A Variant in MCF2L Is Associated with Osteoarthritis

被引：98

作者：

Day-Williams, Aaron G. ^{[1
]}

Southam, Lorraine ^{[1
,2
]}

Panoutsopoulou, Kalliope ^{[1
]}

Rayner, Nigel W. ^{[2
]}

Esko, Tonu ^{[3
,4
,5
]}

Estrada, Karol ^{[6
,7
]}

Helgadottir, Hafdis T. ^{[8
]}

Hofman, Albert ^{[9
]}

Ingvarsson, Throvaldur ^{[10
,11
]}

Jonsson, Helgi ^{[11
,12
]}

Keis, Aime ^{[13
,14
]}

Kerkhof, Hanneke J. M. ^{[6
,7
]}

Thorleifsson, Gudmar ^{[8
]}

Arden, Nigel K. ^{[15
,16
]}

Carr, Andrew ^{[17
]}

Chapman, Kay ^{[17
]}

Deloukas, Panos ^{[1
]}

Loughlin, John ^{[18
]}

McCaskie, Andrew ^{[18
,19
]}

Ollier, William E. R. ^{[20
]}

Ralston, Stuart H. ^{[21
]}

Spector, Timothy D. ^{[22
]}

Wallis, Gillian A. ^{[23
]}

Wilkinson, J. Mark ^{[24
,25
]}

Aslam, Nadim ^{[26
]}

Birell, Fraser ^{[18
,27
]}

Carluke, Ian ^{[27
]}

Joseph, John

Rai, Ashok ^{[28
]}

Reed, Mike ^{[27
]}

Walker, Kirsten ^{[27
]}

Doherty, Sally A. ^{[29
]}

Jonsdottir, Ingileif ^{[8
,11
]}

Maciewicz, Rose A. ^{[30
]}

Muir, Kenneth R. ^{[31
]}

Metspalu, Andres ^{[3
,4
,5
]}

Rivadeneira, Fernando ^{[6
,7
,9
]}

Stefansson, Kari ^{[8
,11
]}

Styrkarsdottir, Unnur ^{[8
]}

Uitterlinden, Andre G. ^{[6
,7
,9
]}

van Meurs, Joyce B. J. ^{[6
,7
]}

Zhang, Weiya ^{[29
]}

Valdes, Ana M. ^{[22
]}

Doherty, Michael ^{[29
]}

Zeggini, Eleftheria ^{[1
]}

机构：

[1] Wellcome Trust Sanger Inst, Hinxton CB10 1HH, Essex, England

[2] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England

[3] Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia

[4] Univ Tartu, Inst Mol & Cell Biol, EE-51010 Tartu, Estonia

[5] Estonian Bioctr, EE-51010 Tartu, Estonia

[6] Erasmus MC, Dept Internal Med, NL-3000 DR Rotterdam, Netherlands

[7] Netherlands Consortium Healthy Aging, Netherlands Genom Initiat, NL-2300 RC Leiden, Netherlands

[8] deCODE Genet, IS-101 Reykjavik, Iceland

[9] Erasmus MC, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands

[10] Univ Akureyri, Dept Hlth Sci, IS-600 Akureyri, Iceland

[11] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland

[12] Landspitali Univ Hosp, Dept Med, IS-101 Reykjavik, Iceland

[13] Univ Tartu, Dept Publ Hlth, EE-51010 Tartu, Estonia

[14] Elva Hosp, EE-61501 Elva, Estonia

[15] Univ Oxford, Natl Inst Hlth Res, Biomed Res Unit, Oxford OX3 7LD, England

[16] Univ Southampton, Epidemiol Resource Ctr, MRC, Southampton SO16 7LB, Hants, England

[17] Univ Oxford, Nuffield Dept Orthopaed Rheumatol & Musculoskelet, Oxford OX3 7LD, England

[18] Newcastle Univ, Musculoskeletal Res Grp, Inst Cellular Med, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England

[19] Newcastle Upon Tyne Hosp NHS Trust Fdn, Freeman Hosp, Newcastle Upon Tyne NE7 7DN, Tyne & Wear, England

[20] Univ Manchester, Ctr Integrated Genom Med Res, Manchester M13 9PT, Lancs, England

[21] Univ Edinburgh, Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland

[22] Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England

[23] Univ Manchester, Wellcome Trust Ctr Cell Matrix Res, Manchester M13 9PT, Lancs, England

[24] Univ Sheffield, Dept Human Metab, Acad Unit Bone Metab, Sheffield S5 7AU, S Yorkshire, England

[25] No Gen Hosp, Ctr Biomed Res, Sheffield NIHR Bone Biomed Res Unit, Sheffield S5 7AU, S Yorkshire, England

[26] Worcestershire Acute Hosp NHS Trust, Dept Orthopaed, Worcester WR5 1DD, Worcs, England

[27] Northumbria Healthcare NHS Fdn Trust, Wansbeck Gen Hosp, Ashington NE63 9JJ, Northumberland, England

[28] Worcestershire Acute Hosp NHS Trust, Dept Rheumatol, Worcester WR5 1DD, Worcs, England

[29] Univ Nottingham, Nottingham NG5 1PB, England

[30] AstraZeneca, Charnwood R&D, Resp & Inflammat Res Area, Loughborough LE11 5RH, Leics, England

[31] Univ Warwick, Warwick Med Sch, Hlth Sci Res Inst, Coventry CV4 7AL, W Midlands, England

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2011年 / 89卷 / 03期

关键词：

GENOME-WIDE ASSOCIATION; MISSING HERITABILITY; KNEE; METAANALYSIS; IMPUTATION; GENOTYPES; PROJECT; GDF5; PAIN;

D O I：

10.1016/j.ajhg.2011.08.001

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Osteoarthritis (OA) is a prevalent, heritable degenerative joint disease with a substantial public health impact. We used a 1000-Genomes-Project-based imputation in a genome-wide association scan for osteoarthritis (3177 OA cases and 4894 controls) to detect a previously unidentified risk locus. We discovered a small disease-associated set of variants on chromosome 13. Through large-scale replication, we establish a robust association with SNPs in MCF2L (rs11842874, combined odds ratio [95% confidence interval] 1.17 [1.11-1.23], p = 2.1 x 10(-8)) across a total of 19,041 OA cases and 24,504 controls of European descent. This risk locus represents the third established signal for OA overall. MCF2L regulates a nerve growth factor (NGF), and treatment with a humanized monoclonal antibody against NGF is associated with reduction in pain and improvement in function for knee OA patients.

引用

页码：446 / 450

页数：5

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