Assessing the causal relationship between plasma proteins and osteoporosis: novel insights into pathological mechanisms and therapeutic implications.

Identifying dysregulated plasma proteins in osteoporosis (OP) progression offers insights into prevention and treatment. This study found 8 such proteins associated with OP, suggesting them as therapy targets. This discovery may cut drug development costs and improve personalized treatments. PURPOSE: This study aims to identify potential therapeutic targets for OP using summary data-based Mendelian randomization (SMR) and colocalization analysis methods. Furthermore, we seek to explore the biological significance and pharmacological value of these drug targets. METHODS: To identify potential therapeutic targets for OP, we conducted SMR and colocalization analysis. Plasma protein (pQTL, exposure) data were sourced from the study by Ferkingstad et al. (n = 35,559). Summary statistics for bone mineral density (BMD, outcome) were obtained from the GWAS Catalog (n = 56,284). Additionally, we utilized enrichment analysis, protein-protein interaction (PPI) network analysis, drug prediction, and molecular docking to further analyze the biological significance and pharmacological value of these drug targets. RESULTS: In the SMR analysis, while 20 proteins showed significance, only 8 potential drug targets (GCKR, ERBB3, CFHR1, GPN1, SDF2, VTN, BET1L, and SERPING1) received support from colocalization (PP.H4 > 0.8). These proteins are closely associated with immune function in terms of biological significance. Molecular docking also demonstrated favorable binding of drugs to proteins, consistent with existing structural data, further substantiating the pharmacological value of these targets. CONCLUSIONS: The study identified 8 potential drug targets for OP. These prospective targets are believed to have a higher chance of success in clinical trials, thus aiding in prioritizing OP drug development and reducing development costs.

Polygenic scores and Mendelian randomization identify plasma proteins causally implicated in Alzheimer's disease.

Background: An increasing body of evidence suggests that neuroinflammation is one of the key drivers of late-onset Alzheimer's disease (LOAD) pathology. Due to the increased permeability of the blood-brain barrier (BBB) in older adults, peripheral plasma proteins can infiltrate the central nervous system (CNS) and drive neuroinflammation through interactions with neurons and glial cells. Because these inflammatory factors are heritable, a greater understanding of their genetic relationship with LOAD could identify new biomarkers that contribute to LOAD pathology or offer protection against it. Methods: We used a genome-wide association study (GWAS) of 90 different plasma proteins (n = 17,747) to create polygenic scores (PGSs) in an independent discovery (cases = 1,852 and controls = 1,990) and replication (cases = 799 and controls = 778) cohort. Multivariate logistic regression was used to associate the plasma protein PGSs with LOAD diagnosis while controlling for age, sex, principal components 1-2, and the number of APOE-e4 alleles as covariates. After meta-analyzing the PGS-LOAD associations between the two cohorts, we then performed a two-sample Mendelian randomization (MR) analysis using the summary statistics of significant plasma protein level PGSs in the meta-analysis as an exposure, and a GWAS of clinically diagnosed LOAD (cases = 21,982, controls = 41,944) as an outcome to explore possible causal relationships between the two. Results: We identified four plasma protein level PGSs that were significantly associated (FDR-adjusted p < 0.05) with LOAD in a meta-analysis of the discovery and replication cohorts: CX3CL1, hepatocyte growth factor (HGF), TIE2, and matrix metalloproteinase-3 (MMP-3). When these four plasma proteins were used as exposures in MR with LOAD liability as the outcome, plasma levels of HGF were inferred to have a negative causal relationship with the disease when single-nucleotide polymorphisms (SNPs) used as instrumental variables were not restricted to cis-variants (OR/95%CI = 0.945/0.906-0.984, p = 0.005). Conclusion: Our results show that plasma HGF has a negative causal relationship with LOAD liability that is driven by pleiotropic SNPs possibly involved in other pathways. These findings suggest a low transferability between PGS and MR approaches, and future research should explore ways in which LOAD and the plasma proteome may interact.

Association between genetically plasma proteins and osteonecrosis: a proteome-wide Mendelian randomization analysis.

