Innovate therapeutic targets for autoimmune diseases: insights from proteome-wide mendelian randomization and Bayesian colocalization.

BACKGROUND: Despite growing knowledge regarding the pathogenesis of autoimmune diseases (ADs) onset, the current treatment remains unsatisfactory. This study aimed to identify innovative therapeutic targets for ADs through various analytical approaches. RESEARCH DESIGN AND METHODS: Utilizing Mendelian randomization, Bayesian co-localization, phenotype scanning, and protein-protein interaction network, we explored potential therapeutic targets for 14 ADs and externally validated our preliminary findings. RESULTS: This study identified 12 circulating proteins as potential therapeutic targets for six ADs. Specifically, IL12B was judged to be a risk factor for ankylosing spondylitis (p = 1.61E - 07). TYMP (p = 6.28E - 06) was identified as a protective factor for ulcerative colitis. For Crohn's disease, ERAP2 (p = 4.47E - 14), HP (p = 2.08E - 05), and RSPO3 (p = 6.52E - 07), were identified as facilitators, whereas FLRT3 (p = 3.42E - 07) had a protective effect. In rheumatoid arthritis, SWAP70 (p = 3.26E - 10), SIGLEC6 (p = 2.47E - 05), ISG15 (p = 3.69E - 05), and FCRL3 (p = 1.10E - 10) were identified as risk factors. B4GALT1 (p = 6.59E - 05) was associated with a lower risk of Type 1 diabetes (T1D). Interestingly, CTSH was identified as a protective factor for narcolepsy (p = 1.58E - 09) but a risk factor for T1D (p = 7.36E - 11), respectively. External validation supported the associations of eight of these proteins with three ADs. CONCLUSIONS: Our integrated study identified 12 potential therapeutic targets for ADs and provided novel insights into future drug development for ADs.

Effects of menstrual disorders and dysmenorrhea on cardiovascular disease: a Mendelian randomization study.

Background: Observational studies have demonstrated associations between menstrual disorders, dysmenorrhea, and cardiovascular disease (CVD). However, it remains unclear whether these associations are causal. This study is to investigate whether menstrual disorders and dysmenorrhea causally affect the risk of CVD. Methods: The summary data for menstrual disorders (excessive menstruation and irregular menses) and dysmenorrhea were obtained from FinnGen study, summary data for CVD were obtained from UK Biobank and meta-analysis. The inverse-variance-weighted method was mainly used in the Mendelian randomization for causality analysis. Sensitivity analyses were performed by several methods under different model assumptions. Results: Genetic liability to excessive menstruation was associated with higher risk of atrial fibrillation (odds ratio (OR), 1.078 [95% confidence interval (CI), 1.015-1.145]; P=0.014), but a lower risk of hypertension (OR, 0.994 [95% CI: 0.989-0.999]; P=0.016). Irregular menses was associated with higher risk of atrial fibrillation (OR, 1.095 [95% CI: 1.015-1.182]; P=0.02), hypertension (OR, 1.007 [95% CI: 1.000-1.013]; P=0.047), myocardial infarction (OR, 1.172 [95% CI: 1.060-1.295]; P=0.02), ischemic heart disease, (OR, 1.005 [95% CI: 1.000-1.010]; P=0.037) and coronary heart disease (OR, 1.004 [95% CI: 1.001-1.008]; P=0.026). Dysmenorrhea was associated with higher risk of atrial fibrillation (OR, 1.052 [95% CI: 1.014-1.092]; P=0.008) and Ischemic stroke (cardioembolic) (OR, 1.122 [95% CI: 1.002-1.257]; P=0.046). After Benjamini-Hochberg correction, irregular menses was associated with higher risk of myocardial infarction. Conclusion: We confirmed a causal relationship of excessive menstruation, irregular menses and dysmenorrhea on cardiovascular outcomes independent of sex hormone levels, with an emphasis on the link between irregular menses and myocardial infarction. These clinical features can be utilized as markers to identify women at higher risk of developing CVD in the future, recommending early clinical intervention of menstrual diseases.

The association between ACE inhibitors and psoriasis based on the drug-targeted Mendelian randomization and real-world pharmacovigilance analyses.

