Introduction

As a chronic autoimmune disease, systemic lupus erythematosus (SLE) is associated with the production of autoantibodies and immune complex deposits and affects multiple organs and systems. The mechanism remains unknown, but there is a strong association between the development of SLE and hormonal, environmental, and genetic factors [1]. Global incidence and prevalence statistics for 2023 showed large geographic variation in SLE [2]. The highest prevalence was in American Indian/Alaskan females, followed by Black females. Consequently, White females and Asian/Pacific Islander females were roughly the same. Compared with North America and Western Europe, although Asian SLE patients have been considered to have a more severe course than White patients [3], the data are less reliable. And retrospective cohort studies in the last decades have shown that SLE appears to be increasing in Asian regions such as China, Japan, and Thailand, both in terms of morbidity and mortality [4,5,6].

Originally discovered to act in antiviral activity, type I interferons (IFNs) are a family of cytokines that target viral replication [7]. Moreover, it was later found to play a crucial part in innate immune activation and adaptive immune responses [8, 9]. At the human genome level, type I IFN include 13 IFN-α isoforms, as well as single forms of IFN-β, IFN-ε, IFN-κ, and IFN-ω. They all bind to the same IFN-α and β receptors, with members of IFN-α and IFN-β being the most widely studied [10,11,12], which is mediated by the type I IFN receptor (IFNAR) [13]. Previous studies demonstrated that higher serum IFN-α levels or type I IFN activity was present in SLE patients [14]. Subsequent microarray analysis revealed that SLE patients highly expressed a set of genes that are upregulated by type I IFN, such as interferon-stimulated gene factor 3 (ISG3) [15], which accounted for more than 50% of the pathogenesis of human SLE. These all suggested that IFN is closely associated with SLE pathogenesis [16]. Recent work in the field of type I IFN has provided additional insights into the pathogenesis of SLE. Insufficient mitophagy is demonstrated in T cells from SLE patients and lupus mouse models [17]. This mitochondrial abnormality enhances T-cell necrosis, which promotes autoantibody production and exacerbates the degree of inflammation and organ damage [18]. Meanwhile, mitophagy also inhibits the ability of type I IFN synthesis [19]. All of these imply the possibility that it could be a therapeutic target for SLE. Some studies estimated Asian ancestry was consistently linked to increased type I IFN responsive genes as well as a difference in type II IFN expression in monocytes and T cells. And they develop SLE at a younger age and with more severe manifestations, including lupus nephritis (LN), tend to develop more severe disease with a greater number of organ manifestations and tissue damage accrual. GWAS has demonstrated that genetic loci such as IRF5, STAT4, TYK2, and IRF8 of the type I IFN signaling system are highly associated with SLE onset and progression [20,21,22]. As one of strongly associated gene combinations, the interaction of STAT4 and IRF5 to increase SLE susceptibility in some populations has been reported in previous studies. But the individual effect or synergy of polymorphisms in Asian populations have not been systematically described.