Background: Previous studies have explored the role of plasma proteins on osteonecrosis. This Mendelian randomization (MR) study further assessed plasma proteins on osteonecrosis whether a causal relationship exists and provides some evidence of causality. Methods: Summary-level data of 4,907 circulating protein levels were extracted from a large-scale protein quantitative trait loci study including 35,559 individuals by the deCODE Genetics Consortium. The outcome data for osteonecrosis were sourced from the FinnGen study, comprising 1,543 cases and 391,037 controls. MR analysis was conducted to estimate the associations between protein and osteonecrosis risk. Additionally, Phenome-wide MR analysis, and candidate drug prediction were employed to identify potential causal circulating proteins and novel drug targets. Results: We totally assessed the effect of 1,676 plasma proteins on osteonecrosis risk, of which 71 plasma proteins had a suggestive association with outcome risk (P < 0.05). Notably, Heme-binding protein 1 (HEBP1) was significant positively associated with osteonecrosis risk with convening evidence (OR, 1.40, 95% CI, 1.19 to 1.65, P = 3.96 × 10-5, P FDR = 0.044). This association was further confirmed in other MR analysis methods and did not detect heterogeneity and pleiotropy (all P > 0.05). To comprehensively explore the health effect of HEBP1, the phenome-wide MR analysis found it was associated with 136 phenotypes excluding osteonecrosis (P < 0.05). However, no significant association was observed after the false discovery rate adjustment. Conclusion: This comprehensive MR study identifies 71 plasma proteins associated with osteonecrosis, with HEBP1, ITIH1, SMOC1, and CREG1 showing potential as biomarkers of osteonecrosis. Nonetheless, further studies are needed to validate this candidate plasma protein.

PTGES2 and RNASET2 identified as novel potential biomarkers and therapeutic targets for basal cell carcinoma: insights from proteome-wide mendelian randomization, colocalization, and MR-PheWAS analyses.

Introduction: Basal cell carcinoma (BCC) is the most common skin cancer, lacking reliable biomarkers or therapeutic targets for effective treatment. Genome-wide association studies (GWAS) can aid in identifying drug targets, repurposing existing drugs, predicting clinical trial side effects, and reclassifying patients in clinical utility. Hence, the present study investigates the association between plasma proteins and skin cancer to identify effective biomarkers and therapeutic targets for BCC. Methods: Proteome-wide mendelian randomization was performed using inverse-variance-weight and Wald Ratio methods, leveraging 1 Mb cis protein quantitative trait loci (cis-pQTLs) in the UK Biobank Pharma Proteomics Project (UKB-PPP) and the deCODE Health Study, to determine the causal relationship between plasma proteins and skin cancer and its subtypes in the FinnGen R10 study and the SAIGE database of Lee lab. Significant association with skin cancer and its subtypes was defined as a false discovery rate (FDR) < 0.05. pQTL to GWAS colocalization analysis was executed using a Bayesian model to evaluate five exclusive hypotheses. Strong colocalization evidence was defined as a posterior probability for shared causal variants (PP.H4) of ≥0.85. Mendelian randomization-Phenome-wide association studies (MR-PheWAS) were used to evaluate potential biomarkers and therapeutic targets for skin cancer and its subtypes within a phenome-wide human disease category. Results: PTGES2, RNASET2, SF3B4, STX8, ENO2, and HS3ST3B1 (besides RNASET2, five other plasma proteins were previously unknown in expression quantitative trait loci (eQTL) and methylation quantitative trait loci (mQTL)) were significantly associated with BCC after FDR correction in the UKB-PPP and deCODE studies. Reverse MR showed no association between BCC and these proteins. PTGES2 and RNASET2 exhibited strong evidence of colocalization with BCC based on a posterior probability PP.H4 >0.92. Furthermore, MR-PheWAS analysis showed that BCC was the most significant phenotype associated with PTGES2 and RNASET2 among 2,408 phenotypes in the FinnGen R10 study. Therefore, PTGES2 and RNASET2 are highlighted as effective biomarkers and therapeutic targets for BCC within the phenome-wide human disease category. Conclusion: The study identifies PTGES2 and RNASET2 plasma proteins as novel, reliable biomarkers and therapeutic targets for BCC, suggesting more effective clinical application strategies for patients.

Plasma Proteomics Analysis of Early Biomarkers for Predicting Female Fecundability: A Nested Case-Control Study.