BACKGROUND: Although a growing number of observational studies suggest that angiotensin-converting enzyme inhibitors (ACEIs) intake may be a risk factor for psoriasis, evidence is still insufficient to draw definitive conclusions. RESEARCH DESIGN AND METHODS: Drug-targeted Mendelian randomization (DTMR) was used to analyze the causality between genetic proxied ACEIs and psoriasis. Furthermore, we performed a disproportionality analysis based on the FDA adverse event reporting system (FAERS) database to identify more suspicious subclasses of ACEIs. RESULTS: Using two kinds of genetic proxy instruments, the present DTMR research identified genetic proxied ACEIs as risk factors for psoriasis. Furthermore, our disproportionality analysis revealed that ramipril, trandolapril, perindopril, lisinopril, and enalapril were associated with the risk of psoriasis, which validates and refines the findings of the DTMR. CONCLUSIONS: Our integrative study verified that ACEIs, especially ramipril, trandolapril, perindopril, lisinopril, and enalapril, tended to increase the risk of psoriasis statistically.

Genetic evidence supporting the causal role of gut microbiota in chronic kidney disease and chronic systemic inflammation in CKD: a bilateral two-sample Mendelian randomization study.

Background: The association of gut microbiota (GM) and chronic kidney disease (CKD), and the relevancy of GM and chronic systemic inflammation in CKD, were revealed on the basis of researches on gut-kidney axis in previous studies. However, their causal relationships are still unclear. Objective: To uncover the causal relationships between GM and CKD, as well as all known GM from eligible statistics and chronic systemic inflammation in CKD, we performed two-sample Mendelian randomization (MR) analysis. Materials and methods: We acquired the latest and most comprehensive summary statistics of genome-wide association study (GWAS) from the published materials of GWAS involving GM, CKD, estimated glomerular filtration rate (eGFR), c-reactive protein (CRP) and urine albumin creatine ratio (UACR). Subsequently, two-sample MR analysis using the inverse-variance weighted (IVW) method was used to determine the causality of exposure and outcome. Based on it, additional analysis and sensitivity analysis verified the significant results, and the possibility of reverse causality was also assessed by reverse MR analysis during this study. Results: At the locus-wide significance threshold, IVW method and additional analysis suggested that the protective factors for CKD included family Lachnospiraceae (P=0.049), genus Eubacterium eligens group (P=0.002), genus Intestinimonas (P=0.009), genus Streptococcu (P=0.003) and order Desulfovibrionales (P=0.001). Simultaneously, results showed that genus LachnospiraceaeUCG010 (P=0.029) was a risk factor for CKD. Higher abundance of genus Desulfovibrio (P=0.048) was correlated with higher eGFR; higher abundance of genus Parasutterella (P=0.018) was correlated with higher UACR; higher abundance of class Negativicutes (P=0.003), genus Eisenbergiella (P=0.021), order Selenomonadales (P=0.003) were correlated with higher CRP levels; higher abundance of class Mollicutes (0.024), family Prevotellaceae (P=0.030), phylum Tenericutes (P=0.024) were correlated with lower levels of CRP. No significant pleiotropy or heterogeneity was found in the results of sensitivity analysis, and no significant causality was found in reverse MR analysis. Conclusion: This study highlighted associations within gut-kidney axis, and the causal relationships between GM and CKD, as well as GM and chronic systemic inflammation in CKD were also revealed. Meanwhile, we expanded specific causal gut microbiota through comprehensive searches. With further studies for causal gut microbiota, they may have the potential to be new biomarkers for targeted prevention of CKD and chronic systemic inflammation in CKD.

Proteome-wide mendelian randomization study implicates therapeutic targets in common cancers.

