Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.

A Genome-Wide Association Study Follow-up Strategy Reveals the Association of IL12RB2 Gene with Systemic Sclerosis in Caucasian Populations.

Bossini-Castillo1,  Lara, Martin1,  Jose Ezequiel, Broen2,  Jasper, Simeon3,  Carmen Pilar, Beretta4,  Lorenzo, Vonk2,  Madelon C., Carreira5,  Patricia E.

Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC, Granada, Spain
Rikshospitalet, Oslo University Hospital, Oslo, Norway
Lund University & Skåne University Hopsital, Lund, Sweden
Karolinska Institute, Stockholm, Sweden
Policlinico G B Rossi, Verona, Italy
University of Glasgow, Glasgow, United Kingdom
Musculoskeletal Research Group, Newcastle, United Kingdom
Rheumatic Diseases Centre, Salford, United Kingdom
University of Texas Health Science Center at Houston, Houston, TX
Univ of Texas Health Science, Houston, TX
Royal Free and University College Medical School, London, United Kingdom
Radboud University Nijmegen Medical Centre, Nijmegen, Nijmegen, Netherlands
Hospital Valle de Hebron, Barcelona, Spain
IRCCS Fondazione Policlinico-Mangiagalli-Regina Elena & University of Milan, Milan, Italy
Instituto de Investigación Hospital 12 de Octubre (I+12), Madrid, Spain
University of Cologne, Cologne, Germany
VU University Medical Center, Amsterdam, Netherlands
Leids Univ Medisch Centrum, Leiden, Netherlands


Recently, our group published the first genome-wide association study (GWAS) conducted to date in Caucasian SSc patients. In the previously mentioned GWAS study, a single nucleotide polymorphism (SNP) at the IL12RB2 locus showed a suggestive association signal.

IL12RB2 encodes IL-12Rb2, which constitutes the transducing component of the IL-12 receptor heterodimer. Moreover, IL12Rb2 knock-out models develop autoimmune events and polymorphisms in the IL12RB2 gene region have been related to several human autoimmune disorders.

Aiming to reveal the possible implication of IL12RB2 gene in SSc, we conducted fine-mapping GWAS follow-up study in different Caucasian cohorts.


The whole analyzed set comprised 15,474 individuals of Caucasian Ancestry (5,991 SSc patients/9,483 controls). Ten GWAS genotyped single nucleotide polymorphisms (SNPs) in the IL12RB2 region were analyzed. Then, we included three relevant SNPs in a first follow-up step comprising 7,192 European individuals (3,344 SSc / 3,848 controls). Only the most associated SNP was considered for a second follow-up phase comprising 1,736 US individuals (597 SSc/1,139 controls). Both follow-up cohorts were genotyped using TaqMan SNP genotyping assays in a real-time PCR System.

Significance was calculated using 2×2 contingency tables and Fisher's exact test or c2 when necessary, to obtain p-values, odds ratios (OR) and 95% confidence intervals (CI) using PLINK (v1.07) software. The logistic regression and conditioned logistic regression analyses, were performed using PLINK software. Linkage disequilibrium patterns across the region in the HapMap Project Phase I and II (CEU population) defined the haplotype tagging SNPs using Haploview (v.4.2) software.


Ten SNPs in the IL12RB2 region were included in the initial GWAS analysis set, six of them were found to be significantly associated with SSc. However, conditioned logistic regression revealed that the significance of the initially observed associations relied on the rs3790567 association. Both the most associated SNP (rs3790567) and its unique tag-SNP (rs3790566) were selected for replication. We also included rs924080 in the first follow-up phase due to its localization in a recombination hotspot in the intergenic region between IL12RB2 and IL23R.

After the first follow-up phase, only the association of rs3790567 was consistent (PMH= 4.84×10-3 OR = 1.12) (Table 1).

Interestingly, the second follow-up phase confirmed this finding (Pc2= 2.82×10-4 OR = 1.34) (Table 1). It is remarkable that rs3790567 pooled analysis in the whole set of individuals reached a highly statistically significant association (PMH= 2.82×10-9 OR = 1.17) (Table 1).

Table 1. Genotype and allele distribution of IL12RB2 rs3790567 genetic variant in SSc patients and controls in a three-step association study.

Population (CTRL/SSc) CTRL    SSc   
GWAS cohort (5,161/2,309)0.06 (332)0.37 (1,911)0.57 (2,918)0.250.08 (196)0.40 (919)0.52 (1,194)0.281.92×10-51.191.10–1.29NS
European follow-up (3,183/3,085)0.08 (241)0.37 (1,169)0.56 (1,773)0.260.09 (282)0.38 (1,187)0.52 (1,616)0.284.48×10-31.121.04–1.22NS
GWAS + European follow-up (8,344/5,394)0.07 (573)0.37 (3,080)0.56 (4,691)0.250.09 (478)0.39 (2,106)0.52 (2,810)0.285.19×10-71.611.09–1.22NS
US follow-up (1,139/597)0.05 (60)0.37 (417)0.58 (662)0.240.10 (59)0.39 (231)0.51 (307)0.292.82×10-4*1.341.14–1.57NA
GWAS + European + US follow-up (9,483/5,991)0.07 (633)0.37 (3,497)0.56 (5,353)0.250.09 (537)0.39 (2,337)0.52 (3,117)0.282.82×10-91.171.11–1.24NS
Controls are used as reference for all comparisons. CTRL: healthy controls; SSc: Systemic sclerosis; MAF: Minor allele (A) frequency; PMH: allelic Mantel-Haenszel fixed effects model p-value;*: Allelic Chi-square uncorrected p-value; OR: odds ratio; 95% CI: 95% confidence interval; PBD: Breslow-Day test p-value; NS: not statistically significant; NA: not applicable.


Our data clearly support IL12RB2 rs3790567 association with SSc, and suggest a relevant role of IL-12 signaling pathway in SSc pathogenesis.

To cite this abstract, please use the following information:
Bossini-Castillo, Lara, Martin, Jose Ezequiel, Broen, Jasper, Simeon, Carmen Pilar, Beretta, Lorenzo, Vonk, Madelon C., et al; A Genome-Wide Association Study Follow-up Strategy Reveals the Association of IL12RB2 Gene with Systemic Sclerosis in Caucasian Populations. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :1491

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