Association of Variants at 1q32 and with Ankylosing Spondylitis Suggests Genetic Overlap with Crohn's Disease

English version České info

Ankylosing spondylitis (AS) is a common inflammatory arthritic condition. Overt inflammatory bowel disease (IBD) occurs in about 10% of AS patients, and in addition 70% of AS cases may have subclinical terminal ileitis. Spondyloarthritis is also common in IBD patients. We therefore tested Crohn's disease susceptibility genes for association with AS, aiming to identify pleiotropic genetic associations with both diseases. Genotyping was carried out using Sequenom and Applied Biosystems TaqMan and OpenArray technologies on 53 markers selected from 30 Crohn's disease associated genomic regions. We tested genotypes in a population of unrelated individual cases (n = 2,773) and controls (n = 2,215) of white European ancestry for association with AS. Statistical analysis was carried out using a Cochran-Armitage test for trend in PLINK. Strong association was detected at chr1q32 near KIF21B (rs11584383, P = 1.6×10⁻¹⁰, odds ratio (OR) = 0.74, 95% CI:0.68–0.82). Association with disease was also detected for 2 variants within STAT3 (rs6503695, P = 4.6×10⁻⁴. OR = 0.86 (95% CI:0.79–0.93); rs744166, P = 2.6×10⁻⁵, OR = 0.84 (95% CI:0.77–0.91)). Association was confirmed for IL23R (rs11465804, P = 1.2×10⁻⁵, OR = 0.65 (95% CI:0.54–0.79)), and further associations were detected for IL12B (rs10045431, P = 5.2×10⁻⁵, OR = 0.83 (95% CI:0.76–0.91)), CDKAL1 (rs6908425, P = 1.1×10⁻⁴, OR = 0.82 (95% CI:0.74–0.91)), LRRK2/MUC19 (rs11175593, P = 9.9×10⁻⁵, OR = 1.92 (95% CI: 1.38–2.67)), and chr13q14 (rs3764147, P = 5.9×10⁻⁴, OR = 1.19 (95% CI: 1.08–1.31)). Excluding cases with clinical IBD did not significantly affect these findings. This study identifies chr1q32 and STAT3 as ankylosing spondylitis susceptibility loci. It also further confirms association for IL23R and detects suggestive association with another 4 loci. STAT3 is a key signaling molecule within the Th17 lymphocyte differentiation pathway and further enhances the case for a major role of this T-lymphocyte subset in ankylosing spondylitis. Finally these findings suggest common aetiopathogenic pathways for AS and Crohn's disease and further highlight the involvement of common risk variants across multiple diseases.

Vyšlo v časopise: Association of Variants at 1q32 and with Ankylosing Spondylitis Suggests Genetic Overlap with Crohn's Disease. PLoS Genet 6(12): e32767. doi:10.1371/journal.pgen.1001195
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1001195

Souhrn

Zdroje

1. BraunJ

SieperJ

2007 Ankylosing spondylitis. Lancet 369 1379 1390

2. BrownMA

KennedyLG

MacGregorAJ

DarkeC

DuncanE

1997 Susceptibility to ankylosing spondylitis in twins: the role of genes, HLA, and the environment. Arthritis Rheum 40 1823 1828

3. BurtonPR

ClaytonDG

CardonLR

CraddockN

DeloukasP

2007 Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet 39 1329 1337

4. ReveilleJD

SimsAM

DanoyP

EvansDM

LeoP

2010 Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci. Nat Genet 42 123 127

5. HindorffLA

SethupathyP

JunkinsHA

RamosEM

MehtaJP

2009 Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc Natl Acad Sci U S A 106 9362 9367

6. MielantsH

VeysEM

CuvelierC

De VosM

GoemaereS

1995 The evolution of spondyloarthropathies in relation to gut histology. II. Histological aspects. J Rheumatol 22 2273 2278

7. Leirisalo-RepoM

TurunenU

StenmanS

HeleniusP

SeppalaK

1994 High frequency of silent inflammatory bowel disease in spondylarthropathy. Arthritis Rheum 37 23 31

8. OrchardTR

HoltH

BradburyL

HammersmaJ

McNallyE

2009 The prevalence, clinical features and association of HLA-B27 in sacroiliitis associated with established Crohn's disease. Aliment Pharmacol Ther 29 193 197

9. Schorr-LesnickB

BrandtLJ

1988 Selected rheumatologic and dermatologic manifestations of inflammatory bowel disease. Am J Gastroenterol 83 216 223

10. Dekker-SaeysBJ

MeuwissenSG

Van Den Berg-LoonenEM

De HaasWH

AgenantD

1978 Ankylosing spondylitis and inflammatory bowel disease. II. Prevalence of peripheral arthritis, sacroiliitis, and ankylosing spondylitis in patients suffering from inflammatory bowel disease. Ann Rheum Dis 37 33 35

11. ThjodleifssonB

GeirssonAJ

BjornssonS

BjarnasonI

2007 A common genetic background for inflammatory bowel disease and ankylosing spondylitis: a genealogic study in Iceland. Arthritis Rheum 56 2633 2639

12. SaxenaR

VoightBF

LyssenkoV

BurttNP

de BakkerPI

2007 Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316 1331 1336

13. ZegginiE

WeedonMN

LindgrenCM

FraylingTM

ElliottKS

2007 Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 316 1336 1341

14. LiY

LiaoW

ChangM

SchrodiSJ

BuiN

2009 Further genetic evidence for three psoriasis-risk genes: ADAM33, CDKAL1, and PTPN22. J Invest Dermatol 129 629 634

15. ZinovievaE

BourgainC

KadiA

LetourneurF

IzacB

2009 Comprehensive linkage and association analyses identify haplotype, near to the TNFSF15 gene, significantly associated with spondyloarthritis. PLoS Genet 5 e1000528 doi:10.1371/journal.pgen.1000528

16. Australia and New Zealand Multiple Sclerosis Genetics Consortium (ANZgene) 2009 Genome-wide association study identifies new multiple sclerosis susceptibility loci on chromosomes 12 and 20. Nat Genet 41 824 828

17. HollandSM

DeLeoFR

ElloumiHZ

HsuAP

UzelG

2007 STAT3 mutations in the hyper-IgE syndrome. N Engl J Med 357 1608 1619

18. NairRP

DuffinKC

HelmsC

DingJ

StuartPE

2009 Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways. Nat Genet 41 199 204