BACKGROUND: The interest in targeted cancer therapies has been growing rapidly. While numerous cancer biomarkers and targeted treatment strategies have been developed and employed, there are still significant limitations and challenges in the early diagnosis and targeted treatment of cancers. Accordingly, there is an urgent need to identify novel targets and develop new targeted drugs. METHODS: The study was conducted using combined cis-Mendelian randomization (cis-MR) and colocalization analysis. We analyzed data from 732 plasma proteins to identify potential drug targets associated with eight site-specific cancers. These findings were further validated using the UK Biobank dataset. Then, a protein-protein interaction network was also constructed to examine the interplay between the identified proteins and the targets of existing cancer medications. RESULTS: This MR analysis revealed associations between five plasma proteins and prostate cancer, five with breast cancer, and three with lung cancer. Subsequently, these proteins were classified into four distinct target groups, with a focus on tier 1 and 2 targets due to their higher potential to become drug targets. Our study indicatied that genetically predicted KDELC2 (OR: 0.89, 95% CI 0.86-0.93) and TNFRSF10B (OR: 0.74, 95% CI 0.65-0.83) are inversely associated with prostate cancer. Furthermore, we observed an inverse association between CPNE1 (OR: 0.96, 95% CI 0.94-0.98) and breast cancer, while PDIA3 (OR: 1.19, 95% CI 1.10-1.30) were found to be associated with the risk of breast cancer. In addition, we also propose that SPINT2 (OR: 1.05, 95% CI 1.03-1.06), GSTP1 (OR: 0.82, 95% CI 0.74-0.90), and CTSS (OR: 0.91, 95% CI 0.88-0.95) may serve as potential therapeutic targets in prostate cancer. Similarly, GDI2 (OR: 0.85, 95% CI 0.80-0.91), ISLR2 (OR: 0.87, 95% CI 0.82-0.93), and CTSF (OR: 1.14, 95% CI 1.08-1.21) could potentially be targets for breast cancer. Additionally, we identified SFTPB (OR: 0.93, 95% CI 0.91-0.95), ICAM5 (OR: 0.95, 95% CI 0.93-0.97), and FLRT3 (OR: 1.10, 95% CI 1.05-1.15) as potential targets for lung cancer. Notably, TNFRSF10B, GSTP1, and PDIA3 were found to interact with the target proteins of current medications used in prostate or breast cancer treatment. CONCLUSIONS: This comprehensive analysis has highlighted thirteen plasma proteins with potential roles in three site-specific cancers. Continued research in this area may reveal their therapeutic potential, particularly KDELC2, TNFRSF10B, CPNE1, and PDIA3, paving the way for more effective cancer treatments.

Causal effects between gut microbiota and IgA nephropathy: a bidirectional Mendelian randomization study.

Background: Therapeutic approaches that target the gut microbiota (GM) may be helpful in the potential prevention and treatment of IgA nephropathy (IgAN). Meanwhile, relevant studies demonstrated a correlation between GM and IgAN, however, these confounding evidence cannot prove a causal relationship between GM and IgAN. Methods: Based on the data from the GM genome-wide association study (GWAS) of MiBioGen and the IgAN GWAS data from the FinnGen research. A bi-directional Mendelian randomization (MR) study was performed to explore the causal relationship between GM and IgAN. We used inverse variance weighted (IVW) method as the primary method to determine the causal relationship between exposure and outcome in our MR study. Besides, we used additional analysis (MR-Egger, weighted median) and sensitivity analysis (Cochrane's Q test, MR-Egger and MR-PRESSO) to select significant results, followed by Bayesian model averaging (MR-BMA) to test the results of MR study. Finally, a reverse MR analysis was conducted to estimate the probability of reverse causality. Results: At the locus-wide significance level, the results of IVW method and additional analysis showed that Genus Enterorhabdus was a protective factor for IgAN [OR: 0.456, 95% CI: 0.238-0.875, p=0.023], while Genus butyricicoccus was a risk factor for IgAN [OR: 3.471, 95% CI: 1.671-7.209, p=0.0008]. In the sensitivity analysis, no significant pleiotropy or heterogeneity of the results was found. Conclusion: Our study revealed the causal relationship between GM and IgAN, and expanded the variety of bacterial taxa causally related to IgAN. These bacterial taxa could become novel biomarkers to facilitate the development of targeted therapies for IgAN, developing our understanding of the "gut-kidney axis".

Pathogenic sphingosine 1-phosphate pathway in psoriasis: a critical review of its pathogenic significance and potential as a therapeutic target.

