BACKGROUND: Previous observational studies indicated a complex association between frailty and arthritis.
OBJECTIVE: To investigate the genetic causal relationship between the frailty index and the risk of common arthritis.
METHODS: We performed a large-scale Mendelian randomization (MR) analysis to assess frailty index associations with the risk of common arthritis in the UK Biobank (UKB), and the FinnGen Biobank. Summary genome-wide association statistics for frailty, as defined by the frailty index, and common arthritis including rheumatoid arthritis (RA), osteoarthritis (OA), psoriatic arthritis (PSA), and ankylosing spondylitis (AS). The inverse-variance weight (IVW) method served as the primary MR analysis. Heterogeneity testing and sensitivity analysis were also conducted.
RESULTS: Our results denoted a genetic association between the frailty index with an increased risk of OA, the odds ratio (OR)IVW in the UKB was 1.03 (95% confidence interval [CI]: 1.01-1.05; P = 0.007), and ORIVW was 1.55 (95% CI: 1.16-2.07; P = 0.003) in the FinnGen. For RA, the ORIVW from UKB and FinnGen were 1.03 (1.01-1.05, P = 0.006) and 4.57 (1.35-96.49; P = 0.025) respectively. For PSA, the frailty index was associated with PSA (ORIVW = 4.22 (1.21-14.67), P = 0.023) in FinnGen, not in UKB (P > 0.05). However, no association was found between frailty index and AS (P > 0.05). These results remained consistent across sensitivity assessments.
CONCLUSIONS: This study demonstrated a potential causal relationship that genetic predisposition to frailty index was associated with the risk of arthritis, especially RA, OA, and PSA, not but AS. Our findings enrich the existing body of knowledge on the subject matter.

OBJECTIVE: Oxidative stress is strongly associated with atopic dermatitis (AD), and increased antioxidant intake could potentially reduce the risk of or alleviate its symptoms. However, the argument is disputed. Therefore, we conducted a Mendelian randomization (MR) analysis to explore the causal relationship between dietary antioxidant vitamin intake and AD.
METHODS: We applied MR analysis to examine the causative association between dietary antioxidant vitamin intake (vitamin C, vitamin E, carotene, and retinol) and AD. The genome-wide association study (GWAS) summary data for antioxidant vitamins intake and AD were obtained from the IEU OpenGWAS database and the UK biobank. Our study consisted of two major parts, MR analysis to detect the causal relationship between exposure and outcome, and sensitivity analysis as supplemental evidence to verify the robustness of the results.
RESULTS: The results revealed a suggestive causal relationship between vitamin E intake and AD (p = 0.038, OR 95% CI = 0.745-0.992). However, there was no causal relationship between the other three vitamins (vitamin C, carotene, and retinol) and AD (p = 0.507, OR 95% CI = 0.826-1.099) (p = 0.890, OR 95% CI = 0.864-1.184) (p = 0.492, OR 95% CI = 0.893-1.264). None of the single nucleotide polymorphisms (SNPs) were detected as heterogeneous and pleiotropy in the sensitivity analysis (p > 0.05).
CONCLUSIONS: The analysis suggested that dietary intake of vitamin E may potentially lower the risk of AD. Conversely, intake of vitamin C, retinol, and carotene is not causally related to AD. Although vitamin E intake could be protective against AD, intake of dietary antioxidant vitamins to prevent or treat AD is not necessary.

