Genome-wide Association Study of Ankylosing Spondylitis Identifies Non-MHC Susceptibility Loci

Overview

Journal Nat Genet

Specialty Genetics

Date 2010 Jan 12

PMID 20062062

Citations 293

Authors

John D Reveille

Anne-Marie Sims

Patrick Danoy

David M Evans

Paul Leo

Jennifer J Pointon

Rui Jin

Xiaodong Zhou

Linda A Bradbury

Louise H Appleton

John C Davis

Laura Diekman

Tracey Doan

Alison Dowling

Ran Duan

Emma L Duncan

Claire Farrar

Johanna Hadler

David Harvey

Tugce Karaderi

Rebecca Mogg

Emma Pomeroy

Karena Pryce

Jacqueline Taylor

Laurie Savage

Panos Deloukas

Vasudev Kumanduri

Leena Peltonen

Sue M Ring

Pamela Whittaker

Evgeny Glazov

Gethin P Thomas

Walter P Maksymowych

Robert D Inman

Michael M Ward

Millicent A Stone

Michael H Weisman

B Paul Wordsworth

Matthew A Brown

Affiliations

Soon will be listed here.

Abstract

To identify susceptibility loci for ankylosing spondylitis, we undertook a genome-wide association study in 2,053 unrelated ankylosing spondylitis cases among people of European descent and 5,140 ethnically matched controls, with replication in an independent cohort of 898 ankylosing spondylitis cases and 1,518 controls. Cases were genotyped with Illumina HumHap370 genotyping chips. In addition to strong association with the major histocompatibility complex (MHC; P < 10(-800)), we found association with SNPs in two gene deserts at 2p15 (rs10865331; combined P = 1.9 x 10(-19)) and 21q22 (rs2242944; P = 8.3 x 10(-20)), as well as in the genes ANTXR2 (rs4333130; P = 9.3 x 10(-8)) and IL1R2 (rs2310173; P = 4.8 x 10(-7)). We also replicated previously reported associations at IL23R (rs11209026; P = 9.1 x 10(-14)) and ERAP1 (rs27434; P = 5.3 x 10(-12)). This study reports four genetic loci associated with ankylosing spondylitis risk and identifies a major role for the interleukin (IL)-23 and IL-1 cytokine pathways in disease susceptibility.

Citing Articles

Genetic Risk of Ankylosing Spondylitis and Second-Line Therapy Need in Crohn's Disease: A Mendelian Randomization Study.

Omar M, Omar M, Patt Y, Ukashi O, Sharif Y, Lahat A J Clin Med. 2025; 13(24.

PMID: 39768419 PMC: 11678710. DOI: 10.3390/jcm13247496.

A guideline on biomarkers in the diagnosis and evaluation in axial spondyloarthritis.

Liu D, Xie Y, Tu L, Wen X, Lv Q, Liu B Front Immunol. 2024; 15:1394148.

PMID: 39539543 PMC: 11557325. DOI: 10.3389/fimmu.2024.1394148.

Precision medicine in axial spondyloarthritis: current opportunities and future perspectives.

So J, Tam L Ther Adv Musculoskelet Dis. 2024; 16:1759720X241284869.

PMID: 39376594 PMC: 11457172. DOI: 10.1177/1759720X241284869.

Environmental and Genetic Determinants of Ankylosing Spondylitis.

Bilski R, Kaminski P, Kupczyk D, Jeka S, Baszynski J, Tkaczenko H Int J Mol Sci. 2024; 25(14).

PMID: 39063056 PMC: 11277374. DOI: 10.3390/ijms25147814.

Exploring the Pathogenesis of Spondylarthritis beyond HLA-B27: A Descriptive Review.

Nagit R, Rezus E, Cianga P Int J Mol Sci. 2024; 25(11).

PMID: 38892265 PMC: 11172491. DOI: 10.3390/ijms25116081.