Mechanism of STAT4-induced SLE

STAT4 is a member of the STAT family. The STAT family serves as a family of proteins that mediate interferon-dependent gene expression and includes STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6, which play important roles in several signaling pathways. STAT4 has been found to be involved in many physiological and pathological regulatory processes ranging from pathogen response to cytokine secretion [23]. It is located in chromosome 2q32.2–32.3 and encodes 748 amino acids and is found to express at the site of inflammation in immune cells such as monocytes, dendritic cells, and macrophages [24]. The studies through GWAS also found that a higher risk of developing SLE and other autoimmune illnesses has been linked to variations in the STAT4 transcription factor gene and numerous other genes in the STAT4 signaling pathway, including IL (interleukin)-12A, IL-12B, JAK2, and TYK2 [25]. Ueno et al. [26] showed that CD11c+ DN (double negative) B cells elevated in the peripheral blood of SLE patients, particularly those who have lupus nephritis. CD11c+ DN B cells may also be discovered in the tissues of lupus kidneys. Additionally, human CD4+ T cells produce IFN- and IL-21 most effectively through the IL-12-STAT4 axis, which may be crucial for the formation of CD11c+ DN B cells in human SLE. A recent study on STAT4 expression [27] showed that abnormal IL-12-mediated STAT4 transcriptional regulation is linked to STAT4 haplotypes associated with SLE. Patients with SLE carrying risk variants have significantly increased CD4 pro-inflammatory capacity, which increases the possibility of disease progression (Fig. 1). In addition, IL-23 signaling and the formation of Th1 and Th17 cells are also involved in STAT4. They are widely associated with some inflammatory responses as well as autoimmune diseases [28, 29]. STAT4 is also essential for type I IFN receptor signaling and Th1 differentiation [24, 30, 31]. Therefore, variants of STAT4 may influence the prevalence of SLE through dysregulation of type I IFN signaling [32].

Fig. 1
figure 1

Mechanism of STAT4-induced SLE IL-12 or IFN-β-induced STAT4 can be activated in Th1 cells. STAT4 is involved in IFN formation via IL-12. IL-12p40 and IL-12p35 bind to IL-12Rb1 and IL-12Rb2, respectively, recruiting the associated kinases (Jak2 and Tyk2) and phosphorylating them upon binding to STAT4. STAT4 homodimer formation and nuclear translocation followed by binding and transcription of specific genes, which in turn induces the pathogenesis of SLE. Also, IL-12-induced activation of MKK3/6 and p38 MAPK is required for its production of IFN

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Association of STAT4 rs7574865 and rs7601754 with SLE in Asian population

The single nucleotide polymorphism (SNP) rs7574865 of STAT4 increases STAT4 transcription and strengthens the response to IL-12 and IFN-I signaling, which increases the likelihood of developing lupus [33,34,35]. In Asian populations, eight SLE studies which were included in the 2008 meta-analysis [32] showed that Asian population’s minor T allele frequency of STAT4 rs7574865 SNP considerably increased (OR = 1.53, 95%CI 1.37–1.72), compared with population of European origin (OR = 1.61, 95%CI 1.39–1.88). An updated meta-analysis in 2022 included 21 studies showed similar results [36], confirming that the STAT4 rs7574865 T allele was strongly positively correlated with SLE and the prevalence of this allele was the highest in Asians and lower in Europeans. Although another SNP rs7601754 was shown to be strongly linked with SLE in the study by Hui Yuan et al. [37], the P-values for this SNP were less significant than those discovered for rs7574865. Yang et al. [38] showed that these two sites were independently associated with SLE risk in Hong Kong and Thailand populations. When controlling for the influence of rs7574865, the correlation P-value of rs7601754 was 0.00034. The results of this study suggested that any functional variation in this locus affects the risk of SLE, which is at variance with what is known about the results in White people. As for other genotypes [39], a meta-analysis of 26 studies, including studies on Asians, Europeans, Americans, and Latin Americans, also demonstrated an increased frequency of T allele detected in rs10168266 SLE cases from Asia. The detection and analysis of autoantibodies including anti-SSA, anti-SSB, and anti-dsDNA (double-stranded DNA) in the research of 675 female SLE patients in northern China indicated that they were strongly associated with SLE patients in the female population in mainland China (Table 1) [40].