The present study aimed to identify and verify new plasma protein markers to predict the female fecundability level. A nested case-control study was conducted involving couples who participated in the Chinese National Free Preconception Check-up Project. Women who successfully conceive within one year were defined as the high fecundability group, and those unable to conceive were defined as the low fecundability group. In the training cohort, potential protein biomarkers were identified using proteomics technology and were further tested in a validation cohort by the Western blotting assay, enzyme-linked immunosorbent assay, and biochemical tests. Meanwhile, receiver operating characteristic curve analysis were used to evaluate the predictive value. Cox proportional hazard regression analyses were conducted to calculate hazard ratios; restricted cubic spline analysis was used to assess the linear relationship between the the protein level and hazard ratios for fecundability. Pyruvate, a key product of glycolysis, was significantly increased in the high fecundability group (P < 0.01) compared to the low fecundability group, and its area under the curve value was 0.68 (P < 0.05). There was a linear positive dose-response association between the pyruvate level and fecundability possibility (hazard ratios = 1.66, 95% CI: 1.07-2.59, p for trend = 0.025, nonlinearity, p-value = 0.2927).

Diagnostic and predictive power of plasma proteins in Alzheimer's disease: a cross-sectional and longitudinal study in China.

Convenient and effective biomarkers are essential for the early diagnosis and treatment of Alzheimer's disease (AD). In the cross-sectional study, 103 patients with AD, 82 patients with aMCI and 508 normal controls (NC) were enrolled. The single-molecule array (Simoa) technique was used to assess the levels of plasma proteins, including NfL, T-tau, P-tau-181, Aß40, Aß42. Montreal Cognitive Assessment (MoCA) was used to assess the overall cognitive function of all subjects. Moreover, Amyloid PET and structural head MRI were also performed in a subset of the population. In the follow-up, the previous 508 normal older adults were followed up for two years, then COX regression analysis was used to investigate the association between baseline plasma proteins and future cognitive outcomes. NfL, T-tau, P-tau-181, Aß40, Aß42 and Aß42/40 were altered in AD dementia, and NfL, Aß42 and Aß42/40 significantly outperformed all plasma proteins in differentiating AD dementia from NC, while NfL and Aß42/40 could effectively distinguish between aMCI and NC. However, only plasma NfL was associated with future cognitive decline, and it was negatively correlated with MoCA (r = - 0.298, p < 0.001) and the volume of the left globus pallidus (r = - 0.278, p = 0.033). Plasma NfL can help distinguish between cognitively normal and cognitively impaired individuals (MCI/dementia) at the syndrome level. However, since we have not introduced other biomarkers for AD, such as PET CT or cerebrospinal fluid, and have not verified in other neurodegenerative diseases, whether plasma NFL can be used as a biomarker for AD needs to be further studied and explored.

Early prediction of spontaneous preterm birth before 34 gestational weeks based on a combination of inflammation-associated plasma proteins.

Background: In order to identify and possibly offer prophylactic treatment to women at risk for preterm birth (PTB), novel prediction models for PTB are needed. Our objective was to utilize high-sensitive plasma protein profiling to investigate whether early prediction of spontaneous PTB (sPTB) before 34 gestational weeks (gw) was possible in a low-risk population. Methods: A case-control study was conducted on 46 women with sPTB before 34 gw and 46 women with normal pregnancies and term deliveries. Prospectively collected plasma sampled at gw 11 (range 7-16) and gw 25 (range 23-30) was analyzed with a high-sensitivity Proximity Extension Assay for levels of 177 inflammation-associated proteins, and statistically processed with multivariate logistic regression analysis. Results: In the first trimester, higher levels of hepatocyte growth factor (HGF) were associated with sPTB <34 gw (OR 1.49 (1.03-2.15)). In the second trimester, higher levels of interleukin (IL)-10 (OR 2.15 (1.18-3.92)), IL-6 (OR 2.59 (1.34-4.99)), and the receptor activator of nuclear factor κB (RANK) (OR 2.18 (1.26-3.77)) were associated with sPTB <34 gw. The area under the curve for the prediction models including these proteins was 0.653 (0.534-0.759) in the first trimester and 0.854 (0.754-0.925) in the second trimester. Conclusion: A combination of inflammation-associated plasma proteins from the second trimester of pregnancy showed a good predictive ability regarding sPTB before 34 gw, suggesting it could be a valuable supplement for the assessment of the clinical risk of sPTB. However, although a high number (n=177) of plasma proteins were analyzed with a high-sensitivity method, the prediction of sPTB in the first trimester remains elusive.

