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.
Extended Haplotypes Between Human Leukocyte Antigen-C and Tumour Necrosis Factor A Gene Loci Reveal Psoriatic Arthritis Susceptibility Hotspots.
Pollock1, Remy, Pellett2, Fawnda, Ayearst2, Renise, Rahman3, Al Amin P., Gladman1, Dafna D., Chandran2, Vinod
Evidence suggests that while psoriasis is strongly associated with alleles of HLA-C, psoriatic arthritis (PsA) susceptibility may lie within the region centromeric to HLA-C that includes HLA-B, MICA, HCP5, MICB, and TNFA loci. Extensive linkage disequilibrium in the major histocompatibility complex makes identification of the exact PsA disease locus difficult. In carefully phenotyped cohorts of PsA, psoriasis, and control subjects, we examined the linkage of these loci and their putative role in disease susceptibility.
The following SNPs were genotyped in 451 Caucasian patients with psoriatic disease (PsD) (264 patients with PsA satisfying CASPAR criteria and 187 patients without arthritis (PsC)) and 183 Caucasian controls: rs2523459, rs2844521 (MICA); rs2395029 (HCP5); rs2516498, rs3132468 (MICB); and rs1799964 (TNF-1031), rs1800630 (TNF-863), rs1799724 (TNF-857), rs1800629 (TNF-308), rs361525 (TNF -238) (Figure 1). HLA-B and C typing was performed by PCR-SSO and MICA129Met/Val was assigned from allelic typing performed by PCR-SSP. The Cochran-Armitage trend test was used to identify alleles associated with (PsD) and PsA compared to controls, and differentiate PsA from PsC. Haplotypes were estimated using the EM algorithm and differences between subject groups were analyzed using GoldenHelix® software. Logistic regression was used to test for independent effects of linked alleles.
Psoriatic disease was associated with HLA-C*02, *06, *12, B*27, *38, *57, rs2526459, rs2844521, MICA129, rs2395029, and TNF-238. The following haplotypes were significantly associated with PsD: HLA-C*06/B*57/rs2523459C/rs2844521A/MICA129Met/rs2395029G/TNF-238A (P = 0.01, OR = 2.2), 12/38/C/A/Met/T/G (P = 0.01, OR = 3.7), and 2/27/C/A/Met/T/G (P = 0.003, OR = 11.5). Compared to controls, PsA was associated with HLA-C*02, *12, B*27, *38, rs2523459, rs2844521, MICA129, and rs2395029 and the haplotypes: C*12/B*38/rs2523459C/rs2844521A/MICA129Met/rs2395029T (P < 0.01, OR = 4.4) and 2/27/C/A/Met/T (P < 0.01, OR = 19.4). When comparing PsA to PsC, PsA was associated with HLA-C*02, *06, *07, B*08, *27, *57, rs3132468, TNF-1031, TNF-863, TNF-308, and TNF-238 and the haplotypes C*07/B*08/ rs3132468T/TNF-1031T/TNF-863C/TNF-308A/TNF-238G (P = 0.02, OR = 1.9), 2/27/T/T/C/G/G (P = 0.001, OR = 4.9), and 1/27/T/T/C/G/G (P = 0.03, OR = 3.7). Logistic regression showed that compared to controls, MICA129Met and HLA-C*06 were independently associated with PsD, while MICA129Met, HLA-B*27 and *38 were associated with PsA. Compared to PsC, rs3132468 (MICB) and TNF-863 were associated with PsA, independent of HLA-C*07, B*08, and B*27.
This study suggests that susceptibility haplotypes for PsD extend from HLA-C to TNFA, while hotspots for PsA susceptibility exist at HLA-B, MICB, and TNFA.
To cite this abstract, please use the following information:
Pollock, Remy, Pellett, Fawnda, Ayearst, Renise, Rahman, Al Amin P., Gladman, Dafna D., Chandran, Vinod; Extended Haplotypes Between Human Leukocyte Antigen-C and Tumour Necrosis Factor A Gene Loci Reveal Psoriatic Arthritis Susceptibility Hotspots. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :1357