title: Association of variants at 1q32 and STAT3 with ankylosing spondylitis suggests genetic overlap with Crohn's disease.
abstract: 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.
authors.affiliation: The University of Queensland Diamantina Institute, Brisbane, Australia.
authors.forename: Patrick
authors.initials: P
authors.lastname: Danoy
authors.forename: Karena
authors.initials: K
authors.lastname: Pryce
authors.forename: Johanna
authors.initials: J
authors.lastname: Hadler
authors.forename: Linda A
authors.initials: LA
authors.lastname: Bradbury
authors.forename: Claire
authors.initials: C
authors.lastname: Farrar
authors.forename: Jennifer
authors.initials: J
authors.lastname: Pointon
authors.forename: Michael
authors.initials: M
authors.lastname: Ward
authors.forename: Michael
authors.initials: M
authors.lastname: Weisman
authors.forename: John D
authors.initials: JD
authors.lastname: Reveille
authors.forename: B Paul
authors.initials: BP
authors.lastname: Wordsworth
authors.forename: Millicent A
authors.initials: MA
authors.lastname: Stone
authors.forename: Walter P
authors.initials: WP
authors.lastname: Maksymowych
authors.forename: Proton
authors.initials: P
authors.lastname: Rahman
authors.forename: Dafna
authors.initials: D
authors.lastname: Gladman
authors.forename: Robert D
authors.initials: RD
authors.lastname: Inman
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Brown
mesh_terms: D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D015331:Cohort Studies; D003424:Crohn Disease / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D050796:STAT3 Transcription Factor / Q000235:genetics*; D013167:Spondylitis, Ankylosing / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D050796:STAT3 Transcription Factor