Table 1 Comparison of the association between STAT4 and IRF5 SNPs polymorphism and SLE in each ethnicity
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The risk allele for STAT4 may raise the likelihood of more severe clinical manifestations in SLE

Previous studies in lupus mice models showed that STAT4 deficiency exacerbates nephritis and elevates the risk of disease [41]. A study of risk alleles and disease associations in European ancestry showed that STAT4 rs7574865 was associated with more severe clinical manifestations of SLE, such as nephritis, the production of anti-dsDNA, and earlier onset age [42]. A later study on the Swedish population had similar conclusions [22]. Meanwhile, another study in a Swedish population [43] found a correlation between the prevalence of STAT4 rs10181656 G allele and increased risk of ischemic cerebrovascular disease (ICVD) and prothrombotic antiphospholipid antibodies (aPL) in SLE patients. This suggested that the risk allele for STAT4 may raise the likelihood of cerebrovascular events in SLE. However, it has not been found in Asian populations. Similarly, rs7582694 or rs7601754, which are associated with particular clinical manifestations of SLE including photosensitivity and malar rash, has not been detected in the Iranian population [44]. Since the new findings all have higher OR values, this may represent disease severity in the Asian population. But more evidence is needed to correlate polymorphisms with disease activity or features of clinical presentation. A recent study on the Vietnamese population [45] observed that rs7582694 C allele carriers on STAT4 had a greater risk of developing lupus nephritis. Compared with the control group, patients with STAT4 rs7582694 C/C or G/C genotypes were more likely to experience hematuria, have greater levels of dsDNA antibodies in their serum, and be more likely to develop lupus nephritis (Table 2).

Table 2 Correlation between the risk allele of STAT4 and IRF5 SNPs and clinical manifestations of SLE
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Mechanism of IRF5-induced SLE

IRF5, a transcriptional mediator of the interferon-induced signaling pathway, is a member of the interferon regulatory factor (IRF) family [46]. Many novel IRF5 isoforms produced by alternative splicing are specifically expressed in SLE patients, which means that they can be used as biomarkers for autoimmune diseases. IRF5 is stimulated by IFN-α/β and positively regulates expression of IFN-α/β itself. It also can induce expression of inflammatory cytokines and apoptosis [47]. IRF5 is a critical downstream mediator of MyD88-dependent Toll-like receptor (TLR) signaling that regulates both arms of the immune system. Genetic variants within or near IRF5 are robustly associated with SLE [48]. And IFN-α itself transcriptionally upregulates IRF5, and circulating SLE triggers, such as TLR-stimulating antigens, induce IRF5 activation and nuclear translocation. In addition, there are many overwhelming evidences for the induction of SLE by IRF5 in a mouse model of lupus erythematosus. For instance, when challenged with methylated BSA in the murine model of acute antigen-induced arthritis, Irf5−/− mice showed reduced knee swelling [49]. A study [50] found that MRL/lpr IRF5-deficient lupus mice had lower titers of anti-nuclear antibodies and anti-dsDNA autoantibodies; complement fixation; lower levels of IgG isoforms IgG2a, IgG2b, and IgG3; lighter kidney accumulation; and higher survival rate (Fig. 2).

Fig. 2
figure 2

Mechanism of IRF5-induced SLE pDC (plasmacytoid dendritic cells) is promoted by T- and B-cell effector functions, in combination with neutrophil (N)-mediated I IFN production and recognition of common TLR ligands: TLR7, TLR8, and TLR9, with MyD88 as mediator of IRF5 activation. RIG-I and MDA5 mainly recognize dsRNA and then bind to the adaptor MAVS, which can activates IRF3 and IRF5. IRAK-4 is recruited by MyD88, which binds and phosphorylates other kinases to create the conditions for IRF5 to enter the nucleus, where it enters the nucleus to bind and transcribe genes such as IFN-α, thus contributing to the development of SLE

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Association of IRF5 gene rs2004640 and other loci with SLE in Asian population

