Elsevier

Journal of Autoimmunity

Volume 41, March 2013, Pages 25-33
Journal of Autoimmunity

Review
Genetic susceptibility to SLE: Recent progress from GWAS

https://doi.org/10.1016/j.jaut.2013.01.008Get rights and content

Abstract

Systemic lupus erythematosus (SLE) is a prototype autoimmune disease with a strong genetic component, characterized by hyperactive T and B cells, autoantibody production, immune complex deposition and multi-organ damage. It affects predominantly women of child-bearing age and has population differences in both disease prevalence and severity. Genetic factors are known to play key roles in the disease through the use of association and family studies. Previously, SLE susceptibility genes were mainly revealed through linkage analysis and candidate gene studies. Since 2008, our understanding of the genetic basis of SLE has been rapidly advanced through genome-wide association studies (GWASs). More than 40 robust susceptibility loci have been identified and conformed to be associated with SLE using this technique. Most of these associated genes productions participate in important pathways involved in the pathogenesis of SLE, such as immune complex processing, toll-like receptor signaling, type I interferon production, and so on. A number of susceptibility loci with unknown functions in the pathogenesis of SLE have also been identified, indicating that additional molecular mechanisms contribute to the risk of developing SLE. It is noteworthy that susceptibility loci of SLE are shared by other immune-related diseases. Thus, common molecular pathways may be involved in the pathogenesis of these diseases. In this review, we summarize the key loci, achieving genome-wide significance, which have been shown to predispose to SLE. Analysis of relevant molecular pathways suggests new etiologic clues to SLE development. These genetic loci may help building the foundation for genetic diagnosis and personalized treatment for patients with SLE in the near future. However, substantial additional studies, including functional and gene-targeted studies, are required to confirm the causality of the genetic variants and their biological relevance in SLE development.

Highlights

► GWASs have advanced our understanding of the genetic basis of SLE. ► Over 40 key loci have been identified and confirmed in various ethnic populations. ► Most SLE-associated gene products implicate key pathways in the disease pathogenesis. ► Common pathways may be involved in the pathogenesis of various autoimmune diseases. ► Environmental factors play important roles in the pathogenesis of SLE.

Introduction

SLE is an unusually heterogeneous disease, characterized by autoantibody production and immune complex (IC) deposition leading to multi-organ damage. SLE affects predominantly women (prevalence ratio of men to women is 1:9), especially during child-bearing years [1]. Epidemiological studies suggest strong contribution of genetic factors in the etiology of SLE. SLE develops with a high heritability (>66%) and high sibling risk ratio (8 < λs < 29), and a higher concordance rates between monozygotic twins (24–69%) relative to dizygotic twins or siblings (2–5%) [2].

Over the past several decades, a large set of genes and genomic regions involved in SLE susceptibility have been revealed through linkage analysis and candidate gene studies. Candidate gene searches for SLE susceptibility, based on their functional relevance to disease pathogenesis, have revealed class II alleles of the major histocompatibility complex (MHC) and the Fcγ receptor (Fcγr) genes confer strong and consistent predisposition to SLE in various ethnic groups [3]. In addition, many non-MHC variants have been identified as common susceptibility genes for SLE in different ethnic groups. Genome-wide linkage study is a method successfully employed in identifying genetic loci of SLE in multiplex families.

Genetic loci discovered by genome-wide linkage studies usually encompass several megabases. The diversity of regions proposed has created a challenge in fine mapping. GWAS is a high throughput technology, capable of “pin-pointing” disease-causing genes (in contrast to genome-wide linkage analysis). Since 2008, numerous GWASs have been performed in patients with SLE in various ethnic populations [1], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19]. This studies (or studies with this approach) confirmed genetic associations of over 40 genes/loci with SLE during the past 4 years (Table 1 and Fig. 1). Interesting, many of these risk loci shared between SLE and other autoimmune diseases (Table 2), implying that common molecular pathways exist among various autoimmune disorder processes. The association of 36 non-MHC loci SLE genes (p < 5 × 10−8) resulted in a dramatic expansion of our understanding of the genetic basis of SLE.

It is noteworthy that all of these non-MHC loci have a modest magnitude of risk with odds ratios range from 1.15 to 2.30 (as shown in Table 1). In this review, we summarize the current understanding in the genetics of SLE, with a focus on the susceptibility loci identified to date (p < 5 × 10−8). Although these loci do not account for the bulk of the disease heritability [5], they do implicate important pathways in the pathogenesis of SLE.

