Elsevier

Human Immunology

Volume 70, Issue 9, September 2009, Pages 738-741
Human Immunology

STAT4 gene polymorphism is associated with psoriasis in the genetically homogeneous population of Crete, Greece

https://doi.org/10.1016/j.humimm.2009.05.008Get rights and content

Abstract

Recent genome-wide association studies (GWAS) of many complex diseases have successfully identified novel susceptibility loci, with many of them being associated with more than one condition. Taking into consideration that different autoimmune diseases may share some common pathogenetic pathways, we hypothesized that STAT4, a susceptibility gene found to be associated with increased risk for systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, Sjögren's syndrome, Wegener's granulomatosis, Crohn's disease, and ulcerative colitis may also have a role in psoriasis. Psoriasis is an autoimmune, chronic inflammatory skin disease. Here we performed a case-control study in the population of island of Crete and demonstrated for the first time the association of a STAT4 single nucleotide polymorphism (SNP) with susceptibility to psoriasis, thus suggesting a putative key role of STAT4 in multiple autoimmune diseases. We found that mutated allele T of the STAT4 rs7574865 SNP, which previously was implicated in the predisposition to many autoimmune diseases, were more common in individuals with psoriasis than in controls (p = 0.045, odds ratio = 1.42, 95% confidence interval 1.01–2.00), thus concluding that the polymorphism examined is associated with the development of psoriasis in our population.

Introduction

Psoriasis (OMIM#177900) is a common, autoimmune, chronic, T-cell–mediated inflammatory skin disease found in most ethnic groups, with a prevalence of 1.5–3% in Caucasians and of less than 1.0% in Asians and Africans [1]. Inflammatory processes induce the migration of interferon (IFN)–γ–producing T-helper 1 (Th1) lymphocytes into the skin that play a key role in the pathogenesis of psoriasis. These Th1 lymphocytes are responsible for the pathological reactions in psoriatic skin leading to keratinocyte hyperproliferation, small vessel proliferation, and inflammatory infiltration. The main signal for Th1 development is interleukin (IL)–12. After binding to their receptors, both IL-12 and IFN-γ promote intracellular IFN-γ production by activating signal transducer and activator of transcription-4 (STAT4) or STAT1 proteins [2].

Familial recurrence of psoriasis is well established and is widely regarded as a multifactorial disease [3]. Linkage studies have provided overwhelming support for a primary disease locus (psoriasis susceptibility 1 [PSORS1]), lying within the major histocompatibility complex (MHC) region containing, in addition to the HLA-B and HLA-C genes, a gene named corneodesmosin (CDSN) [4]. Genome-wide linkage scans have mapped at least nine non-MHC disease regions (PSORS2–10) [5]. GWA and association studies have convincingly identified interleukin-23R (IL23R) and IL12B as disease susceptibility genes [6], [7], [8], whereas larger GWA scan led to the identification of zinc finger protein (ZNF) 313 [9] as well as a number of novel associations including a region on chromosome 13q13 harboring lipoma HMGIC fusion partner (LHFP) and component of oligomeric Golgi complex 6 (COG6), a region on chromosome 15q21 harboring ubiquitin specific peptidase 8 (USP8)–signal peptide peptidase-like 2A (SPPL2A)–tumor necrosis factor–α–induced protein 8–like 3 (TNFAIP8L3), the late cornified envelope (LCE) cluster of genes on chromosome 1q21 from the psoriasis susceptibility 4 (PSORS4) locus, and a region of chromosome 4q27 recently reported to be associated with psoriatic arthritis (PSA) and potentially psoriasis (PS) [10]. Moreover, Li et al. [11] presented data increasing the likelihood that ADAM metallopeptidase domain 33 (ADAM33), CDK5 regulatory subunit associated protein–1–like 1 (CDKAL1) and protein tyrosine phosphatase, nonreceptor type 22 (lymphoid) (PTPN22), are true psoriasis-risk genes.

