, Fernando M.;Inman, Robert D.;Videm, Vibeke;Martin, Javier;Breban, Maxime;Reveille, John D.;Evans, David M.;Kim, Tae-Hwan;Wordsworth, Bryan Paul;Brown, Matthew A.
• 通讯作者: Brown, Matthew A.

Polygenic Risk Scores have high diagnostic capacity in ankylosing spondylitis.

• DOI: 10.1136/annrheumdis-2020-219446
• 发表时间: 2021-09
• 期刊: Annals of the rheumatic diseases
• 影响因子: 27.4
• 作者: Li Z;Wu X;Leo PJ;De Guzman E;Akkoc N;Breban M;Macfarlane GJ;Mahmoudi M;Marzo-Ortega H;Anderson LK;Wheeler L;Chou CT;Harrison AA;Stebbings S;Jones GT;Bang SY;Wang G;Jamshidi A;Farhadi E;Song J;Lin L;Li M;Wei JC;Martin NG;Wright MJ;Lee M;Wang Y;Zhan J;Zhang JS;Wang X;Jin ZB;Weisman MH;Gensler LS;Ward MM;Rahbar MH;Diekman L;Kim TH;Reveille JD;Wordsworth BP;Xu H;Brown MA;TCRI AS Group
• 通讯作者: TCRI AS Group

Association of variants at 1q32 and STAT3 with ankylosing spondylitis suggests genetic overlap with Crohn's disease.

• DOI: 10.1371/journal.pgen.1001195
• 发表时间: 2010-12-02
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Danoy P;Pryce K;Hadler J;Bradbury LA;Farrar C;Pointon J;Australo-Anglo-American Spondyloarthritis Consortium;Ward M;Weisman M;Reveille JD;Wordsworth BP;Stone MA;Spondyloarthritis Research Consortium of Canada;Maksymowych WP;Rahman P;Gladman D;Inman RD;Brown MA
• 通讯作者: Brown MA

Is there a higher genetic load of susceptibility loci in familial ankylosing spondylitis?

• DOI: 10.1002/acr.21601
• 发表时间: 2012-05
• 期刊: ARTHRITIS CARE & RESEARCH
• 影响因子: 4.7
• 作者: Joshi, Reeti;Reveille, John D.;Brown, Matthew A.;Weisman, Michael H.;Ward, Michael M.;Gensler, Lianne S.;Wordsworth, B. Paul;Evans, David M.;Assassi, Shervin
• 通讯作者: Assassi, Shervin

Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants.

• DOI: 10.1038/ng.2007.17
• 发表时间: 2007-11
• 期刊: NATURE GENETICS
• 影响因子: 30.8
• 作者: Newport, Melanie;Sirugo, Giorgio;Lyons, Emily;Vannberg, Fredrik;Hill, Adrian V. S.;Bradbury, Linda A.;Farrar, Claire;Pointon, Jennifer J.;Wordsworth, Paul;Brown, Matthew A.;Franklyn, Jayne A.;Heward, Joanne M.;Simmonds, Matthew J.;Gough, Stephen C. L.;Seal, Sheila;Stratton, Michael R.;Rahman, Nazneen;Ban, Maria;Goris, An;Sawcer, Stephen J.;Compston, Alastair;Conway, David;Jallow, Muminatou;Newport, Melanie;Sirugo, Giorgio;Rockett, Kirk A.;Kwiatkowski, Dominic P.;Bumpstead, Suzannah J.;Chaney, Amy;Downes, Kate;Ghori, Mohammed J. R.;Gwilliam, Rhian;Hunt, Sarah E.;Inouye, Michael;Keniry, Andrew;King, Emma;McGinnis, Ralph;Potter, Simon;Ravindrarajah, Rathi;Whittaker, Pamela;Widden, Claire;Withers, David;Deloukas, Panos;Leung, Hin-Tak;Nutland, Sarah;Stevens, Helen E.;Walker, Neil M.;Todd, John A.;Easton, Doug;Clayton, David G.;Burton, Paul R.;Tobin, Martin D.;Barrett, Jeffrey C.;Evans, David M.;Morris, Andrew P.;Cardon, Lon R.;Cardin, Niall J.;Davison, Dan;Ferreira, Teresa;Pereira-Gale, Joanne;Hallgrimsdottir, Ingeleif B.;Howie, Bryan N.;Marchini, Jonathan L.;Spencer, Chris C. A.;Su, Zhan;Teo, Yik Ying;Vukcevic, Damjan;Donnelly, Peter;Bentley, David;Brown, Matthew A.;Cardon, Lon R.;Caulfield, Mark;Clayton, David G.;Compston, Alastair;Craddock, Nick;Deloukas, Panos;Donnelly, Peter;Farrall, Martin;Barton, Anne;Bruce, Ian N.;Donovan, Hannah;Eyre, Steve;Gilbert, Paul D.;Hilder, Samantha L.;Hinks, Anne M.;John, Sally L.;Potter, Catherine;Silman, Alan J.;Symmons, Deborah P. M.;Thomson, Wendy;Worthington, Jane;Gough, Stephen C. L.;Hall, Alistair S.;Hattersley, Andrew T.;Hill, Adrian V. S.;Kwiatkowski, Dominic P.;Matthew, Christopher G.;McCarthy, Mark I.;Ouwehand, Willem H.;Parkes, Miles;Pembrey, Marcus;Rahman, Nazneen;Samani, Nilesh J.;Stratton, Michael R.;Todd, John A.;Worthington, Jane;Mitchell, Sarah L.;Newby, Paul R.;Brand, Oliver J.;Carr-Smith, Jackie;Pearce, Simon H. S.;Gough, Stephen C. L.;McGinnis, R.;Keniry, A.;Deloukas, P.;Reveille, John D.;Zhou, Xiaodong;Bradbury, Linda A.;Sims, Anne-Marie;Dowling, Alison;Taylor, Jacqueline;Doan, Tracy;Cardon, Lon R.;Davis, John C.;Pointon, Jennifer J.;Savage, Laurie;Ward, Michael M.;Learch, Thomas L.;Weisman, Michael H.;Wordsworth, Paul;Brown, Matthew A.
• 通讯作者: Brown, Matthew A.