The HLA is the most gene-dense region of the genome, encoding more than 120 functional genes in humans distributed over a 3.6 Mbp region. Many of these genes function in the immune system. This region has been associated with almost diseases involving autoimmunity, inflammation and host defense against infections. To date, all SLE GWAS in various populations have identified the HLA region as the strongest determinator of genetic risk [4], [6], [7], [8], [11]. The HLA can be subdivided into three classes (I, II, and III) with a strong linkage disequilibrium (LD) spanning the region.

Genes in HLA Class II are prominent candidates for SLE susceptibility. Three haplotypes in this class have been revealed to be associated with SLE risk [20]. HLA-DRB1 has been identified as a consistent association locus with SLE in different ethnic populations, while the specific risk to these populations varies by haplotype and serotype. Specifically, the DRB1*1501 serotype as well as DRB1*0301 holds the strongest evidence of association [20]. Indeed, these associations have been shown to consistently relate to SLE through GWAS in different ethnic populations [5], [12]. SNP rs2301271 near HLA-DQA2 was associated with anti-dsDNA-negative SLE compared with healthy controls, and this SNP may contribute to the association to HLA-DRB1 locus [1]. Likewise, rs2187668 at HLA-DR3 was significantly associated with anti-dsDNA and the association was even stronger in anti-dsDNA-positive SLE subjects compared with anti-dsDNA-negative subjects [1]. Furthermore, the role of SLE-associated HLA Class II alleles in initiating SLE-relevant autoantibody responses has been revealed in humanized mice expressing the HLA-DR3 transgene but not other DR or DQ alleles [21].

Complete deficiencies of complement components, especially the deficiencies in many of the early components of the classical complement pathway, are associated with SLE. For example, it has been reported that a complete deficiency of the C1q immune complex is associated with a 93% risk of SLE. Although related complete deficiencies of C4 or C2 are rare, they as well confer a high risk of developing SLE [20]. Previous studies have shown that more than 75% of patients with C4-deficiency and approximately 20% of those with C2-deficiency develop SLE or a lupus-like disease [22]. These deficiencies are clearly different from most candidate variants, so they are strong predictors. The deficiency of C4A is related to SLE susceptibility in various ethnic groups, including European populations and East Asian populations [20]. Super viralicidic activity 2-like (SKIV2L) gene, a Class III gene, is considered as a susceptibility gene to the risk of SLE independent of Class II loci [22]. Recently, SNP rs3131379 in MSH5 exhibited a high SLE-associated signal in a GWAS [8].

Notably, a study using high-density SNP screening of the MHC region identified numerous independent loci associated with SLE, including HLA-DRB1*0301, DRB1*1401, DRB1*1501 and the DQB2 alleles, CREBL1, MICB and OR2H2 [22]. Overall, all of these studies highlight the involvement of HLA genes to the pathogenesis of SLE.

Protein phosphatase nonreceptor type 22 (PTPN22) encodes the lymphoid tyrosine phosphate protein, which is known to inhibit T-cell activation through interacting with cytoplasmic tyrosine kinase (CSK) and suppression of T regulatory cells. The SNP rs2476601 has been reported to be associated with SLE and also with T1D and RA [23]. Indeed, PTPN22 has been associated with the development of multiple autoimmune diseases [20], including Graves' disease, Hashimoto thyroiditis, myasthenia gravis, systemic sclerosis, generalized vitiligo, Addison's disease, juvenile idiopathic arthritis, alopecia areata, and SLE. The involvement of PTPN22 in these multiple autoimmune disorders provides evidence for shared pathogenic mechanisms despite of different disease manifestations. SNP rs2476601 at PTPN22 was identified as a susceptibility locus for SLE through both GWAS [8] and replication study [5] in the European, Hispanic and African American populations, but not the Asian population [4], [12]. The difference may be attributable to greater variability in allele frequencies in European populations (2–15%). The associated variant increases the intrinsic lymphoid-specific phosphatase activity of PTPN22, which reduces the threshold for T-cell receptor (TCR) signaling and promotes autoimmunity [24]. In addition, a follow-up study revealed that PTPN22 is also associated with anti-dsDNA-positive but not anti-dsDNA-negative autoantibody production in SLE [1].

