Functional IL6R 358Ala allele impairs classical IL-6 receptor signaling and influences risk of diverse inflammatory diseases.
Functional IL6R 358Ala allele impairs classical IL-6 receptor signaling and influences risk of diverse inflammatory diseases.
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DOI：
10.1371/journal.pgen.1003444
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发表时间：
2013-04
期刊：
影响因子：
4.5
通讯作者：
Todd JA
中科院分区：
文献类型：
--
作者：
Ferreira RC;Freitag DF;Cutler AJ;Howson JM;Rainbow DB;Smyth DJ;Kaptoge S;Clarke P;Boreham C;Coulson RM;Pekalski ML;Chen WM;Onengut-Gumuscu S;Rich SS;Butterworth AS;Malarstig A;Danesh J;Todd JA
炎症由白介素6(IL-6)信号直接调节，与多种慢性疾病的病因有关。尽管IL-6受体基因中一个常见的非同义变异(IL6R Asp358Ala；rs2228145 A>；C)与几种常见疾病的风险相关，358Ala等位基因赋予对冠心病(CHD)、类风湿性关节炎(RA)、房颤(AF)、腹主动脉瘤(AAA)的保护作用，并增加对哮喘的易感性，但该变异对IL-6信号转导的影响尚不清楚。在这里，我们提供了在两个独立的人群中这种非同义变异与1型糖尿病(T1D)风险相关的证据，并确认rs2228145是循环中可溶性IL-6R(sIL-6R)水平的主要决定因素(微小等位基因358Ala的每拷贝sIL-6R增加34.6%；rs2228145[C])。为了进一步研究这种变异的分子机制，我们分析了来自剑桥生物资源中心的128名志愿者外周血单个核细胞(PBMC)中IL-6R的表达。我们证明，尽管358Ala增加了可溶性IL6R异构体(P = 8.3x10−22)的转录，而不是膜结合异构体，但358Ala降低了CD4+T细胞和单核细胞表面IL-6R的表达(每个等位基因最多减少28%；P≤5.6x10−22)。重要的是，膜结合的IL-6R的表达减少导致IL-6的反应性减弱，表现为转录因子STAT3和STAT1在IL-6刺激下的磷酸化降低(P≤5.2×10−7)。我们的发现阐明了IL-6R对IL-6信号的调节，这与几种复杂的疾病有因果关系，确定了针对IL-6/IL-6R轴的新方法的机制，并预测了基于这种常见的IL-6R变体的IL-6治疗的不同治疗反应。白介素6(IL-6)是一种复杂的细胞因子，在炎症反应的调节中起着关键作用。IL-6受体基因的遗传变异与几种含有炎症成分的人类疾病的风险有关，包括冠心病、类风湿性关节炎和哮喘。该基因的一个常见的非同义单核苷酸多态(Asp358Ala)可能是该区域的致病变异，其原因是影响循环中可溶性白介素6R(sIL-6R)的浓度。在这项研究中，我们将该变异体的遗传关联扩展到1型糖尿病，并提供证据表明，该变异体通过调节sIL-6R(通过切割表面受体和选择性剪接可溶性IL-6R亚型而产生)和膜结合的IL-6R之间的平衡来发挥其作用机制。这些数据首次表明，这种非同义变体(Ala358)的次要等位基因直接控制单个免疫细胞上IL-6R的表面水平，并且这些蛋白水平的差异转化为IL-6R信号的功能障碍。这些发现可能对针对涉及IL-6R信号通路的炎症机制的临床试验具有指导意义，并可能为确定从IL-6R信号通路的治疗干预中获得特定益处的患者提供工具。
Inflammation, which is directly regulated by interleukin-6 (IL-6) signaling, is implicated in the etiology of several chronic diseases. Although a common, non-synonymous variant in the IL-6 receptor gene (IL6R Asp358Ala; rs2228145 A>C) is associated with the risk of several common diseases, with the 358Ala allele conferring protection from coronary heart disease (CHD), rheumatoid arthritis (RA), atrial fibrillation (AF), abdominal aortic aneurysm (AAA), and increased susceptibility to asthma, the variant's effect on IL-6 signaling is not known. Here we provide evidence for the association of this non-synonymous variant with the risk of type 1 diabetes (T1D) in two independent populations and confirm that rs2228145 is the major determinant of the concentration of circulating soluble IL-6R (sIL-6R) levels (34.6% increase in sIL-6R per copy of the minor allele 358Ala; rs2228145 [C]). To further investigate the molecular mechanism of this variant, we analyzed expression of IL-6R in peripheral blood mononuclear cells (PBMCs) in 128 volunteers from the Cambridge BioResource. We demonstrate that, although 358Ala increases transcription of the soluble IL6R isoform (P = 8.3×10−22) and not the membrane-bound isoform, 358Ala reduces surface expression of IL-6R on CD4+ T cells and monocytes (up to 28% reduction per