Associations between genetically predicted concentrations of plasma proteins and the risk of prostate cancer.

BACKGROUND: Prostate cancer (PCa) is a leading cause of cancer-related death in men. Understanding the proteomic landscape associated with PCa risk can provide insights into its molecular mechanisms and pave the way for potential therapeutic interventions. METHODS: A proteome-wide Mendelian randomization (MR) analysis was employed to determine associations between genetically predicted protein concentrations in plasma and PCa risk. From an initial list of 4,364 proteins, significant associations were identified and validated. Multiple sensitivity analyses were also conducted to enhance the robustness of our findings. RESULTS: Of the 4,364 genetically predicted proteins, 308 exhibited preliminary associations with PCa risk. After rigorous statistical refinement, genetically predicted concentrations of 14 proteins showed positive associations with PCa risk, with odds ratios spanning from 1.55 (95% CI 1.28-1.87) for ATG4B to 2.67 (95% CI 1.94-3.67) for HCN1. In contrast, genetically predicted concentrations of ATG7, B2M, MSMB, and TMEM108 demonstrated inverse associations with PCa. The replication analysis further substantiated positive associations for MDH1 and LSM1, and a negative one for MSMB with PCa. A meta-analysis harmonizing primary and replication data mirrored these findings. Furthermore, the MVMR analysis pinpointed B2M and MSMB as having significant associations with PCa risk. CONCLUSION: The genetic evidence unveils a refined set of proteins associated with PCa risk. The findings underscore the potential of these proteins as molecular markers or therapeutic targets for PCa, calling for deeper mechanistic studies and exploration into their translational relevance.

Growth factor and cytokine characterization of canine platelet lysate with variable leukocyte concentration, plasma content, and heat-sensitive proteins.

Background: Platelet lysate is an acellular platelet product containing factors released from secretory granules, including cytokines and growth factors. This study aimed to evaluate different centrifugation methods used to prepare canine platelet lysate with variable content of leukocytes, plasma, and heat-sensitive proteins. Methods: Whole blood was collected from six dogs and two double-spin preparation methods were used to generate the platelet-rich plasma with reduced (PRP) and high (L-PRP) concentration of leukocytes. A portion of both methods underwent plasma depletion via centrifugation and platelet lysate was generated via freeze-thaw cycles. A portion of the generated platelet lysate underwent complement inactivation via heat treatment. Growth factors (TGF-ß1, VEGF, TNF-α, PDGF-BB, HGF) were quantified in all different platelet lysate preparations using ELISAs. Results: Both platelet-rich plasma preparations had a 6.7-fold increase in platelet concentration. White blood cell (WBC) concentration compared to whole blood increased 1.2-fold times in PRP and 1.9-fold times in L-PRP. Negligible concentrations of platelets, WBC, and hematocrit were identified in all lysate groups. Statistically significant differences were identified for PDGF, VEGF, and TNF-α, and not for TGF-ß or HGF. No growth factor differences were noted between centrifugation methods. PDGF was significantly higher in platelet lysate that was plasma depleted. VEGF was significantly higher in heat-treated lysate groups. TNF-α concentrations were overall very low, though were noted to significantly increase following plasma depletion. Conclusion: These results support that growth factors and cytokine release can be affected by the platelet lysate preparation and processing.

Elucidating the causal nexus and immune mediation between frailty and chronic kidney disease: integrative multi-omics analysis.