TNFSF4 (also known as OX40L) is a co-stimulatory molecule on the surface of antigen-presenting cells (APCs), and its receptor OX40 is expressed on activated CD4+ and CD8+ T cells. Their interaction has been shown to both promote the activation of conventional T cells and inhibit the generation and function of IL-10-producing CD4+ type 1 regulatory T cells. A study using both family-based and case control approaches identified a risk variant (rs2205960) upstream of TNFSF4 is related to SLE. Protective and risk haplotypes marked by a series of tagging SNPs were also observed. In addition, the risk haplotype was proven to be correlated with increased expression of TNFSF4 [25]. The increased expression of TNFSF4 was thought to predispose to SLE either by augmenting enhances interactions with either APCs or modulating T-cell activation via the TNFSF4 receptor [25]. In vitro, TNFSF4 has been reported to suppress the generation of IL-10-producing T regulatory cells needed for tolerance; whereas mutations in this pathway have been known to cause loss of tolerance and autoimmunity [26]. The initial association of TNFSF4 with the risk of SLE was later confirmed in the European and Chinese populations [4], [5].

STAT4 is a key signaling molecule, which is essential for signal transduction by IL-12, IL-17, IL-23 and type I IFN signaling in T cells and monocytes. It has been demonstrated that STAT4 mediates the differentiation and proliferation of both T helper 1 (Th1) and Th17 cells which may promote the development of autoimmune diseases [27]. Studies on mouse models showed that STAT4-deficient mice display reduced manifestation of T-cell-linked experimental autoimmune diseases, such as myocarditis, arthritis, encephalomyelitis, colitis, and autoimmune diabetes [28]. Recently, several GWASs on SLE have identified STAT4 as a susceptible gene in both the Caucasian and Asian populations [4], [8]. STAT4 has also been associated with other autoimmune disorders [27] such as Sjogren's syndrome, rheumatoid arthritis (RA), inflammatory bowel disease, and type 1 diabetes (T1D). All of these studies suggest that STAT4 plays a pivotal role in the development of inflammatory process, which may be used as a therapeutic target of these diseases.

Two intergenic SNPs (rs2732552 and rs387619), located between PDHX and CD44 on 11p13, were associated with SLE in a recent multiethnic study involving the European, African American and Asian populations [13]. PDHX encodes the E3-binding protein subunit of the pyruvate dehydrogenase (PDH) complex that is involved in the conversion of pyruvate to acetyl coenzyme A. CD44 encodes a cell-surface glycoprotein, which plays important roles in lymphocyte activation, recirculation and homing, apoptosis and so on. Previous studies showed that T cells from SLE patients overexpress CD44 [29]. The overexpression of CD44v3 and CD44v6 isoforms in T cells was not only observed in the blood of SLE patients, but also correlated with its activity [30]. These studies indicate that CD44 might be a more plausible candidate gene for SLE, considering its biological implications for SLE.

Neutrophil cytosolic factor 2 (NCF2, also known as p67phox) is induced by IFNγ and specifically expressed in many immune cell types, including B cells. It is a critical cytosolic subunit of NADPH oxidase system and has an important role in electron transport and reactive oxygen species (ROS) production. NCF2 plays a positive role in B-cell activation [31], resulting in increased autoantibody production. The above evidence suggests that NCF2 is likely a potential susceptibility gene for SLE. Indeed, NCF2 was recently proven to be associated with increased SLE risk in different populations [5], [17], [22].

IL-10, secreted by a variety of cell types in response to several activation stimuli, is an important regulatory cytokine capable of downregulating immune responses. IL-10 is also known to promote B-cell functions through facilitating proliferation, differentiation and antibody production. Increased production of IL-10 by peripheral B cells and monocytes has been shown to correlate with disease activity in SLE patients. The polymorphisms in IL-10 were reported to be associated with SLE in several studies involving small cohorts of European, Hispanic American and Asian populations [22]. Recently, a GWAS of SLE in individuals of European ancestry identified an SNP (rs3024505) in IL-10 that is associated with SLE. The variant associated with SLE was also reported to contribute to risk of ulcerative colitis [32] and type 1 diabetes [33], suggesting the possibility of shared pathophysiology in the IL-10 pathway across different autoimmune disorders.