In previous studies, four IRF5 variants have been prioritized as candidate causal that strongly associate with SLE risk and make up the major risk haplotype in European Caucasians. Two SNPs (rs2004640 and rs10954213, respectively) have been found to be highly correlated with SLE susceptibility in Caucasians [48]. In Asia, rs20046040 seems to be mentioned more often. Hyoung et al. [51] collected a total of 1565 subjects to test whether the Korean population could replicate this association with SLE. The results were similar to those of the White population. The same conclusion can also be confirmed in the Japanese population [52] and Chinese population [53]. In an updated meta-analysis [54], a total of 28 different comparisons including two North American populations and nine Asian populations were included. The findings revealed that SLE was substantially related to the rs2004640 T allele in Asians, Europeans, and Latin Americans. Compared to other ethnic groups, Asians have the lowest prevalence of the T allele. Another interesting finding is that in the Japanese population [52], there were several SNPS in intron 1, such as rs6953165 and rs41298401, whose association with the population was much stronger than that of rs2004640. Lately, the risk allele of rs4728142 switches IRF5 alternative promoter usage by affecting ZBTB3, a likely structural regulator, mediating chromatin looping and ultimately leading to the aberrant transcriptional regulation of IRF5 short transcripts and monocyte/macrophage dysfunction [55]. However, the unique disease-causal mechanisms still needs further study (Table 1).

Anti-dsDNA antibody titers and disease activity are correlated with IRF5 hyperactivity

Experiments in lupus mice have demonstrated that mice IRF5 deficiency could avoid lupus flares and reduce the severity of nephritis. IRF5 hyperactivation is correlated with anti-dsDNA antibody titers and disease activity in SLE patients. A study in a Finnish population [56] revealed a strong connection between discoid lupus erythematosus (DLE) and subacute cutaneous lupus erythematosus (SCLE) and the IRF5 rs10954213 A allele. In the bigger White population, the genetic association study of SLE and disease sub-phenotypes in European populations [57], IRF5 rs729302 associated with nephritis and skin involvement, and rs2070197 was also associated with the latter. There are few studies on IRF5 polymorphisms and SLE disease phenotypes in Asian populations. Although both studies in Chinese populations [53, 58], the frequency of the minimum allele of rs2004640 was substantially lower in Chinese communities than in Western populations. Additionally, there was no significant correlation between IRF5 rs2004640 and the pathology or clinical signs of lupus nephritis in the cohort research of the Chinese population for the time being (Table 2).

The mechanism of STAT4-IRF5

STAT4 and IRF5 are two of the most closely related SLE genes belonging to the same cellular signaling pathway. Both regulate a sizable number of genes in the type I IFN pathway and are the most strongly related and broadly replicated SLE risk genes outside the major histocompatibility complex region [59]. They act together on more than 3190 target genes [59] and also play an important role at different points [60]. IRF5 activates type I IFNs and inflammatory factors by TRL signaling pathways. TLR7 and TLR9 binding to homologous ligands, for example, may significantly transmit downstream signals to activate type I IFN through IRF5 [61]. The type I IFN that is released increases its own production through autocrine and paracrine pathways and activates the IFN-/- receptor (IFNAR) to cause the induction of its target genes. It has been demonstrated that STAT4 binds to IFNAR in humans, causing IFN-/- induced gene transcription and raising cell sensitivity to type I IFN signaling [62]. In different stages of human disease, IRF5 and STAT4 have different impacts on the IFN pathway, and genetic variants in the former that increase the risk of SLE are due to the important role of IRF5 in regulating the production of IFN-α [63], while the STAT4 genotype seems to play a larger role in the elevated IFN-α sensitivity [22]. Early studies have demonstrated that elevated serum IFN-α correlates with SLE activity and severity [64]. In addition, previous findings [59] suggested that IRF5 or STAT4 may not interact directly with type I IFN genes and variants in the regulatory regions of their target genes may be critical for activating the type I IFN pathway. Moreover, the combination with their own functional variants leads to proliferative effects that in turn induce the development of SLE or other immune diseases.