BACKGROUND: Empirical research has consistently documented the concurrent manifestation of frailty and chronic kidney disease (CKD). However, the existence of a reverse causal association or the influence of confounding variables on these correlations remains ambiguous. METHODS: Our analysis of 7,078 participants from National Health and Nutrition Examination Survey(NHANES) (1999-2018) applied weighted logistic regression and Mendelian Randomization (MR) to investigate the correlation between the frailty index (FI) and renal function. The multivariate MR analysis was specifically adjusted for type 2 diabetes and hypertension. Further analysis explored 3282 plasma proteins to link FI to CKD. A two-step network MR highlighted immune cells' mediating roles in the FI-CKD relationship. RESULT: Genetically inferred FI and various renal function markers are significantly correlated, as supported by NHANES analyses. Multivariate MR analysis revealed a direct causal association between the FI and CKD. Additionally, our investigation into plasma proteins identified Tmprss11D and MICB correlated with FI and CKD, respectively. A two-step network MR to reveal 15 immune cell types, notably Central Memory CD4+ T cells and Lymphocytes, as crucial mediators between FI and CKD. CONCLUSION: Our work establishes a causal connection between frailty and CKD, mediated by specific immune cell profiles. These findings highlight the importance of immune mechanisms in the frailty-CKD interplay and suggest that targeting shared risk factors and immune pathways could improve management strategies for these conditions. Our research contributes to a more nuanced understanding of frailty and CKD, offering new avenues for intervention and patient care in an aging population.

Effect of an endothelial regulatory module on plasma proteomics in exercising horses.

Elite performing exercise requires an intricate modulation of the blood pressure to support the working muscles with oxygen. We have previously identified a genomic regulatory module that associates with differences in blood pressures of importance for elite performance in racehorses. This study aimed to determine the effect of the regulatory module on the protein repertoire. We sampled plasma from 12 Coldblooded trotters divided into two endothelial regulatory module haplotype groups, a sub-elite performing haplotype (SPH) and an elite performing haplotype (EPH), each at rest and exercise. The haplotype groups and their interaction were interrogated in two analyses, i) individual paired ratio analysis for identifying differentially abundant proteins of exercise (DAPE) and interaction (DAPI) between haplotype and exercise, and ii) unpaired ratio analysis for identifying differentially abundant protein of haplotype (DAPH). The proteomics analyses revealed a widespread change in plasma protein content during exercise, with a decreased tendency in protein abundance that is mainly related to lung function, tissue fluids, metabolism, calcium ion pathway and cellular energy metabolism. Furthermore, we provide the first investigation of the proteome variation due to the interaction between exercise and related blood pressure haplotypes, which this difference was related to a faster switch to the lipoprotein and lipid metabolism during exercise for EPH. The molecular signatures identified in the present study contribute to an improved understanding of exercise-related blood pressure regulation.

Novel Protein Biomarkers and Therapeutic Targets for Type 1 Diabetes and Its Complications: Insights from Summary-Data-Based Mendelian Randomization and Colocalization Analysis.

Millions of patients suffer from type 1 diabetes (T1D) and its associated complications. Nevertheless, the pursuit of a cure for T1D has encountered significant challenges, with a crucial impediment being the lack of biomarkers that can accurately predict the progression of T1D and reliable therapeutic targets for T1D. Hence, there is an urgent need to discover novel protein biomarkers and therapeutic targets, which holds promise for targeted therapy for T1D. In this study, we extracted summary-level data on 4907 plasma proteins from 35,559 Icelanders and 2923 plasma proteins from 54,219 UK participants as exposures. The genome-wide association study (GWAS) summary statistics on T1D and T1D with complications were obtained from the R9 release results from the FinnGen consortium. Summary-data-based Mendelian randomization (SMR) analysis was employed to evaluate the causal associations between the genetically predicted levels of plasma proteins and T1D-associated outcomes. Colocalization analysis was utilized to investigate the shared genetic variants between the exposure and outcome. Moreover, transcriptome analysis and a protein-protein interaction (PPI) network further illustrated the expression patterns of the identified protein targets and their interactions with the established targets of T1D. Finally, a Mendelian randomization phenome-wide association study evaluated the potential side effects of the identified core protein targets. In the primary SMR analysis, we identified 72 potential protein targets for T1D and its complications, and nine of them were considered crucial protein targets. Within the group were five risk targets and four protective targets. Backed by evidence from the colocalization analysis, the protein targets were classified into four tiers, with MANSC4, CTRB1, SIGLEC5 and MST1 being categorized as tier 1 targets. Delving into the DrugBank database, we retrieved 11 existing medications for T1D along with their therapeutic targets. The PPI network clarified the interactions among the identified potential protein targets and established ones. Finally, the Mendelian randomization phenome-wide association study corroborated MANSC4 as a reliable target capable of mitigating the risk of various forms of diabetes, and it revealed the absence of adverse effects linked to CTRB1, SIGLEC5 and MST1. This study unveiled many protein biomarkers and therapeutic targets for T1D and its complications. Such advancements hold great promise for the progression of drug development and targeted therapy for T1D.

