The present study conducted a bidirectional MR analysis by leveraging the most extensive cumulative GWAS dataset currently available to investigate for the first time the potential causal relationship between COVID-19 infection and MN development in both European and Asian cohorts. The MR forward analysis showed a consistent absence of a causal effect of SARS-CoV-2 infection, COVID-19-related hospitalization, or severe COVID-19 on MN development across all four MR methods. This finding was corroborated by the data from the European and East Asian populations. In contrast, the MR reverse analysis suggested that MN may elevate the risk of COVID-19-related hospitalization in the European cohort. However, the causal relationship between MN development and severe COVID-19 was inconclusive in the East Asian cohort, despite the MR-Egger method indicating a potential causal association.
Current research, although to a limited extent, has reported on the relationship between COVID-19 and MN. Guo et al. documented a case of phospholipase A2 receptor (PLA2R)-positive MN that occurred post-COVID-19 infection(9). Similarly, Mateus C et al. described a case of PLA2R-positive MN following SARS-CoV-2 infection(10). In contrast, Miao et al. reported a case of transition to PLA2R-negative MN after COVID-19 infection(8). Another noteworthy instance is the case in which a previously stable MN for 8 years relapsed after the patient received a SARS-CoV-2 inactivated vaccine(16). A study that examined kidney biopsies from 13 COVID-19 patients with renal damage and proteinuria identified two patients with PLA2R-negative MN; this finding suggested that COVID-19 might exacerbate this condition through an overactive immune response(17). In another 2020 study conducted in New York, kidney biopsies of 17 COVID-19 patients revealed that 2 patients had MN; the authors hypothesized that SARS-CoV-2 infection could exacerbate pre-existing MN, despite the absence of evidence of direct viral-associated damage of renal cells(5). A collective review of these studies indicates a predominant belief among researchers that SARS-CoV-2 infection may activate or aggravate MN, possibly through distinct biological mechanisms.
Angiotensin-converting enzyme 2 (ACE2), the SARS-CoV-2 receptor, is highly expressed in COVID-19 patients; in particular, high ACE2 expression and clusters of viral particles have been detected in the renal tubular epithelial cells and podocytes of patients who died due to COVID-19(18). This observation suggests that SARS-CoV-2 may infect the glomeruli by adhering to ACE2-positive cells(19). This notion is further supported by the isolation of SARS-CoV-2 from the urine of COVID-19 patients, thus implying that the kidneys are a potential target of the virus(20, 21). However, there is a lack reports on viral RNA detection in the glomeruli of patients with MN(5, 22). PLA2R, a principal antigen in MN(23), is also found in the respiratory tract(24), which potentially facilitates anti-PLA2R autoimmune responses(5). Aydın et al. documented two MN patients with positive anti-PLA2R antibodies post-SARS-CoV-2 infection; this finding indicated that the virus might trigger an autoimmune response against PLA2R antigens(16). Liu, W et al. proposed that podocytes activated by foreign antigens such as SARS-CoV-2 could prompt B lymphocytes to produce PLA2R antibodies(25). These antibodies could form immune complexes with PLA2R antigens, which subsequently deposited in the glomerular basement membrane and induce MN. This hypothesis, however, does not fully explain PLA2R-negative MN cases.
In contrast to prior research, our present study showed no direct causal relationship between COVID-19 and MN but rather suggested a role in triggering autoimmune responses(26). This hypothesis is based on the observation that patients with minimal renal impairment, who are presymptomatic or have undiagnosed conditions, showed an exacerbation of renal damage following COVID-19 infection due to an activated immune response(27). Thus, COVID-19 may act more as an initiator of MN rather than its direct cause, a concept that resonates with the perspectives offered by Nasr et al.(17). This theory potentially accounts for MN cases observed post-COVID-19 infection in previous studies and corroborates our conclusion that COVID-19 is not a direct causative agent of MN.
Research on the association between autoimmune diseases and COVID-19 has yielded mixed results. Some studies suggested that individuals with autoimmune diseases were at an increased risk of developing COVID-19(28). In contrast, other studies indicated no direct relationship between genetic predisposition to certain autoimmune diseases (excluding MN) and the incidence or severity of COVID-19 infection(29). Notably, although MN is classified as an autoimmune disease, its causal relationship with COVID-19 has been scarcely studied. Our study posited that the post-COVID-19 occurrence of MN might be coincidental, potentially influenced by shared biological pathways that are beyond the immediate impact of the disease. This perspective enriches our understanding of the COVID-19-MN nexus and highlights the need for future research to determine the underlying associations and mechanisms.
Our research identified a notable risk increase in COVID-19-related hospitalization in European patients with MN and an increased severity of COVID-19 in Asian patients with MN; this phenomenon has not been extensively reported before. MN, which is prevalent in middle-aged and older individuals, has a complex pathogenetic mechanism. It primarily involves the development of autoantibodies against target antigens, with approximately 70–80% of MN patients showing positive results for anti-PLA2R antibodies and 2–5% patients showing positivity for anti-THSD7A antibodies(11). Compared to the broader population, MN patients have an elevated risk of malignancies, particularly those positive for THSD7A and NELL1, with the frequent co-occurrence of cancer with MN(30, 31). Treatment of MN patients with immunosuppressants and corticosteroids can significantly diminish their immune response, thereby increasing their vulnerability to develop other diseases and enhancing the risk and severity of COVID-19 infection and subsequent hospitalization. Additionally, immune dysregulation inherent in MN, including factors such as anti-PLA2R response, cytokine storms, and complement activation, may further worsen the clinical condition of the patients post-SARS-CoV-2 infection, leading to more severe clinical presentation(12).
GWASs have revealed significant associations between MN occurrence and specific genetic markers, notably the combination of HLA alleles (DRB10301-DQA10501-DQB10201) and the PLA2R1 gene(32). The primary risk alleles differ between European and East Asian populations: DRB11501 predominates in East Asians, DQA10501 is more prevalent in Europeans, and DRB10301 remains a major risk allele for both groups(14). These genetic variations may explain the observed differences in MN incidence and severity across these populations, potentially accounting for the varied findings in related studies. Factors such as sample size and differences in research methods could also contribute to these disparities. Despite the inconsistent findings across different populations, the collective evidence suggests the potential influence of MN on COVID-19 progression, thereby highlighting the importance of focusing on these groups in future research to reveal the underlying genetic mechanisms.
This study has several key advantages. Although prior research has suggested a relationship between COVID-19 and MN, comprehensive population-based studies to establish causality between these two diseases have been scarce. In the present study, for the first time, we used the most extensive GWAS meta-analysis dataset currently available and employed the MR approach in both European and Asian populations to find this causal relationship. This approach enabled us to propose novel perspectives that could guide future research in this area. To validate the reliability of our findings, we conducted multiple sensitivity analyses. In the European cohort, the IVW, weighted median, and weighted mode methods indicated a significant causal relationship between MN and the risk of COVID-19-related hospitalization. Although the MR Egger method did not yield a statistically significant result, it should be noted that this method typically has lower statistical power than the other methods.
Our study also has some limitations. First, in cohorts with a smaller sample size, the IVs were chosen based on a less stringent P-value threshold of < 5 × 10− 6. This approach may potentially reduce the robustness of our findings. Second, the strong but high-risk association between MN and severe COVID-19 in Asian populations, as identified by the MR Egger test, requires cautious interpretation before generalizing. Finally, our results are specific to European and East Asian cohorts; therefore, careful consideration is required to extend these findings to other ethnicities or regions to avoid overgeneralization.