DiseaseEndometriosis

One SR and meta-analysis including cohort studies and case–control studies in the study of endometriosis [5] (OR for case–control studies 1.36, 95% CI 1.07–1.73, P = 0.010; RR for cohort studies 1.74, 95% CI 1.10–2.77, P = 0.020), and show the prevalence of SLE in patients with endometriosis was higher than that in the control group. It was rated moderate quality by AMSTAR-2.

Endometriosis is an estrogen-dependent disorder, and the increase in estrogen level can aggravate or induce SLE by suppressing cellular immunity and increasing the formation of autoantibodies [10].

Atopic dermatitis

Atopic dermatitis is associated with an increased risk of cardiovascular, neurological, and autoimmune disease. Meta-analysis showed participants who had atopic dermatitis were at an increased risk of SLE [11] (OR 1.46, 95% CI 1.05–2.04, P = 0.020). The result of AMSTAR-2 was critically low quality.

Allergic rhinitis

Patients with allergic rhinitis had a higher risk of SLE than individuals without [12] (OR 1.36, 95% CI 1.08–1.72, P = 0.009). The result of AMSTAR-2 was critically low quality.

The pathogenesis of atopic dermatitis, allergic rhinitis, and autoimmune disorders was similar and related to the increase of inflammatory mediators and immune dysregulation [13]. The up-regulation of Th2 activity and the increase of IgE production during the development of the disease may be the triggers for SLE in the future.

LifestyleSmoking and drinking

Previous studies showed that moderate drinking reduced the risk of SLE, and smoking increased it [6]. The main mechanisms include the anti-inflammatory mechanism related to alcohol consumption [14], including lower levels of C-reactive protein and fibrinogen in plasma, and Cigarette-related pro-inflammatory mechanisms including an increase in plasma C-reactive protein, oxidative stress, and apoptosis. The effects of drinking status and smoking consumption on chemokine/cytokine concentrations in healthy female nurses in the United States in 2020 and 2021 showed that moderate drinking was related to lower stem cell factor levels [15]. The current smoking status was related to the decrease of B-lymphocyte stimulator and interleukin-10 (IL-10) [16].

An SR of drinking indicated that moderate alcohol consumption might be a protective factor (OR 0.71, 95% CI 0.55–0.93, P = 0.012), while light and heavy alcohol consumption were not related to the risk of SLE [17].

We included four SRs related to smoking from 2004 to 2020. The first [18] pointed out that the current smoking status was correlated with the development of SLE (OR 1.50, 95% CI 1.09–2.08), but there was no correlation among former smokers (OR 0.98, 95% CI 0.75–1.27). The second showed consistent results on the impact of current smoking, but when analyzing non-smokers and former smokers, different regions showed inconsistent results [19]. The third stated that smoking was not only a risk factor for SLE but also hampered disease treatment by reducing the curative effect of belimumab [20]. Therefore, it was suggested that smoking cessation should be the first task in the prevention and treatment of SLE, which was supported in the fourth SR [21].

Vaccination

Vaccination can stimulate antigens to produce a specific immune response, so it is considered the pathogenic factor of SLE. One SR with 12 studies showed that vaccination significantly increased the risk of SLE (RR 1.50, 95% CI 1.05–2.12, P = 0.024) [22]. The results of subgroup analysis and sensitivity analysis both supported this conclusion.

Silicone breast implants

Autoimmune diseases caused by silicone breast implantation have long been a concern, but the SR results seemed to be reassuring. There was no evidence that silicone breast implantation was associated with connective tissue and autoimmune diseases, including SLE (RR 0.65, 95% CI 0.35–1.23) [23].

Helicobacter pylori infection

The molecular simulation, activation of polyclonal lymphocytes, and cell damage produced by Helicobacter pylori may be risk factors for autoimmune diseases. One SR published in 2020 showed that Helicobacter pylori infection was not related to SLE susceptibility (OR 0.97, 95% CI 0.76–1.23, P = 0.820), but its strains (H. pylori cagA positive strains) might be associated with a higher risk of autoimmune diseases (OR 2.65, 95% CI 1.52–4.64, P = 0.001) [24].

Immigrant

It was believed that environmental factors have made a great contribution to its incidence. Based on the findings of five population studies, the incidence of SLE was the highest among immigrants from Africa, Iraq, and South Asia, especially among women and successive immigrant descendants [25]. Assuming that “immigration” is a risk factor for people in the appeal area, the impact of environmental and lifestyle changes behind immigration on the incidence of SLE cannot be ignored.

