To our knowledge, this is the first bi-directional MR design to analyze the causal association between RA and MN. However, our data provided evidence supporting no causal association between RA and MN using the MR approach.
RA is characterized by inflammation and synovitis as typical features, which can eventually lead to cartilage destruction, the destruction of bone tissue in the proximal joints. Although great progress has been made in the treatment of RA despite tremendous advances in the treatment of RA, complete remission of the disease remains a challenge. During the progression of RA, a series of extra-articular manifestations may occur, such as involvement of the eyes, lungs, skin, and heart. Patients with RA typically have renal dysfunction, and MN is a common pathologic finding. Cases directly linked to RA have been reported, albeit being rare[22]. The glomerular disease known as MN can affect people of any age. It is the most typical cause of adult nephrotic syndrome. The remaining cases of MN are linked to drugs or other illnesses including systemic lupus erythematosus, hepatitis virus infection, or cancer. In about 80% of individuals, MN has no underlying etiology (primary MN). To date, several case reports have shown the possibility of MN caused by RA itself[5, 6, 23]. However, its incidence and pathogenetic mechanisms are still uncovered. Neural epidermal growth factor-like 1 (NELL1), a recently identified target antigen in MN, has been examined in observational research[24]. Semaphorin 3B-associated MN is usually seen in children and accounts for approximately 16% of all non-lupus MN in childhood[10]. These findings are already leading to a rethinking of diagnostic and therapeutic algorithms in the direction of more personalized medicine.
The secondary renal damage in RA is mostly caused by the side effects of treatment drugs, which is a pervasive environmental factor that significantly affects susceptibility to renal disorders in RA. Drug-associated nephropathy, which is most frequently brought on by disease-modifying antirheumatic (DMARDs) medications such as D-penicillamine, gold salts and bucillamine, and infrequently by tumor necrosis factor-α (TNF-α) inhibitor, is the most prevalent type of MN linked with RA [8, 9]. Some studies suggest that biologic DMARD may adversely affect renal function in addition to treating RA, but this remains controversial and the overall incidence is low. Although renal disorders caused by biologic DMARD are uncommon, the occurrence of autoimmune renal parenchymal disease has been increasingly reported with the use of biologic DMARDs such as tumor necrosis factor inhibitors, cytotoxic T lymphocyte-associated antigen 4-Ig, and IL-6 receptor antagonists[25–28]. Estimated glomerular filtration rate declines over time in RA patients treated with biologic DMARDs. A retrospective study evaluating risk factors for changes in renal function in patients with RA and ankylosing spondylitis treated with different biologic DMARDs found that male sex may be responsible for the decrease in estimated glomerular filtration rate in these patients, possibly through the involvement of sex hormones in sex-specific differentiation and homeostasis of various organs, including the kidney, resulting in differences in renal function[29].
This MR study explored a possible causal relationship between RA and MN. We found that MR Egger analysis showed a significant inverse association between MN and RA in all three datasets, the other MR methods also did not support a causal relationship. These combined results suggest that there may be other factors or common mechanisms of immune dysregulation that contribute to the co-occurrence of MN and RA and warrant further investigation. Nevertheless, our MR study indicated that genetically predisposed RA was not associated with an increased risk of MN. Though the mechanism for how RA altered the risk of MN remains unclear, there are several possible explanations. Additionally, utilizing the selected IVs and techniques, TSMR and the Reverse TSMR analyses did not consistently show a causal link between RA and MN. Further investigations with larger sample sizes and additional IVs may be necessary to ascertain the potential causal link between these conditions. In addition, we also performed the Leave-one-out sensitivity test for MR. This test mainly calculates the MR results of the remaining IVs after eliminating them one by one. Our results are less than 0. Therefore, the results may be unstable, which suggests that we may need more SNPs for the experiment. Next, we selected 2 GEO databases from MN and 4 databases from RA, and subsequently removed the batch effects separately. After difference analysis as well as cluster analysis, 1 co-up-regulated gene was screened, including CD52 and 7 co-down-regulated genes, including GLUL, MT1X, SLC19A2, RND3, NFIL3, ZBTB16 and C7. In order to examine the roles of these 8 DEGs using the GeneMANIA database, we built a gene-gene interaction network for them. The eight genes share co-expression with other genes for their primary biological roles, and a few other genes interact with these eight genes in different ways. Furthermore, we performed immune infiltration analysis on the collated datasets of the two diseases separately and found significant differences between the following concentrations of immune cells in MN: Plasma cells, T cells CD4, memory resting and monocytes, plasma cells, CD4 naïve T cells, CD4 memory activated T cells, regulatory T cells, NK cells resting and type 2 Macrophages. We further analyzed the correlation of the expression of 8 DEGs in immune cells with significant differences in MN and RA, respectively. The results revealed that the genes that may be associated with the simultaneous occurrence of both diseases are CD52, ZBTB16. The immune cells that may be associated with the simultaneous occurrence of both diseases may be B cells memory cells naïve, Macrophages M2, Monocytes cells resting, Plasma cells CD4 memory resting cells CD4, naïve cells regulatory (Tregs). T cells are a critical component of regulatory and control immune responses that can promote B cell-related responses while also activating inflammation and cytotoxicity that causes kidney tissue damage[30]. Furthermore, earlier research has demonstrated that anti-CD20 antibodies are potent immunosuppressants capable of suppressing B cell proliferation and the generation of pathogenic antibodies in MN. It is worth noting that MN patients have higher levels of lipopolysaccharide than normal people, which can activate resting B lymphocytes to perform antigen presentation[31]. In the meantime, B cells are mostly exposed to soluble antigens, and soluble PLA2R can be detected in the blood of MN patients [32].
Our study has several limitations. Firstly, this is an East Asian-based study. Our findings cannot be generalized to other populations. Second, some of our MR analyses were underpowered to detect small effects because of the limited variance of exposures explained by the SNPs instruments. In this direction, the exclusion of palindromic or ambiguous SNPs from our MR instruments may have further reduced the power of our MR investigation. Third, clinical laboratory data from only twenty-seven individuals, which is especially true for the three-group analysis. This is because the prevalence of RA in China is approximately 1% and that of MN is approximately 1.2/100,000 people. As a result, real-world data suggest that even fewer people suffer from both diseases, and there are comparable difficulties with the accessibility of laboratory data. This is an unavoidable limitation of our research.