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Abstract Number: 2787

−21 HLA-Class I Dimorphism Differentiates Psoriatic Arthritis (PsA) from Psoriasis without Psoriatic Arthritis (PsC)

Vinod Chandran1, Quan Li2, Rohan Machhar2, Fatima Abji1, Justine Y. Ye1, Rajan Nair3, Philip Stuart3, Katerina Oikonomopoulou2, James T. Elder4, Dafna D Gladman2 and Proton Rahman5, 1Rheumatology, University of Toronto, Toronto Western Hospital, Toronto, ON, Canada, 2University of Toronto, Toronto Western Hospital, Toronto, ON, Canada, 3University of Michigan, Ann Arbor, MI, 4University of Michigan Medical School, Ann Arbor, MI, 5Rheumatology, St Claires Mercy Hospital, St Johns, NF, Canada

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: genetics, human leukocyte antigens (HLA), natural killer (NK) cells, pathogenesis and psoriatic arthritis

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Session Information

Date: Tuesday, October 23, 2018

Session Title: 5T046 ACR Abstract: Plenary Session III (2785–2790)

Session Type: ACR Plenary Session

Session Time: 11:00AM-12:30PM

Background/Purpose: The association between human leukocyte antigen (HLA) class I alleles and psoriatic disease indicates a potential role for the innate immune system in disease pathogenesis. HLA class I educates NK cells through interactions with killer cell Immunoglobulin receptors (KIRs) and by supplying peptides that bind HLA-E to form ligands for the more conserved CD94/NKG2A NK receptors. The peptides corresponding to residues −22 to −14 of the leader sequence of HLA-A, HLA-B, and HLA-C specifically bind to the binding site of HLA-E. In ~80% of HLA-B allotypes, methionine at position −21M (21M) is replaced by threonine. Methionine −21 delivers functional peptides, whereas threonine at this position (−21T) does not. This functional dimorphism divides the human population into three groups: −21M/M, M/T, and T/T, with decreased order of potency of the NK CD94/NKG2A+ receptor. We aimed to determine whether the distribution of the M and T haplotypes differed between patients with PsA, PsC and healthy controls.

Methods: Two sets of cohorts were included in this study: (a) A discovery cohort of 664 PsA patients, 1155 PsC patients and 3118 controls. Class I HLA alleles were imputed using SNP2HLA. Logistic regressions were used to obtain the association p values by PLINK. We performed three association analyses between HLA B -21 amino acid polymorphisms and different phenotypes: 1) PsC vs. controls; 2) PsA vs. controls; 3) PsA vs. PsC. Population stratification and sex were controlled by including the top seven principal components and sex as covariates in logistic regression. (b) A replication cohort of 1177 PsA patients, 659 PsC patients and 1096 controls with self reported European ethnicity from a large well-phenotyped single centre cohort. HLA typing was done by sequence specific oligonucleotide (SSO) probes using the reverse line blot technique with ambiguous results resolved using sequence specific primers (PCR-SSP). Association analyses as with the Discovery cohort were repeated. All analyses were conditioned on HLA-B*27.

Results:

PsC patients within our discovery cohort had a significantly lower prevalence of -21M compared to controls as well as those with PsA (Table 1). The results of the replication study showed similar results (Table 2).

Conclusion: The study provides indications for a potential role of NK cells in PsA pathogenesis, as well as provides a genetic marker that differentiates PsA from PsC.

Table 1. Results of the association study in the discovery cohort.

Comparisons

Freq of -21M in affected

Freq -21M in controls

OR (95% CI)

P value

P value

(adjusted)

PsC vs. Controls

0.285

0.331

0.78 (0.70, 0.87)

4.262e-05

4.411e-06

PsA vs. Controls

0.337

0.331

1.04 (0.92, 1.18)

0.671

0.546

PsA vs. PsC

0.337

0.285

1.36 (1.17, 1.58)

0.001

6.692e-05

Table 2. Results of the association study in the replication cohort.

Comparisons

Freq of -21M in affected

Freq -21M in controls

OR (95% CI)

P value

P value

(adjusted)

PsC vs. Control

0.276

0.309

0.82 (0.70, 0.96)

0.042

0.015

PsA vs. Control

0.326

0.309

1.13 (0.99, 1.29)

0.203

0.069

PsA vs. PsC

0.326

0.276

1.40 (1.20, 1.63)

0.002

2.268e-05


Disclosure: V. Chandran, AbbVie Inc., 2,AbbVie Inc., amgen, celgene, eli lilly, Janssen, Novartis, Pfizer and UCB, 5,Eli Lilly and Co., 9; Q. Li, None; R. Machhar, None; F. Abji, None; J. Y. Ye, None; R. Nair, None; P. Stuart, None; K. Oikonomopoulou, None; J. T. Elder, None; D. D. Gladman, Amgen, AbbVie, Celgene, Eli Lilly, Janssen, Novartis, Pfizer and UCB, 2,Amgen, AbbVie, BMS, Celgene, Eli Lilly, Janssen, Novartis, Pfizer and UCB, 5; P. Rahman, AbbVie, Amgen, BMS, Celgene, Eli-Lilly, Janssen, Pfizer, Novartis, Merck, UCB, 5,Janssen, 2,AbbVie, Amgen, BMS, Celgene, Eli-Lilly, Janssen, Pfizer, Novartis, Merck, UCB, 8.

To cite this abstract in AMA style:

Chandran V, Li Q, Machhar R, Abji F, Ye JY, Nair R, Stuart P, Oikonomopoulou K, Elder JT, Gladman DD, Rahman P. −21 HLA-Class I Dimorphism Differentiates Psoriatic Arthritis (PsA) from Psoriasis without Psoriatic Arthritis (PsC) [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/%e2%88%9221-hla-class-i-dimorphism-differentiates-psoriatic-arthritis-psa-from-psoriasis-without-psoriatic-arthritis-psc/. Accessed February 23, 2019.
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