Common variants in the HLA-DQ region confer susceptibility to idiopathic achalasia

被引：83

作者：

Gockel, Ines ^{[1
]}

Becker, Jessica ^{[2
,3
]}

Wouters, Mira M. ^{[4
]}

Niebisch, Stefan ^{[1
]}

Gockel, Henning R. ^{[1
]}

Hess, Timo ^{[2
,3
]}

Ramonet, David ^{[5
]}

Zimmermann, Julian ^{[5
]}

Vigo, Ana Gonzalez ^{[6
]}

Trynka, Gosia ^{[7
]}

de Leon, Antonio Ruiz ^{[8
]}

de la Serna, Julio Perez ^{[8
]}

Urcelay, Elena ^{[6
]}

Kumar, Vinod ^{[7
]}

Franke, Lude ^{[7
]}

Westra, Harm-Jan ^{[7
]}

Drescher, Daniel ^{[1
]}

Kneist, Werner ^{[1
]}

Marquardt, Jens U. ^{[9
]}

Galle, Peter R. ^{[9
]}

Mattheisen, Manuel ^{[10
,11
]}

Annese, Vito ^{[12
]}

Latiano, Anna ^{[13
]}

Fumagalli, Uberto ^{[14
]}

Laghi, Luigi ^{[15
]}

Cuomo, Rosario ^{[16
]}

Sarnelli, Giovanni ^{[16
]}

Mueller, Michaela ^{[17
]}

Eckardt, Alexander J. ^{[17
]}

Tack, Jan ^{[4
]}

Hoffmann, Per ^{[2
,3
,18
,19
]}

Herms, Stefan ^{[2
,3
,18
,19
]}

Mangold, Elisabeth ^{[2
,3
]}

Heilmann, Stefanie ^{[2
,3
]}

Kiesslich, Ralf ^{[20
]}

von Rahden, Burkhard H. A. ^{[21
]}

Allescher, Hans-Dieter ^{[22
]}

Schulz, Henning G. ^{[23
]}

Wijmenga, Cisca ^{[7
]}

Heneka, Michael T. ^{[5
]}

Lang, Hauke ^{[1
]}

Hopfner, Karl-Peter ^{[24
,25
]}

Noethen, Markus M. ^{[2
,3
]}

Boeckxstaens, Guy E. ^{[4
]}

de Bakker, Paul I. W. ^{[26
,27
]}

Knapp, Michael ^{[28
]}

Schumacher, Johannes ^{[2
,3
]}

机构：

[1] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Dept Gen, Visceral & Transplant Surg, Mainz, Germany

[2] Univ Bonn, Inst Human Genet, Bonn, Germany

[3] Univ Bonn, Dept Gen Life & Brain Ctr, Bonn, Germany

[4] Catholic Univ Louvain, Translat Res Ctr Gastrointestinal Disorders, Leuven, Belgium

[5] Univ Bonn, Dept Neurol, Div Clin Neurosci, Bonn, Germany

[6] Hosp Clin San Carlos IDISSC, Inst Invest Sanitaria, Dept Immunol, Madrid, Spain

[7] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands

[8] Hosp Clin San Carlos IDISSC, Inst Invest Sanitaria, Dept Gastroenterol, Madrid, Spain

[9] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Dept Internal Med 1, D-55122 Mainz, Germany

[10] Aarhus Univ, Dept Biomed, Aarhus, Denmark

[11] Aarhus Univ, Ctr Integrat Sequencing ISEQ, Aarhus, Denmark

[12] Univ Florence, Careggi Hosp, Dept Gastroenterol, Florence, Italy

[13] Casa Sollievo Sofferenza Hosp, Ist Ric Cura & Carattere Sci, Div Gastroenterol, San Giovanni Rotondo, Italy

[14] Ist Clin Humanitas, Ist Ric Cura & Carattere Sci, Dept Surg, Milan, Italy

[15] Ist Clin Humanitas, Ist Ric Cura & Carattere Sci, Div Gastroenterol, Milan, Italy

[16] Federico II Univ Hosp, Sch Med, Dept Clin Med & Surg, Div Gastroenterol, Naples, Italy

[17] German Diagnost Clin, Dept Gastroenterol, Wiesbaden, Germany

[18] Univ Basel Hosp, Div Med Genet, CH-4031 Basel, Switzerland

[19] Univ Basel, Dept Biomed, Human Genet Res Grp, Basel, Switzerland

[20] Hosp St Marien, Dept Internal Med, Frankfurt, Germany

[21] Univ Wurzburg, Dept Gen Visceral Vasc & Pediat Surg, D-97070 Wurzburg, Germany

[22] Hosp Garmisch Partenkirchen, Ctr Internal Med, Garmisch Partenkirchen, Germany

[23] Protestant Hosp Castrop Rauxel, Dept Gen & Abdominal Surg, Castrop Rauxel, Germany

[24] Univ Munich, Gene Ctr, Dept Biochem, Munich, Germany

[25] Ctr Integrated Prot Sci, Munich, Germany

[26] Univ Med Ctr Utrecht, Dept Epidemiol, Utrecht, Netherlands

[27] Univ Med Ctr Utrecht, Ctr Mol Med, Dept Med Genet, Utrecht, Netherlands

[28] Univ Bonn, Inst Med Biometry Informat & Epidemiol, Bonn, Germany

来源：

NATURE GENETICS | 2014年 / 46卷 / 08期

关键词：

MHC; ASSOCIATION; INSIGHTS;

D O I：

10.1038/ng.3029

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Idiopathic achalasia is characterized by a failure of the lower esophageal sphincter to relax due to a loss of neurons in the myenteric plexus(1,2). This ultimately leads to massive dilatation and an irreversibly impaired megaesophagus. We performed a genetic association study in 1,068 achalasia cases and 4,242 controls and fine-mapped a strong MHC association signal by imputing classical HLA haplotypes and amino acid polymorphisms. An eight-residue insertion at position 227-234 in the cytoplasmic tail of HLA-DQ beta 1 (encoded by HLA-DQB1*05:03 and HLA-DQB1*06:01) confers the strongest risk for achalasia (P = 1.73 x 10(-19)). In addition, two amino acid substitutions in the. extracellular domain of HLA-DQ alpha 1 at position 41 (lysine encoded by HLA-DQA1*01:03; P = 5.60 x 10(-10)) and of HLA-DQ beta 1 at position 45 (glutamic acid encoded by HLA-DQB1*03:01 and HLA-DQB1*03:04; P = 1.20 x 10(-9)) independently confer achalasia risk. Our study implies that immune-mediated processes are involved in the pathophysiology of achalasia.

引用

页码：901 / 904

页数：4

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