Effect of Magnetite Nanoparticles on Human Blood Components.

The qualitative composition and zeta potential of magnetite nanoparticles (size 4.2±1.2 nm) obtained by co-precipitation method were determined by X-ray and diffraction dynamic light scattering. The zeta potential of Fe3O4 particles was -15.1±4.5 mV. The possibility of interaction of magnetite nanoparticles with human blood plasma proteins and hemoglobin as well as with erythrocyte membranes was demonstrated by spectrophotometry, electrophoresis, and fluorescence methods. No changes in the sizes of hemoglobin molecules and plasma proteins after their modification by Fe3O4 particles were detected. The possibility of modifying the structural state of erythrocyte membranes in the presence of magnetite nanoparticles was demonstrated by means of fluorescent probe 1-anilinonaphthalene-8-sulfonate.

Impact of breast cancer neoadjuvant chemotherapy on plasma and urine amino acid profile, plasma proteins and nitrogen metabolism.

Neoadjuvant chemotherapy (NAC) is the preferred treatment option in locally advanced breast cancer (BC). The administration of NAC is associated with a wide range of adverse effects. This pilot observational prospective study examined the effect of NAC using anthracycline + cyclophosphamide (AC) followed by paclitaxel (PTx) on a portfolio of 22 plasma and urinary amino acids, plasma proteins (albumin, prealbumin, transferrin), and products of nitrogen metabolism (urea, creatinine, uric acid) in plasma and urine. Plasma and 24-h urine samples were obtained from ten patients with early breast cancer (N1-3 N0-2 M0), at the following time points: before the start of NAC and during the AC/PTx treatment period (a total of 8 measurements at three-weekly intervals). Amino acids were analyzed using ion exchange chromatography. There were no significant differences in the measured parameters in plasma and urine between pre-NAC and during AC- and PTx-treatment. No trend was detected. A significant difference in the portfolio of plasma and urinary amino acids was found only in the pre-treatment period compared to the control group. Levels of eight plasma amino acids (8/22) were significantly reduced and those of nine urine amino acids were increased (9/22). Nitrogenous catabolites in plasma and urine were not indicative of increased protein catabolism during the anthracycline and taxane treatment periods. A slightly positive nitrogen balance was accompanied by an average weight gain of 3.3 kg (range 0-6 kg). The AC/PTx treatment regimen did not cause significant changes in the monitored laboratory parameters.

Key Regulators of Angiogenesis and Inflammation Are Dysregulated in Patients with Varicose Veins.

Varicose veins (VVs) are the most common manifestation of chronic venous disease (CVD) and appear as abnormally enlarged and tortuous superficial veins. VVs result from functional abnormalities in the venous circulation of the lower extremities, such as venous hypertension, venous valve incompetence, and venous reflux. Previous studies indicate that enhanced angiogenesis and inflammation contribute to the progression and onset of VVs; however, dysregulations in signaling pathways associated with these processes in VVs patients are poorly understood. Therefore, in our study, we aimed to identify key regulators of angiogenesis and inflammation that are dysregulated in patients with VVs. Expression levels of 18 genes were analyzed in peripheral blood mononuclear cells (PBMC) using real-time PCR, as well as plasma levels of 6 proteins were investigated using ELISA. Higher levels of CCL5, PDGFA, VEGFC, TGF-alpha, TGF-beta 1, and VEGF-A, as well as lower levels of VEGFB and VEGF-C, were found to be statistically significant in the VV group compared to the control subjects without VVs. None of the analyzed factors was associated with the venous localization of the varicosities. The presented study identified dysregulations in key angiogenesis- and inflammation-related factors in PBMC and plasma from VVs patients, providing new insight into molecular mechanisms that could contribute to the development of VVs and point out promising candidates for circulatory biomarkers of this disease.

Plasma proteome mediate the impact of PM2.5 on stroke: A 2-step Mendelian randomization study.

