Systemic Lupus Erythematosusis A Heterogeneous Complex

Published Date: 02 Nov 2017

Key Words:Systemic Lupus Erythematosus, ETS1, WDFY4

Running Title:ETS1, WDFY4polymorphism and SLE

Introduction

Systemic Lupus Erythematosus(SLE) is a relapsing-remitting autoimmune disorder involvingmany different organ systems, characterized by severalimmunological abnormalities, such as the presence of hyper reactive T and B cells andproducing an array of auto-antibodies against serological, intra-cellular, nucleic acid and cell surface antigens (Bengtsson and others 2002; Cunninghame Graham and others 2011).the prevalence of SLE is approximately1 in 2,500 in European populations with a sex ratio of 9:1,however,The disease is more frequent in non-European ancestry populations(Cunninghame Graham and others 2011; Guerra and others 2012). Considering the wide range of clinical manifestations and heterogeneous nature of SLE phenotype, American College of Rheumatology (ACR) has defined Eleven clinical criteria to identify patients,namelymalar rash, discoid rash, photosensitivity, oral ulcers, non-erosivearthritis, pleuritis, renal disorders, neurologic disorders, hematologic disorders, immunologic disorders and positive antinuclear antibody. (1997 update of the 1982 ACR revised criteria for classification of SLE).

Despite the fact that the exact etiology of SLE remains unclear, strong genetic linkage has been wellacceptedfor SLE.Since, its heritability is estimated about 66%; with concordance rates of 24% to 57% in monozygotic twins and 2% to 5% in dizygotic twins(Ahmad and Bruce 2001),the role of genetic predisposition is highly attributable to the disease. According to recent studies, SLE is characterized as a polygenic genetic model so that as many as 100 genes might be involved, and every gene may have only a moderate effect size(Yuan and others 2010). According to recentgenome-wide association studies (GWAS), ETS1 and WDFY4are introduced as novel predisposing genes for SLE(Lee and others 2007).

Ets-1is a negative regulator of B-cell differentiation and T helper 17 (Th17) cell proliferations. It has been shown that Patients with SLE present a reduced expression of ETS1, which mightcontribute toabnormal B-cell differentiation into auto-antibodysecreting plasma cells and increased number of Th17 cells(Guerra and others 2012). Moreover, two recent genome wide association studies on Asian population indicatedthat, variants (rs6590330, rs7932088, rs10893872, rs4937333, rs1128334) of ETS1 gene have significant association with SLE(Han and others 2009; Yang and others 2010)confirming the SLE-like disease observed in ETS1-deficient mice (Pan and others 2011).

WDFY4 is a huge protein with unknown function. WDFY4 is expressed predominantly in immune tissues such as a lymph node, spleen, thymus and tonsils(UniGene Hs.287379, http://www.ncbi.nlm.nih.gov/UniGene/ESTProfileViewer.cgi?uglist=Hs.287379). Two recent genome wide studies in Asia have identified severalvariants (rs7097397, rs10857650, rs877819) ofthisgene associated with SLE(Han and others 2009; Yang and others 2010).

In this study, we have investigated association ofETS1 (rs10893872, rs1128334), and WDFY4 (rs877819, rs707397) polymorphisms with SLE in Iranian patients. We have also investigated the association of these polymorphisms with different clinical features of patients with SLE

SystemicLupus Erythematosus (SLE) is a complex autoimmune disease,which is clinically heterogeneous with a wide-range of clinical manifestations, differing from patient to patient(Singh and Kamen 2012). It is now well-accepted that genetic components play important roles in the abnormal immune responses and pathogenesis of SLE, so that carrying special genes confers susceptibility to the disease. Studies in animal models have alsoconfirmed that a large part of susceptibility to SLE is due to geneticpredisposition, (Kono and Theofilopoulos 2006).However, SLE does not follow the simple Mendelian inheritance and not a major single gene governsthe pathogenesis, instead a polygenic model is expected, as genome-wide association studies have identified more than 30 associated loci(Guerra and others 2012; Rhodes and Vyse 2008).

Ets-1 or v-ets,erythroblastosis virus E26 oncogene homolog 1, is a member of Ets family of transcription factors defined by the conservedDNA-binding domainknownas ETS, which is a winged helix turn helix motif, located on chromosome number 11.The protein contains 485 amino acids, functioning as transcriptional activator and suppressor of numerous genes(Wang and others 2005)(http://www.ncbi.nlm.nih.gov/gene/2113). Ets-1 regulates lymphocyte differentiation and development through regulating B-cell differentiation and T helper 17 proliferation(Moisan and others 2007; Wang and others 2005). ETS-1deficient Th1cells show increased and reduced secretion of IL-10 and IL-2 respectively(Guerra and others 2012), and Ets-1 deficient B-cells show enhanced differentiation to IgM secreting plasma cells and arehyper responsive to TLR9(Leng and others 2011)indicating the possible involvement of Ets-1 inthe pathogenesis of SLE.

Kathleen et al. showed a microsatellite repeat polymorphism in ETS1 3`flanking region is associated by SLE phenotypes(Sullivan and others 2000). Two genome wide association studies, in Asian population also demonstratedhigh association of rs6590330 and rs10893872 with SLE (Han and others 2009; Yang and others 2010).In our study weadoptedrs1128334 instead of rs6590330 due to Yang etalstudy;it is in 3`UTR and is correlated with ETS1 expression(Yang and others 2010).Rs10893872was alsoselectedwhich has a high LD with rs4937333(Yang and others 2010). Our results did not confirm previously presenteddata in GWA studies, we observed no significant association between none of the SNPs and SLE in our study population(Table 2).

WDFY family member 4 is a 3184 amino acid protein with unknown function, which is observed to be expressed in secondary immune tissues. The protein includes WD40 and beach (Beige and Chediak-Higashi) domains (http://www.ncbi.nlm.nih.gov/gene/57705).WD40 is found in a number of eukaryotic proteins having many functions including adaptor/regulatory modules in signal transduction, pre-mRNA processing and cytoskeleton assembly.The domain typically contains a GH dipeptide near the N-terminus and a WD dipeptide at the C-terminus, between which a conserved core exists that creates a propeller-like platform to bind other proteins either stably or reversibly (http://www.ncbi.nlm.nih.gov/Structure/cdd/cddsrv.cgi?uid=100117), and beach domain is important in membrane trafficking (http://www.ncbi.nlm.nih.gov/Structure/cdd/cddsrv.cgi?uid=207648).

We decided onrs7097397 and rs877819 to investigate, due to the results of genome wide association studiesin Asian population (Han and others 2009; Yang and others 2010). Both of the SNPs showed association with SLE. rs7097397is in the coding region, Arg1816Gln, of the gene and can be considered as a functional SNP(Yang and others 2010), while rs877819 has been shown to change the binding affinity of Yinyang1 transcription factor and down regulate WDFY4(Zhao and others 2012). Our results were not consistent with those of the GWA studies in Asian population, since there were no associations between both SNPs with the disease (Table2).

As a conclusion, our results did not confirm the results of genome wideassociation studiesperformed on Asian population, these differences may be due to differences between the populations or the sample size studied.