RasGRP3, expressed in numerous B-cell lines and endothelial cells, is a Ras activator. In a recent study, Rasgrp3−/− mice showed modestly lower serum levels of some immunoglobulin types, accompanied by reduced basal and BCR-regulated Ras-Erk signaling in vitro, suggesting that RasGRP3 functions downstream of BCR [34]. A large-scale association study in a Chinese Han population identified that an SNP (rs13385731) at the RasGRP3 locus to be associated with SLE [4]. This variant may cause suppression of RasGRP3. Further studies showed that rs13385731 is associated with a number of specific phenotypes of SLE, such as malar rash, discoid rash, serositis and antinuclear antibody in case-only analyses [35].

BLK encodes a nonreceptor tyrosine kinase of the src family that is typically involved in B-cell receptor signaling and B-cell development. Similarly, LYN encodes a tyrosine protein kinase, which has unique roles in B lymphocyte signaling. BANK1 encodes for a B-cell-specific scaffold protein involved in B-cell receptor signaling. The activation of BANK1 can regulate B-cell receptor-induced calcium mobilization from intracellular calcium stores, altering the B-cell activation threshold. The proteins encoded by these three genes (BLK, LYN, BANK1) operate in the B-cell receptor signaling and have been reported to be related to SLE [36]. Specifically, two SNPs (rs2618476 and rs13277113) of BLK were reported to be associated with SLE in European populations. The rs13277113 was further proved to be associated with reduced expression of BLK [8]. Both SNPs were subsequently validated in the Asian populations [22]. In addition, the polymorphisms of BANK1 and LYN have been shown to contribute to SLE risk in European-derived populations by GWAS [8], [11]. However, neither BANK1 nor LYN were shown to be associated with SLE in Chinese or Asian GWAS, except that rs10516487 of BANK1 showed a weak association with SLE in a GWAS on Asian population [4], [12]. This phenomenon might due to the low frequencies of these SNPs in Asian populations. A genotype–phenotype correlation study revealed BANK1 is also related to anti-dsDNA-positive but not anti-dsDNA-negative autoantibody production in SLE patients [1].

PRDM1 and ATG5 are involved in B-cell differentiation and development. Therefore, both of them may have potential roles in the pathogenesis of SLE considering their biological functions. To date, the variants within PRDM1ATG5 gene region have been shown to be associated with SLE risk in different populations [4], [5], [8], with the strongest association at rs548234. The variant has been shown to increase the transcript level of ATG5 in individuals with homozygous for the C allele. Because of the role in B-cell differentiation for PRDM1, the variants that affect PRDM1 could allow the differentiation of plasma cell differentiation, which further propagates B-cells activity and autoantibody production [27]. Therefore, both ATG5 and PRDM1 could potentially have causal effects for SLE. Further studies are needed to establish which (or both) of these genes plays a role in genetic susceptibility to the SLE.

IKZF1 encodes a transcription factor which belongs to the zinc-finger DNA-binding proteins family, associated with lymphocyte differentiation and proliferation, as well as self-tolerance through regulation of B-cell receptor signaling. In addition, it has also been shown to play a role in regulation of STAT4 transcription [37]. Reduced expression levels of IKZF1 in peripheral blood are observed in patients with SLE [12]. A recent GWAS in a Chinese Han population has identified rs4917014 within IKZF1 as a novel SLE susceptibility locus, indicating it may play a role in downregulating IKZF1 expression [4], and it has been considered as a strong candidate locus in European populations [5]. In addition to SLE, case-only study has associated IKZF1 with renal nephritis and malar rash [35].

IFIH1 (also called MDA5), a DEAD box helicase, is a cytoplasmic sensor of dsRNA that promotes IFN-I production when activated by viruses. It has been hypothesized to play an important role in the pathogenesis of multiple autoimmune diseases [38]. Variants in IFIH1 have been shown to be associated with several autoimmune diseases [22], such as T1D, Graves' disease, and psoriasis. A missense allele of IFIH1 (rs1990760) has been identified to be related to SLE, which could increase transcript levels of IFIH1 [5]. In addition, a study showed that IFIH1 rs1990760 T allele was correlated with increased levels of IFN-induced gene expression in PBMCs in response to a given amount of serum IFN-α in anti-dsDNA-positive patients [39]. It is worth mentioning that the SNP rs1990760 has been considered as a significant association to SLE without reaching GWAS significant level (P = 3.3 × 10−7).