UNASSIGNED: Alzheimer\'s disease (AD) is a leading cause of dementia, characterized by the accumulation of amyloid-beta (Aβ) and hyperphosphorylated tau proteins, leading to neuroinflammation and neuronal damage. The role of the immune system in AD pathogenesis is increasingly recognized, prompting an exploration of the causal relationship between immune cells and AD by using Mendelian randomization (MR) approaches.
UNASSIGNED: Utilizing genome-wide association study (GWAS) data from European cohorts, we conducted an MR study to investigate the causal links between immune cell phenotypes and AD. We selected single nucleotide polymorphisms (SNPs) associated with immune cell traits at a genome-wide significance threshold and applied various MR methods, including MR Egger, Weighted median, and inverse variance weighted analysis, to assess the causality between 731 immune phenotypes and AD.
UNASSIGNED: Our MR analysis identified 15 immune cell types with significant causal relationships to AD pathogenesis. Notably, the absolute count of CD28-CD4-CD8- T cells and the expression of HLA DR on B cells were linked to a protective effect against AD, while 13 other immune phenotypes were identified as contributing to the risk factors for the disease. The causal effects of AD on immunophenotypic traits are predominantly negative, implying that AD may impair the functionality of immune cells. Validation through independent datasets, such as FinnGen and GCST90027158, confirmed the causal association between six specific immune cells and AD.
UNASSIGNED: This comprehensive MR study elucidates the intricate network of causal relationships between diverse immunophenotypic traits and AD, providing novel insights into the immunopathogenesis of AD. The findings suggest potential immunological targets that could be leveraged for early diagnosis, disease monitoring, and therapeutic intervention.

[This corrects the article DOI: 10.3389/fmicb.2023.1190866.].

UNASSIGNED: To determine the causal correlations of lifestyle behaviours and body fat distribution on diabetic microvascular complications through a Mendelian Randomization (MR).
UNASSIGNED: Genetic variants significantly associated with lifestyle behaviours, abdominal obesity, generalized obesity and diabetic microvascular complications were extracted from the UK Biobank (UKB) and FinnGen. The inverse variance weighted (IVW) method was regarded as the primary method. The main results were presented in odds ratio (OR) per standard deviation (SD) increase, and a series of sensitivity analyses were also conducted to validate the stability of the results.
UNASSIGNED: There was a positive causal correlation between smoking and the development of diabetic retinopathy (OR = 1.16; 95%CI: 1.04-1.30; p = 0.01). All of the indicators representing abdominal obesity had a statistically significant causal association with diabetic microvascular complications. Concerning generalized obesity, there were significant causal associations of body mass index (BMI) on diabetic nephropathy (OR = 1.92; 95%CI: 1.58-2.33; p < 0.001), diabetic retinopathy (OR = 1.27; 95%CI: 1.15-1.40; p < 0.001), and diabetic neuropathy (OR = 2.60; 95%CI: 1.95-3.45; p < 0.001). Other indicators including leg fat mass (left), and arm fat mass (left) also had a significant positive causality with diabetic microvascular complications.
UNASSIGNED: Our findings suggested that smoking has a genetically causal association with the development of diabetic retinopathy rather than diabetic nephropathy and diabetic neuropathy. In addition, both abdominal obesity and generalized obesity are risk factors for diabetic microvascular complications. To note, abdominal obesity represented by waist circumference (WC) is the most significant risk factor.

UNASSIGNED: Observational studies suggest a connection between ACE2 (angiotensin-converting enzyme 2) and lung cancer. However, it\'s not apparent if confounding variables are interfering with the link. Therefore, we aimed to define the relationships between ACE2 and the risk of lung cancer.
UNASSIGNED: With the aim of developing genetic tools, we selected SNPs substantially associated with ACE2 using a statistically significant criterion. The relevant SNPs were then taken from the lung cancer GWAS dataset for additional research. After that, we used two-sample Mendelian randomization (MR) to ascertain if ACE2 is causally linked to the risk of developing lung cancer. To investigate the causal links\' directions, we also performed a reverse MR analysis.
UNASSIGNED: According to our findings, there is strong evidence that ACE2 is linked to a decreased chance of developing lung cancer (odds ratio: 0.94; 95% confidence interval: 0.90-0.98; P = 0.0016). The IVW method, the major MR analysis, was not impacted by heterogeneity in any of the analyses, according to Cochrane\'s Q test ( P Cochran e \' sQ = 0.207). The MR-Egger intercept (P intercept = 0.622) showed no indication of horizontal pleiotropy in any of the investigations. Outlier SNPs were not detected by the MR-PRESSO global test (P globaltest = 0.191). The leave-one-out analysis was performed, and the results showed a steady outcome. Nonsignificant causal estimates between lung cancer and ACE2 were produced by reverse MR analysis.
UNASSIGNED: MR investigation revealed a significant causal link between ACE2 and the risk of getting lung cancer. These findings may have implications for public health measures aimed at reducing the incidence of lung cancer.

