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.

Is There a Higher Genetic Load of Susceptibility Loci in Familial Ankylosing Spondylitis?

Joshi1,  Reeti K., Reveille2,  John D., Brown3,  Matthew A., Weisman4,  Michael H., Ward5,  Michael M., Gensler6,  Lianne S., Wordsworth7,  B. Paul

Washington University in St. Louis, Saint Louis, MO
University of Texas Health Science Center at Houston, Houston, TX
Wellcome Trust Centre, Headington, United Kingdom
Cedars Sinai Med Ctr, Los Angeles, CA
UCSF, San Francisco, CA
Bichester, Oxon, United Kingdom
Chesterfield, MO
Univ of Texas Health Science, Houston, TX


Several genes have been recently confirmed as genetic susceptibility loci for Ankylosing Spondylitis (AS) in genome wide association studies. The goal of this study is to examine whether the familial AS cases have a higher genetic load of these susceptibility loci.


Overall, 502 patients with AS were examined, consisting of 312 who had first-degree relatives (FDR) with AS (familial) and 190 who had no FDR with AS or spondyloarthritis (sporadic). All patients and affected FDRs fulfilled the modified New York Criteria for AS. The patients were recruited from North American Spondylitis Consortium (NASC), Prospective Study of Outcomes in Ankylosing Spondylitis (PSOAS) and United Kingdom- Oxford (UK-Oxford) cohorts.Only one AS case per family was included in the analysis. The frequency of AS susceptibility loci in IL23R, IL1R2, ANTRX2, ERAP1, two intergenic regions on chromosomes 2 and 21, as well as, a HLA B27 tag single nucleotide polymorphism (SNP), rs4349859 was compared between the familial and sporadic AS patients. Association between SNPs and multiplex status was assessed by logistic regression controlling for sibship size and Eigenstrat derived principal components from a previous genome-wide association study of AS.


The UK –Oxford cohort included 160 familial AS cases with mean age of 47.9 years at enrollment, 60% being male. US cohort included 152 familial AS patients from NASC study with mean age of enrollment 44.4 years, 58% being male. PSOAS group included 190 sporadic AS cases with mean age 47.1 years, 76% being male. The risk allele in HLA-B27 tag SNP, rs4349859 was significantly more prevalent in familial cases (p=0.002, OR: 3.69, CI: (1.61, 8.46)). The frequency of AS susceptibility loci in the ERAP1, IL23R, IL1R2, ANTXR2 genes in addition to two gene desert regions on 2p15 and 21q22 did not differ significantly between the familial and sporadic cases. However, the susceptibility locus on 21q22 showed a trend toward association (p=0.054) with the protective minor allele being less frequent in the familial cases. Further details of the results are shown in Table 1.

Table 1. Comparison of AS susceptibility loci between familial and sporadic AS cases after adjustment for sibship size

SNPCandidate GeneMinor AlleleOdds ratio (95% C.I.)P-value
rs11209026IL23RA(P†)0.55 (0.22, 1.36)0.193
rs108653312p15*A(R‡)0.85 (0.61, 1.2)0.365
rs2310173IL1R2A(R)1.34 (0.94, 1.9)0.105
rs4333130ANTXR2G(P)0.9 (0.61, 1.32)0.577
rs27434ERAP1A(R)0.96 (0.64, 1.45)0.855
rs224294421q22*A(P)0.68 (0.46, 1.01)0.054
rs4349859HLA B27 tag SNPA(R)3.69 (1.61, 8.46)0.002
* These SNPs are located in gene deserts
† P: Protective Allele against AS
‡ R: Risk Allele for AS

We also repeated the analysis after restricting the sample to the US cases. The investigation of only US familial and sporadic AS cases showed similar results.


HLA tag SNP, rs4349859 which tracks closely with HLA-B27 is a susceptibility locus for familial AS. This finding confirms higher heritability in HLA-B27 positive subtype of AS. The frequency of the recently described non-MHC susceptibility loci is not markedly different between the sporadic and familial cases of AS.

To cite this abstract, please use the following information:
Joshi, Reeti K., Reveille, John D., Brown, Matthew A., Weisman, Michael H., Ward, Michael M., Gensler, Lianne S., et al; Is There a Higher Genetic Load of Susceptibility Loci in Familial Ankylosing Spondylitis? [abstract]. Arthritis Rheum 2011;63 Suppl 10 :153

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