Sphingosine-1-phosphate (S1P) is a sphingolipid mediator that exerts a variety of biological functions, including immune, cardiovascular, and neurological regulation as well as tumor promotion, through high-affinity G protein-coupled receptors (S1P1-5). It has been reported that circulating S1P levels remain higher in patients with psoriasis than in healthy individuals and that circulating S1P levels do not decrease after anti-TNF-α treatment in those patients. The S1P-S1PR signaling system plays an important role in inhibiting keratinocyte proliferation, regulating lymphocyte migration, and promoting angiogenesis, thus contributing to the regulation of psoriasis pathogenesis. Here, we review the mechanisms by which S1P-S1PR signaling affects the development of psoriasis and the available clinical/preclinical evidence for targeting S1P-S1PR in psoriasis. S1P-S1PR signaling mechanisms may partially explain the link between psoriasis and its comorbidities. Although the detailed mechanisms remain to be elucidated, S1P may be a new target for future psoriasis remission.

The causality between intestinal flora and allergic diseases: Insights from a bi-directional two-sample Mendelian randomization analysis.

Background: Growing evidence shows a significant association between intestinal flora and allergic diseases, specifically atopic dermatitis (AD), allergic rhinitis (AR), and allergic asthma (AA). However, the causality has not yet been clarified. Objective: We conducted a bidirectional two-sample Mendelian randomization (TSMR) analysis to study the causal relationships between intestinal flora classification and AD, AR, or AA. Materials and methods: We obtained summary data of intestinal flora, AD, AR, and AA from a genome-wide association research. The inverse-variance weighted method is the primary method for analyzing causality in the TSMR analysis. Several sensitivity analyses were conducted to examine the stability of TSMR results. Reverse TSMR analysis was also performed to assess whether there was a reverse causality. Results: A total of 7 bacterial taxa associated with AD, AR, and AA were identified by the current TSMR analysis. Specifically, the genus Dialister(P=0.034)and genus Prevotella(P=0.047)were associated with a higher risk of AD, whereas class Coriobacteriia (P=0.034) and its child taxon, order Coriobacteriales (P=0.034) and family Coriobacteriaceae (P=0.034), all had a protective effect on AR. In addition, the family Victivallaceae (P=0.019) was identified as a risk factor for AR. We also noticed a positive association between the genus Holdemanella (P=0.046) and AA. The reverse TSMR analysis didn't suggest any evidence of reverse causality from allergic diseases to the intestinal flora. Conclusion: We confirmed the causal relationship between intestinal flora and allergic diseases and provided an innovative perspective for research on allergic diseases: targeted regulation of dysregulation of specific bacterial taxa to prevent and treat AD, AR, and AA.

Characteristics of registered studies for Coronavirus disease 2019 (COVID-19): A systematic review.

BACKGROUND: The World Health Organization characterized the Coronavirus disease 2019 (COVID-19) as a pandemic on March 11th. Many clinical trials on COVID-19 have been registered, and we aim to review the study characteristics and provide guidance for future trials to avoid duplicated effort. METHODS: Studies on COVID-19 registered before March 3rd, 2020 on eight registry platforms worldwide were searched and the data of design, participants, interventions, and outcomes were extracted and analyzed. RESULTS: Three hundred and ninety-three studies were identified and 380 (96.7%) were from mainland China, while 3 in Japan, 3 in France, 2 in the US, and 3 were international collaborative studies. Two hundred and sixty-six (67.7%) aimed at therapeutic effect, others were for prevention, diagnosis, prognosis, etc. Two hundred and two studies (51.4%) were randomized controlled trials. Two third of therapeutic studies tested Western medicines including antiviral drugs (17.7%), stem cell and cord blood therapy (10.2%), chloroquine and derivatives (8.3%), 16 (6.0%) on Chinese medicines, and 73 (27.4%) on integrated therapy of Western and Chinese medicines. Thirty-one studies among 266 therapeutic studies (11.7%) used mortality as primary outcome, while the most designed secondary outcomes were symptoms and signs (47.0%). Half of the studies (45.5%) had not started recruiting till March 3rd. CONCLUSION: Inappropriate outcome setting, delayed recruitment and insufficient numbers of new cases in China implied many studies may fail to complete. Strategies and protocols of the studies with robust and rapid data sharing are warranted for emergency public health events, helping the timely evidence-based decision-making.