UNASSIGNED: Observational studies have shown that oxidative stress (OS) is associated with Parkinson\'s disease (PD). However, whether such observations reflect cause-effect remains largely unknown. To test this, we performed a two-sample bidirectional Mendelian randomization (MR) analysis to investigate the causal-effects between OS biomarkers and PD.
UNASSIGNED: We selected summary statistics data for single-nucleotide polymorphisms (SNPs) associated with catalase (n = 13), glutathione peroxidases (n = 12), superoxide dismutase (n = 13), vitamin A (n = 7), vitamin C (n = 10), vitamin E (n = 12), vitamin B12 (n = 8), folate (n = 14), copper (n = 6), Zinc (n = 7), and iron (n = 23) levels, and the corresponding data for PD from the International Parkinson Disease Genomics Consortium (IPDGC, 33,674 cases and 449,056 controls). Inverse-variance weighted (IVW) MR analyses were conducted to estimate associations of OS with PD. Reverse MR analysis was further performed to predict the causal effects of PD on the above OS biomarkers.
UNASSIGNED: As for PD, the IVW method suggested that the Zinc (Zn) levels was significantly associated with PD (OR = 1.107, 95% CI 1.013-1.211; p = 0.025), which is consistent with results from the weighted median analyses. Moreover, the results remained consistent and robust in the sensitivity analysis. However, there were no significant associations of catalase, glutathione peroxidases, superoxide dismutase, vitamin A, vitamin C, vitamin E, vitamin B12, folate, copper, or iron with PD. As for OS, our reverse MR analysis also did not support a causal effect of liability to PD on OS.
UNASSIGNED: The MR study supported the causal effect of Zn on PD. These findings may inform prevention strategies and interventions directed toward OS and PD.

BACKGROUND: Walking stands as the most prevalent physical activity in the daily lives of individuals and is closely associated with physical functioning and the aging process. Nonetheless, the precise cause-and-effect connection between walking and aging remains unexplored. The epigenetic clock emerges as the most promising biological indicator of aging, capable of mirroring the biological age of the human body and facilitating an investigation into the association between walking and aging. Our primary objective is to investigate the causal impact of walking with epigenetic age acceleration (EAA).
METHODS: We conducted a two-sample two-way Mendelian randomization (MR) study to investigate the causal relationship between walking and EAA. Walking and Leisure sedentary behavior data were sourced from UK Biobank, while EAA data were gathered from a total of 28 cohorts. The MR analysis was carried out using several methods, including the inverse variance weighted (IVW), weighted median, MR-Egger, and robust adjusted profile score (RAPS). To ensure the robustness of our findings, we conducted sensitivity analyses, which involved the MR-Egger intercept test, Cochran\'s Q test, and MR-PRESSO, to account for and mitigate potential pleiotropy.
RESULTS: The IVW MR results indicate a significant impact of usual walking pace on GrimAge (BETA = - 1.84, 95% CI (- 2.94, - 0.75)), PhenoAge (BETA = - 1.57, 95% CI (- 3.05, - 0.08)), Horvath (BETA = - 1.09 (- 2.14, - 0.04)), and Hannum (BETA = - 1.63, 95% CI (- 2.70, - 0.56)). Usual walking pace is significantly associated with a delay in epigenetic aging acceleration (EAA) (P < 0.05). Moreover, the direction of effect predicted by the gene remained consistent across RAPS outcomes and sensitivity MR analyses. There is a lack of robust causal relationships between other walking conditions, such as walking duration and walking frequency, on EAA (P > 0.05).
CONCLUSIONS: Our evidence demonstrates that a higher usual walking pace is associated with a deceleration of the acceleration of all four classical epigenetic clocks acceleration.