allele; P≤5.6×10−22). Importantly, reduced expression of membrane-bound IL-6R resulted in impaired IL-6 responsiveness, as measured by decreased phosphorylation of the transcription factors STAT3 and STAT1 following stimulation with IL-6 (P≤5.2×10−7). Our findings elucidate the regulation of IL-6 signaling by IL-6R, which is causally relevant to several complex diseases, identify mechanisms for new approaches to target the IL-6/IL-6R axis, and anticipate differences in treatment response to IL-6 therapies based on this common IL6R variant. Interleukin-6 (IL-6) is a complex cytokine, which plays a critical role in the regulation of inflammatory responses. Genetic variation in the IL-6 receptor gene is associated with the risk of several human diseases with an inflammatory component, including coronary heart disease, rheumatoid arthritis, and asthma. A common non-synonymous single nucleotide polymorphism in this gene (Asp358Ala) has been suggested to be the causal variant in this region by affecting the circulatory concentrations of soluble IL-6R (sIL-6R). In this study we extend the genetic association of this variant to type 1 diabetes and provide evidence that this variant exerts its functional mechanism by regulating the balance between sIL-6R (generated through cleavage of the surface receptor and by alternative splicing of a soluble IL6R isoform) and membrane-bound IL-6R. These data show for the first time that the minor allele of this non-synonymous variant (Ala358) directly controls the surface levels of IL-6R on individual immune cells and that these differences in protein levels translate into a functional impairment in IL-6R signaling. These findings may have implications for clinical trials targeting inflammatory mechanisms involving IL-6R signaling and may provide tools for identifying patients with specific benefit from therapeutic intervention in the IL-6R signaling pathway.
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影响因子：
168.9
作者：
Ferreira, Manuel A. R.;Matheson, Melanie C.;Duffy, David L.;Marks, Guy B.;Hui, Jennie;Le Souef, Peter;Danoy, Patrick;Baltic, Svetlana;Nyholt, Dale R.;Jenkins, Mark;Hayden, Catherine;Willemsen, Gonneke;Ang, Wei;Kuokkanen, Mikko;Beilby, John;Cheah, Faang;de Geus, Eco J. C.;Ramasamy, Adaikalavan;Vedantam, Sailaja;Salomaa, Veikko;Madden, Pamela A.;Heath, Andrew C.;Hopper, John L.;Visscher, Peter M.;Musk, Bill;Leeder, Stephen R.;Jarvelin, Marjo-Riitta;Pennell, Craig;Boomsma, Dorret I.;Hirschhorn, Joel N.;Walters, Haydn;Martin, Nicholas G.;James, Alan;Jones, Graham;Abramson, Michael J.;Robertson, Colin F.;Dharmage, Shyamali C.;Brown, Matthew A.;Montgomery, Grant W.;Thompson, Philip J.
通讯作者：
Thompson, Philip J.
影响因子：
15.8
作者：
Danesh, John;Kaptoge, Stephen;Mann, Andrea G.;Sarwar, Nadeem;Wood, Angela;Angleman, Sara B.;Wensley, Frances;Higgins, Julian P. T.;Lennon, Lucy;Eiriksdottir, Gudny;Rumley, Ann;Whincup, Peter H.;Lowe, Gordon D. O.;Gudnason, Vilmundur
通讯作者：
Gudnason, Vilmundur
影响因子：
7.7
作者：
Howson, Joanna M. M.;Stevens, Helen;Todd, John A.
通讯作者：
Todd, John A.
