Background/Purpose:

Psoriatic arthritis (PsA) is a seronegative immune mediated arthritis that develops in about a third of patients with cutaneous psoriasis (PsC). The cellular pathways which distinguish the skin and joint manifestations in PsA are poorly understood. Through microarray and qPCR array studies, we have identified several genes which are dysregulated in PsA. The goal of this study was to validate the expression of these genes and associated signaling pathways in a large cohort of patients.

Methods:

Total RNA was isolated from peripheral blood of PsA patients satisfying CASPAR criteria and PsC patients. All patients were Caucasian and were not receiving treatment with biological agents. Quantification of mRNA expression of 49 genes was completed using the Nanostring nCounter® system (NanoString Technologies). Fold change differences between PsA and PsC patients were determined from normalized results. Significance was determined by performing multivariate logistic regression analyses and controlling for clinical variables (FDR<0.05).

Results:

Gene expression was computed in 48 PsA patients (mean age 46 years, 52% males, psoriasis duration 17 years, PASI 7.5, active joint count 6.3) and 48 PsC patients (mean age 46 years, 50% males, psoriasis duration 17 years, PASI 4.9). Twenty-nine genes were found to be significantly altered (FDR < 0.05) in PsA patients compared to PsC patients (Table 1), including several genes linking the innate immune system and chromatin modification. Downstream signaling molecules in the toll like receptor pathway, such as CXCL10, EZR, MyD88, and CD14, were upregulated in PsA. SMARCA4 is a component of the BAF complex linked to chromatin modification upon TLR4 activation which was also over-expressed in our PsA cohort. Out of these genes, 21 genes were upregulated and 8 genes were downregulated. No significant differences in clinical covariates for any gene were found. Cluster analysis revealed 19 PsA patients that grouped together.

Conclusion:

We validated genes involved in the regulation and activation of signaling pathways of the innate immune system that were dysregulated in PsA compared to PsC patients. Future studies will focus on understanding how expression of these genes is linked to clinical variables and progression of PsA, and distinguish whether these genes can serve as biomarkers of PsA susceptibility in patients with PsC.

Table 1: Significantly altered genes (FDR<0.05) in PsA patients compared to PsC

 

Gene	Description	Fold Change	OR (95% CI)	FDR
TLR7	Toll-like receptor 7	1.62	4.03 (1.82, 8.90)	0.0008
CXCL10 (IP10)	Chemokine (C-X-C motif) ligand 10	1.45	1.46 (0.95, 2.24)	0.0420
PARP1	Poly (ADP-ribose) polymerase 1	1.41	2.91 (1.44, 5.88)	0.0028
XRCC6	X-ray repair complementing defective repair in Chinese hamster cells 6	1.36	5.23 (2.37, 11.58)	0.0004
SMARCA4	SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4	1.35	4.28 (2.03, 9.01)	0.0005
EZR	Ezrin	1.35	2.01 (1.07, 3.77)	0.0196
SYNCRIP	Synaptotagmin binding, cytoplasmic RNA interacting protein	1.34	4.10 (1.87, 9.03)	0.0007
EHMT2	Euchromatic histone-lysine N-methyltransferase 2	1.31	4.12 (1.95, 8.95)	0.0006
TICAM1 (TRIF)	Toll-like receptor adaptor molecule 1	1.31	3.36 (1.72, 6.53)	0.0006
SETD1A	SET domain containing 1A	1.31	2.28 (1.27, 4.09)	0.0049
RP11-94I2.2	NBPF11 neuroblastoma breakpoint family, member 11	1.30	2.33 (1.33, 4.10)	0.0028
IFNA1	Interferon, alpha 1	1.29	1.77 (1.02, 3.09)	0.0261
CD14	CD14 molecule	1.27	2.16 (1.21, 3.86)	0.0072
PRMT6	Protein arginine methyltransferase 6	1.24	2.13 (1.15, 3.96)	0.0120
TRAM1	Translocation associated membrane protein 1	1.22	3.23 (1.60, 6.51)	0.0011
PUM1	Pumilio homolog 1 (Drosophila)	1.20	3.28 (1.66, 6.50)	0.0008
MSN	Moesin	1.16	2.02 (1.06, 3.85)	0.0201
IL15	Interleukin 15	1.16	1.81 (1.01, 3.26)	0.0278
SMYD3	SET and MYND domain containing 3	1.15	1.57 (0.96, 2.57)	0.0352
HAT1	Histone acetyltransferase 1	1.12	1.99 (1.08, 3.67)	0.0196
MyD88	Myeloid differentiation primary response 88	1.07	1.83 (0.95, 3.50)	0.0352
CXCL1	Chemokine (C-X-C motif) ligand 1 (melanoma growth stimulating activity, alpha)	0.61	0.27 (0.13, 0.54)	0.0006
LY96 (MD2)	Lymphocyte antigen 96	0.69	0.23 (0.11, 0.48)	0.0005
BCL2A1	BCL2-related protein A1	0.73	0.24 (0.11, 0.52)	0.0006
CD58	CD58 molecule	0.77	0.24 (0.12, 0.48)	0.0004
CLEC2B	C-type lectin domain family 2, member B	0.79	0.40 (0.22, 0.74)	0.0028
N2N	NOTCH2NL notch 2 N-terminal like	0.80	0.35 (0.19, 0.64)	0.0009
TLR2	Toll-like receptor 2	0.88	0.59 (0.33, 1.05)	0.0352
SETD2	SET domain containing 2	0.92	0.62 (0.38, 1.01)	0.0317

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/validation-of-gene-expression-biomarkers-of-psoriatic-arthritis/