Mendelian randomization as a tool to gain insights into the mosaic causes of autoimmune diseases

Chen, Cong; Wang, Peng; Zhang, Ruo-Di; Yang, Fang; Jiang, Ling-Qiong; Fang, Xi; Zhao, Yan; Wang, Deguang; Ni, Jing; Pan, Hai‐Feng

doi:10.1016/j.autrev.2022.103210

Cited by 33 publications

(18 citation statements)

References 159 publications

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“…Mendelian randomization analysis, with its unique advantages and insights into etiology, has been applied to the study of factors influencing autoimmune diseases 21 . In this study, we performed a comprehensive two-way two-sample MR study to reveal the causal relationship between the risk of several EHAIDs and PBC.…”

Section: Discussionmentioning

confidence: 99%

Dissecting causal relationships between primary biliary cholangitis and extrahepatic autoimmune diseases based on Mendelian randomization

Ma,

Yang,

Wang

et al. 2024

Sci Rep

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As an autoimmune disease, up to 73% of patients with primary biliary cholangitis (PBC) have a combination of extrahepatic autoimmune diseases (EHAIDs); however, the causal relationship between PBC and EHAIDs is unclear. The genome-wide association analyses provided 14 GWAS data for PBC and EHAIDs, and bidirectional, two-sample MR analyses were performed to examine the relationship between PBC and EHAIDs. The analysis using MR provides a strong and meaningful estimation of the bidirectional correlation between PBC and 7 EHAIDs: rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, autoimmune hypothyroidism, inflammatory bowel disease and ulcerative colitis of its types. In addition, PBC increases the risk of autoimmune thyroid diseases such as autoimmune hyperthyroidism and Graves' disease, as well as multiple sclerosis and psoriasis. Additionally, PBC is identified as a risk factor for Crohn's disease and Celiac disease. Based on genetic evidence, there may be connections between PBC and specific EHAIDs: not all coexisting EHAIDs induce PBC, and vice versa. This underscores the significance of prioritizing PBC in clinical practice. Additionally, if any liver function abnormalities are observed during treatment or with EHAIDs, it is crucial to consider the possibility of comorbid PBC.

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Section: Discussionmentioning

confidence: 99%

Dissecting causal relationships between primary biliary cholangitis and extrahepatic autoimmune diseases based on Mendelian randomization

Ma,

Yang,

Wang

et al. 2024

Sci Rep

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“…Unfortunately, no relationship was reported between SSc with BC. Over the years, MR analysis has focused on elucidating the etiology of Autoimmune diseases (ADs) by exploring potential assumptions between exposure factors and disease or other outcomes, providing a novel method 40 .…”

Section: Discussionmentioning

confidence: 99%

Negative causal exploration of systemic sclerosis: a Mendelian randomization analysis

Han,

Wang

et al. 2024

Sci Rep

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Systemic sclerosis (SSc), also known as scleroderma, is an autoimmune-related connective tissue disease with a complex and unknown pathophysiological mechanism with genes association. Several articles have reported a high prevalence of thyroid disease in SSc patients, while one study suggested a potential contribution of appendicitis to the development of SSc. To investigate this causal association, we conducted Mendelian randomization (MR) analysis using instrumental variables (IVs) to assess exposure and outcome. In the MR study involving two cohorts, all analyses were conducted using the TwoSampleMR package in R (version 4.3.0). Single nucleotide polymorphisms (SNPs) meeting a statistically significant threshold of 5E−08 were included in the analysis. Multiple complementary approaches including MR-IVW, MR-Egger, weighted median, simple mode, and weighted mode were employed to estimated the relationship between the exposure and outcome. Leave-one-out analysis and scatter plots were utilized for further investigation. Based on the locus-wide significance level, all of the MR analysis consequences manifested no causal association between the risk of appendicitis with SSc (IVW OR 0.319, 95% CI 0.063–14.055, P = 0.966). Negative causal effects of autoimmune thyroiditis (AT) on SSc (IVW OR 0.131, 95% CI 0.816–1.362, P = 0.686), Graves’ disease (GD) on SSc (IVW OR 0.097, 95% CI 0.837–1.222, P = 0.908), and hypothyroidism on SSc (IVW OR 1.136, 95% CI 0.977–1.321, P = 0.096) were derived. The reverse MR revealed no significant causal effect of SSc on thyroid disease. According to the sensitivity analysis, horizontal pleiotropy was unlikely to distort the causal estimates. The consequences indicated no significant association between AT, GD, and hypothyroidism with SSc. Similarly, there was no observed relationship with appendicitis.

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“…95 Zinc deficiency can lead to increased oxidative stress and the production of pro-inflammatory cytokines, 96,97 affecting immune cells' survival, proliferation, and maturation. 87 Selenium plays an essential role in the activation, differentiation, and proliferation of immune cells. Selenium can also reduce the expression of pro-inflammatory mediators and regulate excessive immune response and chronic inflammation.…”

Section: Discussionmentioning

confidence: 99%

“…Ca, iron, copper, magnesium, zinc, selenium, and other minerals usually play a role in autoimmune diseases through different immunomodulatory mechanisms. 87 …”

Section: Discussionmentioning

confidence: 99%

Appraising causal risk and protective factors for rheumatoid arthritis

Gu,

Pu,

Liu

et al. 2023

Bone Joint Res

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AimsMendelian randomization (MR) is considered to overcome the bias of observational studies, but there is no current meta-analysis of MR studies on rheumatoid arthritis (RA). The purpose of this study was to summarize the relationship between potential pathogenic factors and RA risk based on existing MR studies.MethodsPubMed, Web of Science, and Embase were searched for MR studies on influencing factors in relation to RA up to October 2022. Meta-analyses of MR studies assessing correlations between various potential pathogenic factors and RA were conducted. Random-effect and fixed-effect models were used to synthesize the odds ratios of various pathogenic factors and RA. The quality of the study was assessed using the Strengthening the Reporting of Observational Studies in Epidemiology using Mendelian Randomization (STROBE-MR) guidelines.ResultsA total of 517 potentially relevant articles were screened, 35 studies were included in the systematic review, and 19 studies were eligible to be included in the meta-analysis. Pooled estimates of 19 included studies (causality between 15 different risk factors and RA) revealed that obesity, smoking, coffee intake, lower education attainment, and Graves’ disease (GD) were related to the increased risk of RA. In contrast, the causality contribution from serum mineral levels (calcium, iron, copper, zinc, magnesium, selenium), alcohol intake, and chronic periodontitis to RA is not significant.ConclusionObesity, smoking, education attainment, and GD have real causal effects on the occurrence and development of RA. These results may provide insights into the genetic susceptibility and potential biological pathways of RA.Cite this article: Bone Joint Res 2023;12(9):601–614.

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Mendelian randomization as a tool to gain insights into the mosaic causes of autoimmune diseases

Cited by 33 publications

References 159 publications

Dissecting causal relationships between primary biliary cholangitis and extrahepatic autoimmune diseases based on Mendelian randomization

Dissecting causal relationships between primary biliary cholangitis and extrahepatic autoimmune diseases based on Mendelian randomization

Negative causal exploration of systemic sclerosis: a Mendelian randomization analysis

Appraising causal risk and protective factors for rheumatoid arthritis

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