影响因子：
30.8
作者：
Deloukas, Panos;Kanoni, Stavroula;Willenborg, Christina;Farrall, Martin;Assimes, Themistocles L.;Thompson, John R.;Ingelsson, Erik;Saleheen, Danish;Erdmann, Jeanette;Goldstein, Benjamin A.;Stirrups, Kathleen;Koenig, Inke R.;Cazier, Jean-Baptiste;Johansson, Asa;Hall, Alistair S.;Lee, Jong-Young;Willer, Cristen J.;Chambers, John C.;Esko, Tonu;Folkersen, Lasse;Goel, Anuj;Grundberg, Elin;Havulinna, Aki S.;Ho, Weang K.;Hopewell, Jemma C.;Eriksson, Niclas;Kleber, Marcus E.;Kristiansson, Kati;Lundmark, Per;Lyytikainen, Leo-Pekka;Rafelt, Suzanne;Shungin, Dmitry;Strawbridge, Rona J.;Thorleifsson, Gudmar;Tikkanen, Emmi;Van Zuydam, Natalie;Voight, Benjamin F.;Waite, Lindsay L.;Zhang, Weihua;Ziegler, Andreas;Absher, Devin;Altshuler, David;Balmforth, Anthony J.;Barroso, Ines;Braund, Peter S.;Burgdorf, Christof;Claudi-Boehm, Simone;Cox, David;Dimitriou, Maria;Do, Ron;Doney, Alex S. F.;El Mokhtari, NourEddine;Eriksson, Per;Fischer, Krista;Fontanillas, Pierre;Franco-Cereceda, Anders;Gigante, Bruna;Groop, Leif;Gustafsson, Stefan;Hager, Joerg;Hallmans, Goran;Han, Bok-Ghee;Hunt, Sarah E.;Kang, Hyun M.;Illig, Thomas;Kessler, Thorsten;Knowles, Joshua W.;Kolovou, Genovefa;Kuusisto, Johanna;Langenberg, Claudia;Langford, Cordelia;Leander, Karin;Lokki, Marja-Liisa;Lundmark, Anders;McCarthy, Mark I.;Meisinger, Christa;Melander, Olle;Mihailov, Evelin;Maouche, Seraya;Morris, Andrew D.;Mueller-Nurasyid, Martina;Nikus, Kjell;Peden, John F.;Rayner, N. William;Rasheed, Asif;Rosinger, Silke;Rubin, Diana;Rumpf, Moritz P.;Schaefer, Arne;Sivananthan, Mohan;Song, Ci;Stewart, Alexandre F. R.;Tan, Sian-Tsung;Thorgeirsson, Gudmundur;van der Schoot, C. Ellen;Wagner, Peter J.;Wells, George A.;Wild, Philipp S.;Yang, Tsun-Po;Amouyel, Philippe;Arveiler, Dominique;Basart, Hanneke;Boehnke, Michael;Boerwinkle, Eric;Brambilla, Paolo;Cambien, Francois;Cupples, Adrienne L.;de Faire, Ulf;Dehghan, Abbas;Diemert, Patrick;Epstein, Stephen E.;Evans, Alun;Ferrario, Marco M.;Ferrieres, Jean;Gauguier, Dominique;Go, Alan S.;Goodall, Alison H.;Gudnason, Villi;Hazen, Stanley L.;Holm, Hilma;Iribarren, Carlos;Jang, Yangsoo;Kahonen, Mika;Kee, Frank;Kim, Hyo-Soo;Klopp, Norman;Koenig, Wolfgang;Kratzer, Wolfgang;Kuulasmaa, Kari;Laakso, Markku;Laaksonen, Reijo;Lee, Ji-Young;Lind, Lars;Ouwehand, Willem H.;Parish, Sarah;Park, Jeong E.;Pedersen, Nancy L.;Peters, Annette;Quertermous, Thomas;Rader, Daniel J.;Salomaa, Veikko;Schadt, Eric;Shah, Svati H.;Sinisalo, Juha;Stark, Klaus;Stefansson, Kari;Tregouet, David-Alexandre;Virtamo, Jarmo;Wallentin, Lars;Wareham, Nicholas;Zimmermann, Martina E.;Nieminen, Markku S.;Hengstenberg, Christian;Sandhu, Manjinder S.;Pastinen, Tomi;Syvanen, Ann-Christine;Hovingh, G. Kees;Dedoussis, George;Franks, Paul W.;Lehtimaki, Terho;Metspalu, Andres;Zalloua, Pierre A.;Siegbahn, Agneta;Schreiber, Stefan;Ripatti, Samuli;Blankenberg, Stefan S.;Perola, Markus;Clarke, Robert;Boehm, Bernhard O.;O'Donnell, Christopher;Reilly, Muredach P.;Maerz, Winfried;Collins, Rory;Kathiresan, Sekar;Hamsten, Anders;Kooner, Jaspal S.;Thorsteinsdottir, Unnur;Danesh, John;Palmer, Colin N. A.;Roberts, Robert;Watkins, Hugh;Schunkert, Heribert;Samani, Nilesh J.
通讯作者：
Samani, Nilesh J.
影响因子：
4.4
作者：
Briso, Eva M.;Dienz, Oliver;Rincon, Mercedes
通讯作者：
Rincon, Mercedes