The interaction between STAT4 and IRF5 on SLE

A previous study in Swedish population [22] found that rs10181656 and rs7582694 had the strongest association signals among the 53 analyzed SNP in STAT4. The risk allele of rs7582694 was linked to the production of anti-dsDNA antibodies and showed a 1.82-fold SLE risk multiplied by two separate risk alleles of the IRF5, with a strong combined effect. In a study conducted in 2009 with 1581 cases and 1844 controls [65], covering several countries including Spain, Germany, and Italy, although high levels of STAT4 expression were shown to be associated with SNPs rs3821236, rs3024866, and rs7574865, no interaction with IRF5-related SNPs was observed by regression analysis. Another study in the same year demonstrated similar results [60]: STAT4 genotype demonstrated a dominant effect on the IRF5 rs3807306, the risk variant of IRF5, which was linked to increased serum IFN-α in individuals with STAT4 SLE risk genotype. A study [66] that selected SNP rs2004640 of IRF5 and SNP rs7574865 of STAT4 considered be strongly linked with SLE in the Han Chinese population showed that rs2004640 is less associated with SLE than rs2004640 × rs7574865 (IRF5xSTAT4). In addition, the SNP rs2004640 is found in the IRF5’s 5′ untranslated region (5′ UTR), supporting the notion that rs7574865 superimposing raises the risk of SLE. SLE patients had greater rates of risk-pure TT carriage than controls for both rs7574865 and rs2004640. However, the significant findings of this study need to be further confirmed in a broader population due to the study’s limited sample size.

Targeting type I interferons and their signaling pathways

Important results have been achieved in the development of drugs targeting the type I IFN pathway for the treatment of SLE, and three therapeutic monoclonal antibodies are currently available that directly inhibit IFN-α, called rontalizumab, sifalimumab, and AGS-009 [67]. Rontalizumab, a humanized IgG1-type monoclonal antibody, causes a sustained decrease in the expression of interferon regulatory genes (IRGS) in mildly active SLE patients [68]. However, treatment is not effective in moderate to severe cases [69]. Sifalimumab, a fully human immunoglobulin G1-type monoclonal antibody [67], also is considered a promising therapeutic agent due to the reduction of disease activity in a high IFN signature subgroup of SLE patients in a phase IIb study within safety limits [70]. AGS-009 is a human-derived antibody that utilizes a monoclonal anti-interferon-α antibody to neutralize multiple IFN-α isoforms in patients with SLE [71, 72]. Dose tolerance and safety of AGS-009 were strongly demonstrated in phase Ia. Meanwhile, IFN-I gene signatures (IFNGS) at doses > 0.6 mg/kg for AGS-009 using was neutralized [73]. Due to the fact that it is challenging to properly assess IFN-I protein in the circulation, IFNGS are high in 50–73% of adult patients [74]. Therefore, IFNGS are used to quantify activation of the interferon-I pathway [75]. In addition, successful phase I and phase II trials have found anifrolumab, which directed against IFNAR1, to be particularly effective against high baseline IFNGS and to show positive results in patients with cutaneous and arthritic manifestations [74]. A recent study that combined analysis of the TULIP-1 trial (contains 364 study individuals) and the TULIP-2 trial (contains 362 study individuals) showed [76] ethnic differences in IFNGS expression: Asian populations had the highest rates of high IFNGS expression, and they had higher rates of abnormal serum markers at baseline. Lowered joint induration and edema counts, C3 and C4 levels, and a trend toward improved anti-dsDNA antibody levels were all observed in individuals with high IFNGS treated with anifrolumab from baseline to week 52. Regarding safety, common adverse effects were nasopharyngitis, bronchitis, upper respiratory tract infection, and herpes zoster. In conclusion, treatment with anifrolumab was more effective and well tolerated in subgroups with high rates of abnormal baseline serum markers or high rates of IFNGS expression in patients with moderate or even severe SLE who received consistent and standard therapy. These results are essentially comparable across a variety of demographic and clinical categories, but a bigger sampling of studies in other subgroups, such as age, is still required (Table 3) [76].