UNASSIGNED: Existing literature has not clearly elucidated whether SARS-CoV-2 infection increases the incidence of Parkinson\'s disease or if Parkinson\'s disease patients are more susceptible to the effects of SARS-CoV-2 infection. To clarify the issue, this study employs a genetic epidemiological approach to investigate the association.
UNASSIGNED: This study utilizes a two-sample Mendelian randomization analysis. The primary analysis employs the inverse variance-weighted (IVW) method, supplemented by secondary analyses including MR-Egger regression, weighted median, IVW radial method, and weighted mode, to evaluate the bidirectional causal relationship between Parkinson\'s disease and SARS-CoV-2 infection.
UNASSIGNED: IVW results showed no genetic causality between SARS-CoV-2 susceptibility, hospitalization rate and severity and Parkinson\'s disease. (IVW method: p = 0.408 OR = 1.10 95% CI: 0.87 ~ 1.39; p = 0.744 OR = 1.11 95% CI: 0.94 ~ 1.09; p = 0.436 OR = 1.05 95% CI: 0.93 ~ 1.17). Parkinson\'s disease was not genetically associated with susceptibility to new crown infections, hospitalization rates, and severity (IVW method: p = 0.173 OR = 1.01 95% CI: 0.99 ~ 1.03; p = 0.109 OR = 1.05 95% CI: 0.99 ~ 1.12; p = 0.209 OR = 1.03 95% CI: 0.99 ~ 1.07). MR-Egger regression, weighted median, IVW radial method, and weighted mode results are consistent with the results of the IVW method.
UNASSIGNED: This study does not support a genetic link between Parkinson\'s disease and SARS-CoV-2 infection, and the association observed in previous cohort studies and observational studies may be due to other confounding factors.

UNASSIGNED: IgA nephropathy (IgAN), a prevalent form of glomerulonephritis globally, exhibits complex pathogenesis. Cathepsins, cysteine proteases within lysosomes, are implicated in various physiological and pathological processes, including renal conditions. Prior observational studies have suggested a potential link between cathepsins and IgAN, yet the precise causal relationship remains unclear.
UNASSIGNED: We conducted a comprehensive bidirectional and multivariable Mendelian randomization (MR) study using publicly available genetic data to explore the causal association between cathepsins and IgAN systematically. Additionally, immunohistochemical (IHC) staining and enzyme-linked immunosorbent assay (ELISA) were employed to evaluate cathepsin expression levels in renal tissues and serum of IgAN patients. We investigated the underlying mechanisms via gene set variation analysis (GSVA), gene set enrichment analysis (GSEA), and immune cell infiltration analysis. Molecular docking and virtual screening were also performed to identify potential drug candidates through drug repositioning.
UNASSIGNED: Univariate MR analyses demonstrated a significant link between increased cathepsin S (CTSS) levels and a heightened risk of IgAN. This was evidenced by an odds ratio (OR) of 1.041 (95% CI=1.009-1.073, P=0.012) as estimated using the inverse variance weighting (IVW) method. In multivariable MR analysis, even after adjusting for other cathepsins, elevated CTSS levels continued to show a strong correlation with an increased risk of IgAN (IVW P=0.020, OR=1.037, 95% CI=1.006-1.069). However, reverse MR analyses did not establish a causal relationship between IgAN and various cathepsins. IHC and ELISA findings revealed significant overexpression of CTSS in both renal tissues and serum of IgAN patients compared to controls, and this high expression was unique to IgAN compared with several other primary kidney diseases such as membranous nephropathy, minimal change disease and focal segmental glomerulosclerosis. Investigations into immune cell infiltration, GSEA, and GSVA highlighted the role of CTSS expression in the immune dysregulation observed in IgAN. Molecular docking and virtual screening pinpointed Camostat mesylate, c-Kit-IN-1, and Mocetinostat as the top drug candidates for targeting CTSS.
UNASSIGNED: Elevated CTSS levels are associated with an increased risk of IgAN, and this enzyme is notably overexpressed in IgAN patients\' serum and renal tissues. CTSS could potentially act as a diagnostic biomarker, providing new avenues for diagnosing and treating IgAN.