IRF5, IRF7 and IRF8 are the members of the interferon regulatory factor (IRF) family. These genes are characterized by a conserved N-terminal DNA-binding domain containing tryptophan (W) repeats. They belong to a group of transcription factors involved in modulation of immune cell growth, differentiation, apoptosis and type I IFN signaling pathway. The associations between polymorphisms of these three gene and SLE risk have been identified in several large-scale association studies [1], [4], [5], [7], [8], [9], [17]. Besides, several variants of these three genes (IRF5, IRF7 and IRF8) have already been further proven to be correlated with increased levels of their transcript and protein expressions, respectively [40]. Among of them, IRF5 is one of the most strongly and consistently associated SLE loci outside the MHC region with six variants detected in multiple ethnic groups (using both candidate gene and GWAS approaches) [1], [4], [5], [7], [8]. Studies in animal models demonstrated that IRF5 is necessary for the development of lupus-like disease in mice, implying that IRF5 plays a critical role in mediating SLE pathogenesis [22]. However, relevant report about IRF7 and IRF8 is very little to date. Therefore, further studies for these genes are needed to clarify the roles of them in the pathogenesis of SLE.

ETS1 is a prototype ETS family transcription factor that has been to bind to IFN stimulated response elements (ISRE) and may function as a negative regulator of IFN-I induced transcription. ETS1 is also reported as a negative regulator of the differentiation of Th17 cells and B cells [12]. ELF1 is a member of ETS family of transcription factors and play important roles in T-cell development and function. Previous study has shown that ETS1-deficient mice can develop lupus-like disease with high titers of autoantibodies, immune complex-mediated glomerulonephritis and local activation of complement [41]. ETS1 has been identified as a novel SLE susceptibility locus in Asian populations [4], [12]. The SNP rs6590330 is the top associated variant at this locus which may potentially play a role in decreasing ETS1 expression [4]. As for rs1128334, expression of ETS1 from the risk “A” allele is reduced comparing to that from the “G” allele in the PBMC of healthy individuals, confers an increase in the risk of developing SLE [12]. ELF1 has been identified as a novel SLE susceptibility locus through a GWAS in Asian populations [14]. Further database analysis and subsequent RT-PCR experiment have supported a role of ELF1 in SLE risk and suggested a potentially tight regulation for ELF1 expression [14].

Tyrosine kinase 2 (TYK2) is a member of the tyrosine kinase and involves in the STAT signaling pathway that is important for signaling by type I IFN and induction of Th1 cell differentiation upon antigen stimulation of dendritic cells. Indeed, previous study has identified the association between variants in TYK2 and increased expression of type 1 IFN gene [42]. Thus, TYK2 may be an interesting candidate gene for SLE. A variant (rs280519) of TYK2 has been confirmed to associate with susceptibility to SLE in a recent GWAS [17], which was further confirmed that rs280519 is associated with increased gene expression and IFN production [43]. Furthermore, a large-scale meta-analysis has detected a significant genetic association of TYK2 SNPs (rs34536443 and rs2304256) with autoimmune and inflammatory diseases [44].

UBE2L3 (also known as UbcH7) is an E2 ubiquitin-conjugating enzyme that is widely expressed by lymphocytes. UBE2L3 is involved in the degradation of Toll-like receptors (TLR) [45]. In SLE, signaling through the endosomal TLR is considered to be a key pathway for the generation of interferon-α (IFN-α) [46]. Recently, GWAS in multiple populations confirmed that genetic variations in the UBE2L3 or HIC2-UBE2L3 region are associated with SLE [4], [5], [8]. Additionally, UBE2L3 gene has been also shown to confer risk to several autoimmune diseases, including rheumatoid arthritis [47] and Crohn's disease [48].

TNFAIP3 encodes a zinc-finger protein and ubiqitin-editing enzyme (A20), which has been shown to inhibit NF-κB activation as well as TNF-mediated apoptosis. TNIP1 gene encodes an A20-binding protein (TNFAIP3-interacting protein 1) which involves in autoimmunity and tissue homeostasis through the regulation of NF-κB activation [49]. The proteins encoded by TNFAIP3 and TNIP1 are important regulators of the NF-κB signaling pathway, hence, indicating their potential roles in the pathogenesis of SLE. The association between the polymorphisms of TNFAIP3 and SLE was revealed through several large-scale GWASs in European and Asian populations [4], [5], [6], [50] with the strongest association at rs2230926 (located in the third exon of TNFAIP3). Furthermore, variants near TNFAIP3 have been associated with risk of developing many other autoimmune diseases [38], including RA, T1D, psoriasis, and celiac disease. TNIP1 was identified by GWAS as a novel susceptibility locus for SLE in a Chinese Han population and subsequently validated in a European-derived population [6].