References

Laval S, Timms A, Edwards S, Bradbury L, Brophy S, Milicic A . Whole-genome screening in ankylosing spondylitis: evidence of non-MHC genetic-susceptibility loci. Am J Hum Genet. 2001; 68(4):918-26. PMC: 1275646. DOI: 10.1086/319509. View

Goto Y, Tanji H, Hattori A, Tsujimoto M . Glutamine-181 is crucial in the enzymatic activity and substrate specificity of human endoplasmic-reticulum aminopeptidase-1. Biochem J. 2008; 416(1):109-16. DOI: 10.1042/BJ20080965. View

Mielants H, Veys E, Cuvelier C, De Vos M, Goemaere S, De Clercq L . The evolution of spondyloarthropathies in relation to gut histology. II. Histological aspects. J Rheumatol. 1995; 22(12):2273-8. View

Burton P, Clayton D, Cardon L, Craddock N, Deloukas P, Duncanson A . Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet. 2007; 39(11):1329-37. PMC: 2680141. DOI: 10.1038/ng.2007.17. View

Kugathasan S, Baldassano R, Bradfield J, Sleiman P, Imielinski M, Guthery S . Loci on 20q13 and 21q22 are associated with pediatric-onset inflammatory bowel disease. Nat Genet. 2008; 40(10):1211-5. PMC: 2770437. DOI: 10.1038/ng.203. View

van der Linden S, VALKENBURG H, Cats A . The risk of developing ankylosing spondylitis in HLA-B27 positive individuals: a family and population study. Br J Rheumatol. 1983; 22(4 Suppl 2):18-9. DOI: 10.1093/rheumatology/xxii.suppl_2.18. View

Braun J, Bollow M, Remlinger G, Eggens U, Rudwaleit M, Distler A . Prevalence of spondylarthropathies in HLA-B27 positive and negative blood donors. Arthritis Rheum. 1998; 41(1):58-67. DOI: 10.1002/1529-0131(199801)41:1<58::AID-ART8>3.0.CO;2-G. View

Devlin B, Roeder K . Genomic control for association studies. Biometrics. 2001; 55(4):997-1004. DOI: 10.1111/j.0006-341x.1999.00997.x. View

Calin A, Marder A, Becks E, Burns T . Genetic differences between B27 positive patients with ankylosing spondylitis and B27 positive healthy controls. Arthritis Rheum. 1983; 26(12):1460-4. DOI: 10.1002/art.1780261207. View

10.

Armaka M, Apostolaki M, Jacques P, Kontoyiannis D, Elewaut D, Kollias G . Mesenchymal cell targeting by TNF as a common pathogenic principle in chronic inflammatory joint and intestinal diseases. J Exp Med. 2008; 205(2):331-7. PMC: 2271010. DOI: 10.1084/jem.20070906. View

11.

Cui X, Rouhani F, Hawari F, Levine S . Shedding of the type II IL-1 decoy receptor requires a multifunctional aminopeptidase, aminopeptidase regulator of TNF receptor type 1 shedding. J Immunol. 2003; 171(12):6814-9. DOI: 10.4049/jimmunol.171.12.6814. View

12.

Cui X, Hawari F, Alsaaty S, Lawrence M, Combs C, Geng W . Identification of ARTS-1 as a novel TNFR1-binding protein that promotes TNFR1 ectodomain shedding. J Clin Invest. 2002; 110(4):515-26. PMC: 150410. DOI: 10.1172/JCI13847. View

13.

Brown M, Kennedy L, MacGregor A, Darke C, Duncan E, Shatford J . Susceptibility to ankylosing spondylitis in twins: the role of genes, HLA, and the environment. Arthritis Rheum. 1997; 40(10):1823-8. DOI: 10.1002/art.1780401015. View

14.

Taft R, Glazov E, Cloonan N, Simons C, Stephen S, Faulkner G . Tiny RNAs associated with transcription start sites in animals. Nat Genet. 2009; 41(5):572-8. DOI: 10.1038/ng.312. View

15.

Dixon A, Liang L, Moffatt M, Chen W, Heath S, Wong K . A genome-wide association study of global gene expression. Nat Genet. 2007; 39(10):1202-7. DOI: 10.1038/ng2109. View

16.

Lappalainen M, Halme L, Turunen U, Saavalainen P, Einarsdottir E, Farkkila M . Association of IL23R, TNFRSF1A, and HLA-DRB1*0103 allele variants with inflammatory bowel disease phenotypes in the Finnish population. Inflamm Bowel Dis. 2008; 14(8):1118-24. DOI: 10.1002/ibd.20431. View

17.

Brown M, Laval S, Brophy S, Calin A . Recurrence risk modelling of the genetic susceptibility to ankylosing spondylitis. Ann Rheum Dis. 2000; 59(11):883-6. PMC: 1753017. DOI: 10.1136/ard.59.11.883. View

18.

Waschke K, Villani A, Vermeire S, Dufresne L, Chen T, Bitton A . Tumor necrosis factor receptor gene polymorphisms in Crohn's disease: association with clinical phenotypes. Am J Gastroenterol. 2005; 100(5):1126-33. DOI: 10.1111/j.1572-0241.2005.40534.x. View