Others

The SR about vitamin D showed that vitamin D level was negatively related to SLE disease activity [26]. Although there were some reported risk factors, such as ultraviolet radiation, silica, air pollution, pesticides, heavy metals, and so on [6, 27], they were not covered in this paper due to the lack of SR evaluation.

Gene polymorphism

Gene polymorphism means that the structure or nucleotide sequence of the same gene is not the same in different individuals, which is the variation of alleles. Human gene polymorphism plays an important role in elucidating the susceptibility and tolerance of the human body to disease, the diversity of clinical manifestations of diseases, and the responsiveness to drug treatment.

There are three types of genes related to SLE: genes regulating the function of B cells and T cells, genes regulating interferon (IFN), and genes repairing DNA [28]. The gene polymorphism study of this article mainly includes two aspects of B Cell and T Cell Function-related genes and genes regulating IFN.

B cell and T cell function-related genesVitamin D

The vitamin D receptor (VDR) is a member of the nuclear receptor superfamily. By binding to VDR, vitamin D can exert biological functions such as cell proliferation, differentiation, and immune response in the human body, and inhibit the pro-inflammatory activity of Th1 cells and the production of cytokines, such as IL-2, IFN-γ and TNF-α [29].

The polymorphism of the VDR gene was related to SLE, and its polymorphism mainly included the following four types: VDR BsmI(rs1544410), Fok1(rs2228570), ApaI(rs7975232), and TaqI(rs731236). In three studies from 2014 to 2016 [29,30,31], the results showed that the polymorphism of BsmI(rs1544410) and FokI(rs2228570) in the Asian population contributed to the pathogenesis of SLE, but the findings were not replicated in the Caucasian population.

B‑cell lymphocyte kinase

B-cell lymphocyte kinase (BLK), a member of the Src family, is involved in signal transduction downstream of B-cell receptors, B-cell development, differentiation, and signal transduction, and further affects B-cell function [32]. The risk allele variation of BLK may cause changes in the level of BLK protein, which may affect the tolerance mechanism of B cells and induce immune diseases. There was a significant correlation with BLK(rs4840568) (OR 1.32, 95% CI 1.22–1.43, P = 0.010) [33] and BLK(rs13277113) A-type allele (OR 1.36, 95% CI 1.29–1.43, P < 0.001) [34].

Cytotoxic T lymphocyte-associated Antigen-4

Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), expressed on T cells, is a key down-regulated molecule that inhibits T cell activation and regulates its peripheral tolerance [35]. The relationship between rs231775(+49A/G) polymorphism [35,36,37,38] and SLE was studied, and the conclusions based on different races showed significant heterogeneity. The rs231775(+49A/G) polymorphism mainly contributed to the SLE development in the Asian population.

Tumor necrosis factor-α and related gene

Tumor necrosis factor-α (TNF-α) is a proinflammatory cytokine, which can stimulate the production of cytokines, enhance the expression of adhesion molecules, increase neutrophil activation, and act as a costimulatory factor for T cell activation and antibody production. Its function-related proteins and receptors are actively involved in the pathogenesis of SLE. Five SR-based meta-analyses reported TNF-α promoter-308A/G polymorphism [39,40,41,42,43]. These studies were carried out in the China population, and whether the conclusions could be extended to other populations remained to be verified. There were also a series of genes related to TNF, such as tumor necrosis factor-α-induced protein 3 (TNFAIP3) (rs2230926) [44,45,46,47], tumor necrosis factor ligand superfamily member 4 (TNFSF4) (rs2205960) [48,49,50,51], and tumor necrosis factor receptor-associated factor 1, complement component 5 (TRAF1/ C5)(rs10818488) [52] were also related to SLE susceptibility.

Interleukin

Interleukin (IL), a kind of cytokine produced by many kinds of cells, plays an important role in a series of processes such as the maturation, activation, proliferation, and regulation of immune cells. IL-1 gene polymorphism, including IL-1A-889C/T, IL-1B-31T/C, and IL-1B-511C/T, might be associated with a higher risk of SLE [53], which needed more research to prove. IL-6 polymorphisms, rs1800796 and rs1800795, might be risk factors in the previous studies [54,55,56]. However, one study in 2021 showed that rs1800795 was a protective factor, and rs1800796 was not associated with susceptibility [57], which was inconsistent with results from previous studies. IL-10 gene polymorphism rs1800896 was related to susceptibility [28, 58, 59], while rs1800871 and rs1800872 were not related to susceptibility. Although some of them were different in subgroup analysis, we wrote the report based on the results of the general population. The results of research on IL-18 rs187238 were inconsistent. One study showed that there was no relationship between rs187238 polymorphism and SLE in all populations, including the Chinese population [60]. Another study with hierarchical analysis showed that rs187238 was a risk factor for SLE, especially in the Asian population [61].