SLC15A4, a solute channel protein, is a member of the solute carrier superfamily of intrinsic membrane transporters. It has been reported that SLC15A4 is involved in Nod1-dependent NF-κB signaling and plays a potential role in the antigen presentation in immune response [51], indicating its contribution to SLE. Recently, SLC15A4 has been identified as a candidate susceptibility locus for SLE through GWAS in a Chinese population [4], and the rs10847697 variation has been shown to be associated with discoid rash in case-only analysis of SLE [35]. Such association has not yet been identified in other ethnic populations.

PRKCB is a member of the protein kinase C (PKC). PKC comprises a family of closely related serine–threonine protein kinases that can be activated by calcium and second messenger diacylglycerol. PRKCB has been reported to be involved in B-cell receptor (BCR)-mediated NF-κB activation. Furthermore, inhibition of PRKCB promotes cell death in B lymphomas characterized by exaggerated NF-κB activity [52]. All of these suggest that PRKCB might play a potential role in the pathogenesis of SLE. A GWAS performed in a Chinese Han population has identified a variant in PRKCB is association with SLE [15], however, it has not been reported in any other populations. Therefore, further researches are needed to prove its role in the SLE risk.

ITGAM (also known as CD11b or complement receptor 3) is a single-pass type I membrane protein predominantly expressed in a number of myeloid cells including macrophages, monocytes and neutrophils. As a receptor for iC3b fragment that is produced during complement activation, and ITGAM thereby takes part in the uptake of complement-coated particles and the clearance of immune complexes, suggesting that it might be relevant to SLE [53]. Associations between SLE susceptibility and ITGAM or the ITGAMITGAX region have been reported through GWASs in European populations [7], [8]. SNP rs9888739 showed the strongest association at this locus. However, a fine-mapping study indicated the causal variant as rs1143679, with an effect on structural and functional changes of ITGAM, contributed to SLE risk [54]. The SNP rs1143679 was subsequently confirmed to be associated with SLE susceptibility through meta-analysis in multiple populations [55]. This association has not been confirmed in Asian populations due to the low frequency of this risk allele [55], [56].

Although most of SLE risk loci identified through GWAS are implicated in known SLE pathways, a few other loci do not have apparent function in pathways known to lead to SLE. These genes include PXK, TMEM39A, AFF1, PTTG1, TNXB, UHRF1BP1, JAZF1, XKR6, C8orf12, WDFY4 and CLEC16A. With TMEM39A as an example, the SNP (rs1132200) identified as being associated with SLE in this locus has also been implicated in the risk of MS [57], [58]. The mechanisms by which TMEM39A increases the risk for SLE and MS are unknown. Therefore, further studies are required in order to fully understand how variations in these loci are involved in the pathogenesis of SLE.

Although SLE is an autoimmune disease with higher concordance rate in monozygotic twins than in dizygotic twins or siblings (24–69% versus 2–5%) [2], but not all monozygotic twins develop SLE. This will be a strong evidence to show an important role of the environmental factors in the pathogenesis of SLE [59], [60], [61]. Since 1997, more interests have been focused on different environmental factors contributing to autoimmune diseases like SLE, RA, MS and psoriasis [59]. Some certain environmental triggers including smoking and infections have already been identified [62]. In addition, the effects of environmental exposures on epigenetic determinants such as DNA methylation have been taken into consideration [59]. For example, hydralazine and procainamide can induce lupus-like syndromes and are known to inhibit T-cell DNA methylation [62]. Recent animal and preliminary human studies have shown that T-cell functions affected by DNA hypomethylation may contribute to the risk of idiopathic and drug-induced SLE [63].

Section snippets

Conclusion

In the past 4 years, GWAS has contributed tremendously to the identification of key loci that are associated with the risk of developing SLE. In this review, we summarized and evaluated the importance of these loci in respective molecular signaling pathways, and suggested new etiologic clues to SLE development. Fully identifying these genetic variants will help to pave the way toward accurate genetic diagnosis and render personalized treatment for patients with SLE a reality. Considering that

Epilogue

The advent of GWASs, in which hundreds of SNPs are genotyped to capture indirectly majority of the genome's common variations, has revolutionized the field of human genetics by identification and robust replication of common gene variants that confer susceptibility to SLE. In this review, we summarize the current advances in the understanding the genetic basis of SLE and focus on the established associated risk loci identified to date (p < 5 × 10−8) through GWASs. However, most of these

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