Table 3 Agents targeting interferon pathways, STAT4, and IRF5 in SLE
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Targeting STAT4 and IRF5

Numerous cytokines and hormones are signaled by the Janus kinase/signal transducers and activators of the transcription (JAK/STAT) pathway, such as type I and II IFN, whose activating and inactivating mutations may lead to abnormal immune homeostasis and induce the development of SLE [77]. The past study has demonstrated that STAT4 rs7574865 exacerbates the clinical symptoms of SLE and also significantly increases the risk of vascular disease. To address this, a phase Ib/IIa trial of the JAK inhibitor tofacitinib [78] showed that lecithin and HDL cholesterol levels were improved in individuals with mild-to-moderate SLE who received tofacitinib treatment. Additionally, it changes arterial wall stiffness and improves vascular endothelial cell function. In SLE patients with STAT4 risk alleles, several of these therapeutic effects were more significant. As for IRF5, its excessive activation and ISG expression are not influenced by SLE disease activity or using standard therapies or not, regardless of the administration of prednisolone (PSL), hydroxychloroquine (HCQ), or mycophenolate mofetil (MMF). Although anifrolumab showed a statistically significant reduction in disease activity versus a placebo in SLE patients, the reduction was not dramatic, and besides, a considerable rate of relapse was observed. Nonetheless, inhibition of IRF5 may solve this problem, and more importantly, it can overcome the limitations of current SLE therapies. Scientists created a number of peptide mimics for IRF5, among which N5-1 [79] showed a high affinity for IRF5. It binds and inhibits the activation of IRF5 on a non-toxic basis. It currently shows good protective effects in various lupus mouse models, such as reducing mortality by preventing kidney damage and lowering anti-dsDNA antibody titers. This research provides new evidence for the development and study of IRF5 inhibitors to treat SLE (Table 3).

Discussion

Particularly between White people and Asians, SLE genetic loci are always different. Among these, STAT4 is a clear-cut gene susceptibility for SLE in several racial groups. IRF5 has also been found to be one of the genes most frequently linked to various racial groups. In this review, we summarized their associations with SLE patients. Both activate type I IFNs and inflammatory factors by different ways and in turn induce the development of SLE or other immune diseases. Differences in SLE pathogenesis and clinical manifestations across races arise from differences in STAT4 and IRF5 risk alleles. In addition, we discussed the therapeutic options for type I IFN, STAT4, and IRF5 in terms of their progress so as to provide ideas for developing drugs against targets involved in disease progression.

Racial antibody differences

Different ancestral groups experience diseases differently and with different results. Patients with non-European ancestry, especially those from African, Spanish, and Asia, usually have more severe symptoms and concomitant conditions with an earlier beginning of disease than Europeans [80]. It has been noted that [81] genetic loci that cause heterogeneity in disease inheritance have a high probability of being involved in regulating antibody production. IgG levels, for instance, are heritable and significantly differ between ancestors. Non-Europeans, particularly individuals with SLE who are of African and Asian ancestry, have greater serum IgG levels than Europeans in the general population.

Environmental factors

For the majority of patients, the interaction of susceptibility alleles and environmental variables has a stronger impact on the onset and progression of disease. The results of a large epidemiological survey based on the Anhui population in China [82] showed that the peak prevalence of SLE occurred at the age of 40–50 years. Various factors such as living environment, dietary habits, birth conditions, sun exposure, and vaccination were associated with SLE. In addition, a study addressed the geographical and climatic differences between North and South China, suggesting that because northern China has more sunlight intensity than southern China [83]. Patients in southern China are more likely to develop lupus nephropathy than those in the north, and they also seem to have more disease activity [84]. Another regional research study carried out in Hong Kong that came to the same conclusion also supported it. It turned out that the colder months were when lupus nephritis flared up more frequently [85]. The management of SLE may benefit by maintaining a warm living environment and limiting exposure to temperature extremes. But more research on the related mechanism is required [84]. Besides, it has previously been demonstrated that air pollution causes a systemic inflammatory response [86] and it has also been hypothesized as a potential cause for the onset of autoimmune rheumatic illnesses [87]. A prospective cohort study of the Taiwanese population and air pollution conditions over a 10-year period [88] suggested that may be an increased risk of SLE connected with exposure to elevated levels of airborne gaseous pollutants (CO and NO2) and PM2.5 related to traffic. On the other hand, increased exposure to O3 and SO2 was adversely linked to a higher risk of SLE.