Human leukocyte antigen

The frequency change of the human leukocyte antigen (HLA) allele is related to SLE. One study focusing on the relationship between HLA-DRB1 allele polymorphism and SLE susceptibility demonstrated that HLADR3, DR9, and DR15 were risk factors [62]. Another study provided evidence to support HLA-DR3 and HLA-DR15 as the risk factors for SLE, and the study acknowledged the existence of inter-ethnic heterogeneity [63].

Interferon regulatory genesInterferon regulatory factor 5

Interferon regulatory factor 5 (IRF5) belongs to the transcription factor family that regulates the activity of the immune system. It is expressed in antigen-presenting cells (including dendritic cells, macrophages, and B cells) and monocytes, and it participates in the pathogenesis of SLE by influencing the antigen-presenting cells [64]. IRF5 rs2070197 T allele and rs2004640 C allele were positively associated with the pathogenesis of SLE [65, 66]. Although rs2070197 showed susceptibility to SLE in the general population (OR 2.13, 95% CI 1.86–2.44, P < 0.001), it had no effect in the Asian population [67]. Since this gene is monomorphic in China and Korea, the population in the two countries was not affected by the disease susceptibility caused by this gene polymorphism. It was speculated that it may be caused by the linkage imbalance between regions, and further studies on the specificity of ethnic populations are therefore needed.

STAT4

The signal transducer and activator of transcription 4 (STAT4) is a transcription factor activated by IFN-α signal transduction, and the increase of IFN-α signal transduction is the main pathogenic promotor of SLE. The genetic variation of STAT4 is related to the risk of SLE. Three SRs showed that there was a significant relationship between the STAT4 rs7574865 T allele and the risk of developing SLE, and the OR value was around 1.60 [68,69,70].

MiR-146a

MiR-146a is identified as a negative regulator of natural immunity, which directly inhibits the downstream transactivation of type-I IFN at the molecular level and targets IRF5. There were some contradictions in the results of miR-146a. No association between miR-146a and SLE susceptibility was found in 2015 [71] and 2017 [72], which might be attributed to the small number of included studies. MiR-146a rs57095329 was found to correlate with the risk of SLE in two studies [73, 74], but this correlation was not supported in a recent study [75]; the rs2431697 and susceptibility to SLE were confirmed by two studies [73, 75].

Integrin Subunit Alpha M

Complement dysfunction impairs the ability to clear apoptotic cell fragments, which may stimulate the production of autoantibodies in SLE. The rs1143679 G/A polymorphism in Integrin Subunit Alpha M (ITGAM) severely impaired the phagocytosis of complement-coated particles and was positively associated with the risk of SLE [76], consistent with the findings of two studies in 2011 [77] and 2021 [76].

Evidence from Mendelian randomization study

The evidence from SRs including case–control or cohort studies was meaningful to confirm the correlation between risk factors and SLE development, but it is insufficient to make causal inferences. MR is an analytical method of causal estimation based on epidemiological data. it has been widely used in the medical field in recent years to assess the causal effect between exposure and outcome. We summarized the findings from the included 13 MR studies on SLE below.

Serum selenium, iron, growth differentiation factor 15, and circulating adiponectin

Three MR analyses were performed [78,79,80], showing that the rise in serum selenium (OR 0.85, 95% CI 0.77–0.93, P = 0.001) [78], serum iron (OR 0.79, 95% CI 0.66–0.94) [79] and growth differentiation factor 15 (GDF-15) (OR 0.80, 95% CI 0.68–0.92) [80] were all related to the decrease of SLE risk, which provided the potential causal evidence of the protective effect of selenium, iron and GDF-15 on SLE.

Another study showed that there was no causal relationship between circulating adiponectin levels and SLE (OR 1.38, 95% CI 0.91–1.35, P = 0.130) [81]. The test of reverse causation in the study was also negative, and the several analyses performed also supported this conclusion.

Gut microbiome

Xiang et al. [82] conducted a study on the composition of the gut microbiome (211 gut microbiota), supporting a causal relationship between its positive and negative effects on SLE risk (Table 2). The results of inverse variance weighted, MR Egger, and weighted median methods were slightly different. The levels of Bacillales, Coprobacter, Lachnospira, and Actinobacteria were negatively correlated with the risk of SLE, while Bacilli, Lactobacillales, and Eggerthella might be risk factors for SLE. Although the overlapping in the study samples—a limitation in two-sample MR studies—might affect the robustness of the findings, these findings intrigue thoughts about the development of new treatment modalities, such as probiotics supplements, for the treatment of SLE.

Statins

Recently, an MR used HMGCR inhibition to genetically mimic s