Genes and mechanisms involved in autoimmune diseases still remain obscure, but there are many data strongly suggesting that common genetic factors might predispose to multiple autoimmune disorders. There is an increasing tendency currently for investigating other promising genes that confer a modest level of risk. Thus, it has been recently documented that a common variant allele of STAT4, a gene located in the region 2q33, expressed in various cell types at sites of inflammation in human beings [12] is associated with an increased risk for diverse complex autoimmune diseases, i.e., rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjögren's syndrome (SS), type 1 diabetes (T1D), and Wegener's granulomatosis (WG) [13], [14], [15], [16], [17]. This finding provided support for the evolving concept that common risk genes underlie multiple autoimmune disorders, and suggested the involvement of common pathways of pathogenesis among these different diseases. Nevertheless, the exact functional consequence of this polymorphism has not yet been thoroughly investigated.

The STAT proteins are a family of latent cytosolic transcription factors, including STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6. They are activated in response to many cytokines, growth factors, and hormones; and, after the binding of cytokines or growth factors to their receptors, STAT proteins can be phosphorylated for activation on either tyrosine or serine residues [18], [19]. STAT4 lies in the signaling pathway of several important cytokines, including IL-12 and type I interferons (IFNs), as well as IL-23 [20]. STAT4 mediates IL-12 signaling that is critical for the development of protective immunity in intracellular infection. The mechanism of STAT4-mediated IL-12 signaling in such protection is dependent on the induction of Th1 responses and IFN-γ production [21], [22]. With regard to psoriasis, it has been reported that psoriatic T cells have increased and prolonged responses to IFN-α, on the level of STAT activation, compared with infiltrating T cells from skin of non-psoriatic donors. Functionally, the increased IFN-α signaling leads to an increased binding of STAT4 to the IFN-γ promoter, IFN-γ production, and inhibition of T cell growth [23].

To the best of our knowledge, no studies have so far analyzed a possible association of the STAT4 rs7574865 polymorphism with psoriasis. Therefore, inspired by the above-mentioned recent results from other autoimmune diseases, we analyzed in this report for the first time the possible association of this polymorphism with psoriasis in the genetic homogeneous population of the island of Crete, aiming to define whether this gene plays a key role in multiple autoimmune diseases. Crete (situated 25° E and 35° N) is the largest island of Greece, with approximately 0.65 million inhabitants who share the same genetic and cultural background and a common environment.

Section snippets

Study population

The study group comprised 341 healthy subjects and 163 patients with psoriasis from unrelated families living in Crete. Age- and gender-matched healthy volunteers from the Department of Transfusion Medicine of the University Hospital of Crete served as controls. All psoriasis patients were seen by an experienced dermatologist (S.K.-K.) from the Department of Dermatology of the University Hospital of Crete, from July to November 2008. Patients with psoriatic arthritis (PsA) were also evaluated

Results

The psoriasis study group (N = 163) consisted of 86 (52.7%) men and 77 (47.3%) women. The unrelated healthy controls (N = 341) were of similar age and gender (176 [51.6%] men and 165 [48.4%] women). The mean (±SD) age in patients with psoriasis was 43 ± 8.86 years, whereas the mean age of the controls was 41 ± 10.47 years. The mean (±SD) age of onset of the disease in male and female patients was 31.2 ± 2.35 and 32.3 ± 2.27 years, respectively. Allele (326 cases and 682 controls) and genotype

Discussion

The STAT4 gene is emerging as a novel, non-HLA gene common risk factor for diverse complex diseases. This is the first study to report an association between a variant allele of STAT4 rs7574865 and psoriasis, which was validated in a genetic homogeneous cohort. The T allele of rs7574865 was significantly associated with the susceptibility to psoriasis in the population of Crete. Intriguingly, it is the same allele that predisposes for psoriasis also predisposes to other autoimmune disorders,

Acknowledgments

We thank Prof. M. Kogevinas (University of Crete) for his constructive criticism and I. Nikoloudi (Department of Transfusion Medicine of the University Hospital of Crete) for her help in the collection of healthy specimens. We also thank Kallia Psaroudaki (Dermatology Department, University Hospital of Heraklion) and the personnel of the Rheumatology Department of University Hospital of Heraklion, for their help in the collection of psoriasis and psoriatic arthritis patients' specimens,

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