The objectives of this study were to measure the mediation effect of plasma proteins and to clarify their mediating role in the relationship between stroke risk and particulate matter 2.5 (PM2.5) exposure. The possible mediating role of plasma proteins on the causative link between PM2.5 exposure and stroke incidence were examined using a two-step Mendelian randomization (MR) approach based on two-sample Mendelian randomization (TSMR). The findings revealed a significant positive causal relationship between PM2.5 exposure and stroke, with an inverse variance weighted odds ratio of 1.219 (95 % CI: 1.002 - 1.482, P < 0.05). Additionally, a positive causal association was identified between PM2.5 exposure and several plasma proteins, including FAM134B, SAP, ITGB7, Elafin, and DCLK3. Among these, FAM134B, ITGB7, Elafin, and DCLK3 also demonstrated a positive causal association with stroke, whereas only SAP was found to be negatively causally associated with stroke. Remarkably, four plasma proteins, namely DCLK3, FAM134B, Elafin, and ITGB7, were identified as mediators, accounting for substantial proportions (14.5 %, 13.6 %, 11.1 %, and 9.9 %) of the causal association between PM2.5 and stroke. These results remained robust across various sensitivity analyses. Consequently, the study highlights the significant and independent impact of PM2.5 on stroke risk and identifies specific plasma proteins as potential targets for preventive interventions against PM2.5-induced stroke.

Exploration of potential novel drug targets for diabetic retinopathy by plasma proteome screening.

The aim of this study is to identify novel potential drug targets for diabetic retinopathy (DR). A bidirectional two-sample Mendelian randomization (MR) analysis was performed using protein quantitative trait loci (pQTL) of 734 plasma proteins as the exposures and clinically diagnosed DR as the outcome. Genetic instruments for 734 plasma proteins were obtained from recently published genome-wide association studies (GWAS), and external plasma proteome data was retrieved from the Icelandic Decoding Genetics Study and UK Biobank Pharma Proteomics Project. Summary-level data of GWAS for DR were obtained from the Finngen Consortium, comprising 14,584 cases and 202,082 population controls. Steiger filtering, Bayesian co-localization, and phenotype scanning were used to further verify the causal relationships calculated by MR. Three significant (p < 6.81 × 10-5) plasma protein-DR pairs were identified during the primary MR analysis, including CFH (OR = 0.8; 95% CI 0.75-0.86; p = 1.29 × 10-9), B3GNT8 (OR = 1.09; 95% CI 1.05-1.12; p = 5.9 × 10-6) and CFHR4 (OR = 1.11; 95% CI 1.06-1.16; p = 1.95 × 10-6). None of the three proteins showed reverse causation. According to Bayesian colocalization analysis, CFH (coloc.abf-PPH4 = 0.534) and B3GNT8 (coloc.abf-PPH4 = 0.638) in plasma shared the same variant with DR. All three identified proteins were validated in external replication cohorts. Our research shows a cause-and-effect connection between genetically determined levels of CFH, B3GNT8 and CFHR4 plasma proteins and DR. The discovery implies that these proteins hold potential as drug target in the process of developing drugs to treat DR.

Causal roles and clinical utility of cardiovascular proteins in colorectal cancer risk: a multi-modal study integrating mendelian randomization, expression profiling, and survival analysis.

PURPOSE: This comprehensive investigation delved into the intricate causal interplay existing between cardiovascular-related plasma proteins and the susceptibility to colorectal cancer, leveraging the robust framework of Mendelian randomization, and employed expression profiling and survival analysis to unravel the latent clinical worth embedded within pertinent gene expressions. METHODS: Protein quantitative trait loci (pQTLs) of 85 cardiovascular proteins were employed as instrumental variables to investigate the causal relationship between proteins and CRC risk using a Mendelian randomization approach. Causal inferences were graded as strong, intermediate or weak based on statistical checks. Drug-target MR examined VEGF receptors for their potential as therapeutic targets for colorectal cancer. Differential expression analysis, diagnostic ROC curves, and survival analyses were performed for identified proteins using RNA-seq data from The Cancer Genome Atlas (TCGA) colorectal cancer cohort. RESULTS: Using cis-pQTLs, LOX-1, VEGF-A and OPG were associated with increased CRC risk (strong evidence), while PTX3, TNF-R2 and MMP-7 were protective (strong evidence). Pan-pQTL analysis found MMP-10 increased risk (intermediate evidence) and ADM increased risk (weak evidence). Drug-target MR found VEGF R1 may be promising therapeutic targets. Differential expression analysis revealed seven genes encoding the identified proteins were dysregulated in tumors. ROC analysis showed five gene expression had high diagnostic accuracy. KM analysis showed four genes had prognostic value. CONCLUSIONS: This large-scale MR study implicates several cardiovascular proteins in CRC susceptibility and progression. Findings highlight roles for VEGF signaling and extracellular matrix regulation. Results nominate specific proteins as potential diagnostic biomarkers or therapeutic targets warranting further investigation.