Combined effects of smoking

In SLE, cardiovascular disease (CVD) is the leading cause of death [89]. According to a study published in 2021 [90], smoking and the STAT4 rs11889341 (T) risk allele together enhance the likelihood of myocardial infarction and nephritis in SLE patients. This finding was also demonstrated in European populations. Smoking has long been thought to contribute to the onset of SLE. Although the biological pathways by which smoking increases the transient risk of SLE are unknown, many potential mechanisms exist. Some researchers have speculated that when STAT4 is activated and phosphorylated (pSTAT4), it homodimerizes and translocates to the nucleus where it induces expression of hundreds of genes, resulting in production of IFN-γ, T-helper type 1 and 17 (Th1, Th17) differentiation, and activation of monocytes. The levels of pSTAT4 were almost twofold higher in smokers. However, how SLE risk alleles affect established risk variables that increase the incidence or severity of clinical manifestations of SLE also warrants further investigation in Asians.

Coffee and tea intake influences

Coffee and tea are one of the most commonly consumed beverages all over the world. They consist of a number of bioactive compounds including polyphenols and caffeine. Caffeine could induce an increase of intracellular cAMP, which activating protein kinase A. Therefore, it could interact with different components of the immune system, suppress the release of pro-inflammatory cytokines, influence the activity of macrophages and natural killer cells, and reduce T- and B-cell proliferation and, ultimately, antibody production [91].

An earlier Japanese study [92] showed that consumption of coffee and tea was all associated with an increased risk of SLE, despite differences in the degree of association. Moreover, there are significant interactions between the NAT2 polymorphism and consumption of tea or coffee in relation to SLE risk. Among consumers of black tea, individuals with the rapid acetylator genotype presented lower SLE risk than those with the nonrapid acetylator genotype. However, a recent two-sample analysis using Mendelian randomization (MR) [93] has come to different conclusions that the absence of an association tea intake with RA and SLE in individuals of European. Although rs2472297 has the strongest association with tea intake, genetically predicted tea intake was not causally associated with SLE. Several studies published so far, but no conclusive data are available about the possible contribution of diet to SLE. Since different ethnic populations such as Europeans and Asians have different tea and coffee intake habits, more research is required to investigate. Meanwhile, we need to find more promising approaches that can minimize potential biases in conventional observational studies.

Conclusion

Despite some convincing evidence that STAT4 and IRF5 have functionally related mutations that raise the risk of SLE, but no convincing correlation has been found between the two interacting to increase SLE susceptibility. Studies on the relationship between these two genetic SNPs and the clinical symptoms and activities of disease in Asians are currently lacking, especially Chinese populations, a country with a huge population.

As GWAS begins to bear fruit, susceptibility genes for many complex diseases are widely shared in the population, and several specific Asian disease loci are being identified at an unprecedented rate. The genetic makeup of SLE enables now is better understood thanks to all the studies. To date, genetic analysis is providing new ideas for the treatment of SLE in its own unique way. Precision medicine is currently being used to treat SLE in an effort to increase efficacy by linking genetic targets with clinical heterogeneity to distinctive pathways that are active in patient subgroups [94]. This approach will also increase the approval and study of therapeutic agents for SLE. Due to the uncertainty of the etiology of SLE, comparing genetic variations among various groups and looking into the relationship between genetic background and disease expression can aid in our understanding of disease mechanisms. It is also worthwhile to further explore the impact of interactions between different susceptibility genes in SLE on pathogenesis and clinical manifestations.