title: A GWAS follow-up study reveals the association of the IL12RB2 gene with systemic sclerosis in Caucasian populations.
abstract: A single-nucleotide polymorphism (SNP) at the IL12RB2 locus showed a suggestive association signal in a previously published genome-wide association study (GWAS) in systemic sclerosis (SSc). Aiming to reveal the possible implication of the IL12RB2 gene in SSc, we conducted a follow-up study of this locus in different Caucasian cohorts. We analyzed 10 GWAS-genotyped SNPs in the IL12RB2 region (2309 SSc patients and 5161 controls). We then selected three SNPs (rs3790567, rs3790566 and rs924080) based on their significance level in the GWAS, for follow-up in an independent European cohort comprising 3344 SSc and 3848 controls. The most-associated SNP (rs3790567) was further tested in an independent cohort comprising 597 SSc patients and 1139 controls from the USA. After conditional logistic regression analysis of the GWAS data, we selected rs3790567 [P(MH)= 1.92 × 10(-5) odds ratio (OR) = 1.19] as the genetic variant with the firmest independent association observed in the analyzed GWAS peak of association. After the first follow-up phase, only the association of rs3790567 was consistent (P(MH)= 4.84 × 10(-3) OR = 1.12). The second follow-up phase confirmed this finding (P(χ2) = 2.82 × 10(-4) OR = 1.34). After performing overall pooled-analysis of all the cohorts included in the present study, the association found for the rs3790567 SNP in the IL12RB2 gene region reached GWAS-level significant association (P(MH)= 2.82 × 10(-9) OR = 1.17). Our data clearly support the IL12RB2 genetic association with SSc, and suggest a relevant role of the interleukin 12 signaling pathway in SSc pathogenesis.
authors.affiliation: Instituto de ParasitologÍa y Biomedicina López-Neyra, IPBLN-CSIC, Granada 18100, Spain. larabc@ipb.csic.es
authors.forename: Lara
authors.initials: L
authors.lastname: Bossini-Castillo
authors.forename: Jose-Ezequiel
authors.initials: JE
authors.lastname: Martin
authors.forename: Jasper
authors.initials: J
authors.lastname: Broen
authors.forename: Olga
authors.initials: O
authors.lastname: Gorlova
authors.forename: Carmen P
authors.initials: CP
authors.lastname: Simeón
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Beretta
authors.forename: Madelon C
authors.initials: MC
authors.lastname: Vonk
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Callejas
authors.forename: Ivan
authors.initials: I
authors.lastname: Castellví
authors.forename: Patricia
authors.initials: P
authors.lastname: Carreira
authors.forename: Francisco José
authors.initials: FJ
authors.lastname: García-Hernández
authors.forename: Mónica
authors.initials: M
authors.lastname: Fernández  Castro
authors.forename: Marieke J H
authors.initials: MJ
authors.lastname: Coenen
authors.forename: Gabriela
authors.initials: G
authors.lastname: Riemekasten
authors.forename: Torsten
authors.initials: T
authors.lastname: Witte
authors.forename: Nicolas
authors.initials: N
authors.lastname: Hunzelmann
authors.forename: Alexander
authors.initials: A
authors.lastname: Kreuter
authors.forename: Jörg H W
authors.initials: JH
authors.lastname: Distler
authors.forename: Bobby P
authors.initials: BP
authors.lastname: Koeleman
authors.forename: Alexandre E
authors.initials: AE
authors.lastname: Voskuyl
authors.forename: Annemie J
authors.initials: AJ
authors.lastname: Schuerwegh
authors.forename: Øyvind
authors.initials: Ø
authors.lastname: Palm
authors.forename: Roger
authors.initials: R
authors.lastname: Hesselstrand
authors.forename: Annika
authors.initials: A
authors.lastname: Nordin
authors.forename: Paolo
authors.initials: P
authors.lastname: Airó
authors.forename: Claudio
authors.initials: C
authors.lastname: Lunardi
authors.forename: Raffaella
authors.initials: R
authors.lastname: Scorza
authors.forename: Paul
authors.initials: P
authors.lastname: Shiels
authors.forename: Jacob M
authors.initials: JM
authors.lastname: van Laar
authors.forename: Ariane
authors.initials: A
authors.lastname: Herrick
authors.forename: Jane
authors.initials: J
authors.lastname: Worthington
authors.forename: Christopher
authors.initials: C
authors.lastname: Denton
authors.forename: Filemon K
authors.initials: FK
authors.lastname: Tan
authors.forename: Frank C
authors.initials: FC
authors.lastname: Arnett
authors.forename: Sandeep K
authors.initials: SK
authors.lastname: Agarwal
authors.forename: Shervin
authors.initials: S
authors.lastname: Assassi
authors.forename: Carmen
authors.initials: C
authors.lastname: Fonseca
authors.forename: Maureen D
authors.initials: MD
authors.lastname: Mayes
authors.forename: Timothy R D J
authors.initials: TR
authors.lastname: Radstake
authors.forename: Javier
authors.initials: J
authors.lastname: Martin
mesh_terms: D005060:Europe / Q000208:ethnology; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D053707:Receptors, Interleukin-12 / Q000235:genetics*; D012595:Scleroderma, Systemic / Q000235:genetics*; D014481:United States / Q000208:ethnology; D044465:White People / Q000235:genetics*
chemical_list: C508439:IL12RB2 protein, human; D053707:Receptors, Interleukin-12
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