Effect of apheresis plasma donation on plasma uric acid levels, the lipid profile, and major plasma proteins in plasma donors in China: A multicenter, prospective cohort study.

Abnormal plasma uric acid (UA) levels, the lipid profile, and plasma proteins in blood are associated with a range of adverse health outcomes. This multicenter, prospective cohort study aimed to determine the possible effects of multiple apheresis plasma donations on plasma UA levels, the lipid profile, and major proteins in plasma donors. Participants were enrolled from 1 April 2021 to 31 August 2022. When their plasma UA (men: >420 µmol/L, women: >360 µmol/L) and/or lipid levels (total cholesterol [TC]: ≥6.2 mmol/L, triglycerides [TGs]: ≥2.3 mmol/L, low-density lipoprotein cholesterol: ≥4.1 mmol/L, or high-density lipoprotein cholesterol [HDL-C]: <1.0 mmol/L) were abnormal at their first plasma donation, the enrolled participants were followed up until they had completed 10 plasma donations. A total of 11485 participants were enrolled, of whom 1861 met the inclusion criteria. During the study period, 320 donors completed 10 plasma donations. None of the participants took any corrective medicine for their abnormal index. The measured parameters were significantly different from the first to the tenth plasma donations (donors with asymptomatic hyperuricemia: UA, P < 0.001; donors with asymptomatic hyperlipidemia: HDL-C, P < 0.001; TC, P = 0.025; TGs, P < 0.001; apolipoprotein B, P = 0.025; all of the plasma donors, immunoglobulin G, P < 0.001). The levels of HDL-C, TC, and apolipoprotein B were increased, and the levels of UA, TGs, and immunoglobulin G were decreased over this time. However, immunoglobulin G levels were still in the normal range. Moreover, the changes in these parameters were closely associated with the frequency of plasma donation during the study period. Repeated apheresis plasma donations can reduce plasma UA and TG levels and increase HDL-C levels; and further evaluation of the clinical significance with a larger sample size is required.

Proteome-wide Mendelian randomization identifies therapeutic targets for ankylosing spondylitis.

Background: Ankylosing Spondylitis (AS) is a chronic inflammatory disorder which can lead to considerable pain and disability. Mendelian randomization (MR) has been extensively applied for repurposing licensed drugs and uncovering new therapeutic targets. Our objective is to pinpoint innovative therapeutic protein targets for AS and assess the potential adverse effects of druggable proteins. Methods: We conducted a comprehensive proteome-wide MR study to assess the causal relationships between plasma proteins and the risk of AS. The plasma proteins were sourced from the UK Biobank Pharma Proteomics Project (UKB-PPP) database, encompassing GWAS data for 2,940 plasma proteins. Additionally, GWAS data for AS were extracted from the R9 version of the Finnish database, including 2,860 patients and 270,964 controls. The colocalization analysis was executed to identify shared causal variants between plasma proteins and AS. Finally, we examined the potential adverse effects of druggable proteins for AS therapy by conducting a phenome-wide association study (PheWAS) utilizing the extensive Finnish database in version R9, encompassing 2,272 phenotypes categorized into 46 groups. Results: The findings revealed a positive genetic association between the predicted plasma levels of six proteins and an elevated risk of AS, while two proteins exhibited an inverse association with AS risk (P fdr < 0.05). Among these eight plasma proteins, colocalization analysis identified AIF1, TNF, FKBPL, AGER, ALDH5A1, and ACOT13 as shared variation with AS(PPH3+PPH4>0.8), suggesting that they represent potential direct targets for AS intervention. Further phenotype-wide association studies have shown some potential side effects of these six targets (P fdr < 0.05). Conclusion: Our investigation examined the causal connections between six plasma proteins and AS, providing a comprehensive understanding of potential therapeutic targets.