The immune factors have complex causal regulation effects on kidney stone disease: a mendelian randomization study.
BMC immunology
PURPOSE:Previous studies have reported the potential impact of immune cells on kidney stone disease (KSD), but definitive causal relationships have yet to be established. The purpose of this paper is to elucidate the potential causal association between immune cells and KSD by Mendelian randomization (MR) analysis. METHODS:In our study, a thorough two-sample Mendelian randomization (MR) analysis was performed by us to determine the potential causal relationship between immune cell traits and kidney stone disease. We included a total of four immune traits (median fluorescence intensity (MFI), relative cellular (RC), absolute cellular (AC), and morphological parameters (MP)), which are publicly available data. GWAS summary data related to KSD (9713 cases and 366,693 controls) were obtained from the FinnGen consortium. The primary MR analysis method was Inverse variance weighted. Cochran's Q test, MR Egger, and MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO) were used to assess the stability of the results. RESULTS:After FDR correction, the CD8 on HLA DR + CD8br (OR = 0.95, 95% CI = 0.93-0.98, p-value = 7.20 × 10, q-value = 0.088) was determined to be distinctly associated with KSD, and we also found other 25 suggestive associations between immune cells and KSD, of which 13 associations were suggested as protective factors and 12 associations were suggested as risk factors. There was no horizontal pleiotropy or significant heterogeneity in our MR analysis, as determined by the p-value results of our Cochrane Q-test, MR Egger's intercept test, and MR-PRESSO, which were all > 0.05. CONCLUSIONS:Our study has explored the potential causal connection between immune cells and KSD by Mendelian randomization analysis, thus providing some insights for future clinical studies.
10.1186/s12865-024-00627-x
Exploring the association between multiple factors and urolithiasis: A retrospective study and Mendelian randomization analysis.
Medicine
To investigate the relationship between several factors and urinary stone as well as different stone compositions. To guide the diagnosis, treatment, and prevention of urinary stone recurrence. We used bidirectional Mendelian randomization to analyze the causal relationship between hypertension and urinary stones, diabetes and urinary stones, and body mass index (BMI) and urinary stones. We retrospectively analyzed the medical records of patients with urinary stones admitted to a tertiary care hospital in Chongqing, China, from July 2015 to October 2022. Patients were included when they were first diagnosed with urinary stones. The odds ratio of calculi on hypertension estimated by inverse variance weighted was 8.46 (95%CI: 4.00-17.90, P = 2.25 × 10-8). The stone composition analysis showed that there were 3101 (67.02%) mixed, 1322 (28.57%) calcium oxalate monohydrate, 148 (3.20%) anhydrous uric acid, 16 (0.35%) magnesium ammonium phosphate hexahydrate, 11 (0.24%) dicalcium phosphate dihydrate, 10 (0.22%) carbonate apatite, 8 (0.17%) L-cystine, 4 ammonium uric acid (0.09%), and 7 other stone types (0.15%). Mendelian randomization studies have proven that urinary stones may be a potential risk factor for hypertension, while there is no causal relationship between diabetes and stones, BMI, and stones. Our retrospective study has shown that urinary stone components are closely associated with sex, age, hypertension, diabetes, and BMI. It is reasonable to suspect that treating a single stone component is ineffective in preventing recurrence. We also found that the peak incidence of urinary stones was at the most active stage of most people's working lives.
10.1097/MD.0000000000037968
Inflammatory cytokines and their potential role in kidney stone disease: a Mendelian randomization study.
International urology and nephrology
PURPOSE:Previous studies have reported a complex relationship between inflammatory cytokines and kidney stone disease (KSD). The purpose of this paper is to investigate the potential causal impact of inflammatory cytokines on KSD by Mendelian randomization (MR) analysis. METHODS:In our study, a thorough two-sample Mendelian randomization (MR) analysis was performed by us to determine the potential causal relationship between inflammatory cytokines and kidney stone disease. Utilizing GWAS summary data of inflammatory cytokines and KSD, we performed the first two-sample MR analysis. Genetic variants in GWASs related to inflammatory cytokines were employed as instrumental variables (IVs). The data on cytokines were derived from 14,824 participants and analyzed by utilizing the Olink Target-96 Inflammation Panel. GWAS summary data related to KSD (9713 cases and 366,693 controls) were obtained from the FinnGen consortium. The primary MR analysis method was Inverse variance weighted. Reverse MR analysis, Cochran's Q test, MR Egger, and MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO) were used to assess the stability of the results. RESULTS:91 cytokines were enrolled in the MR analysis after strict quality control of IV. The IVW analysis revealed 2 cytokines as risk factors for KSD: Cystatin D (OR 1.06, 95% CI 1.01-1.11), Fibroblast growth factor 5 (OR 1.06, 95% CI 1.00-1.12), suggesting they are positively associated with the occurrence of kidney stones. We also found 3 protective associations between cytokines and KSD: Artemin (OR 0.86, 95% CI 0.78-0.96), T-cell surface glycoprotein CD6 isoform (OR 0.92, 95% CI 0.88-0.98), STAM-binding protein (OR 0.83, 95% CI 0.69-0.99). There was no horizontal pleiotropy or significant heterogeneity in our MR analysis, as determined by the p-value results of our MR Egger's intercept test, Cochrane Q-test, and MR-PRESSO, which were all > 0.05. CONCLUSIONS:Our study explored a variety of inflammatory cytokines related to KSD through MR analysis, which validated several previous findings and provided some new potential biomarkers for KSD. However, the findings require further investigation to validate their exact functions in the pathogenesis and evolution of KSD.
10.1007/s11255-024-04084-8
Causal effects of modifiable risk factors on kidney stones: a bidirectional mendelian randomization study.
BMC medical genomics
BACKGROUND:Increasing epidemiological studies demonstrated that modifiable risk factors affected the risk of kidney stones. We aimed to systemically assess these causal associations using a bidirectional Mendelian randomization study. METHODS:We obtained instrumental variables related to each exposure at the genome-wide significant threshold (P < 5 × 10). Summary level data for outcomes from the FinnGen consortium and UK Biobank were utilized in the discovery and replication stage. The Inverse-variance weighted (IVW) method was used as the primary analysis, with additional sensitivity analyses and fix-effect meta-analysis to verify the robustness of IVW results. RESULTS:Among 46 risk factors, five were significantly associated with nephrolithiasis risk in the FinnGen consortium, UK Biobank, and meta-analyses collectively. The odds ratios (ORs) (95% confidence intervals [95%CIs]) of kidney stones were 1.21 (1.13, 1.29) per standard deviation (SD) increase in serum calcium, 1.55 (1.01, 2.36) per SD increase in serum 25(OH)D, 1.14 (1.00, 1.29) per SD increase in total triglycerides, 2.38 (1.34, 4.22) per SD increase in fasting insulin, and 0.28 (0.23, 0.35) per unit increase in log OR of urine pH. In addition, genetically predicted serum phosphorus, urinary sodium, tea consumption, and income affected the risk of kidney stones (false discovery rate [FDR] P < 0.05) based on the outcome data from the FinnGen consortium, and the significant associations of education and waist-to-hip ratio with nephrolithiasis risks were found after FDR correction (FDR P < 0.05) based on the outcome data from UK Biobank. CONCLUSIONS:Our findings comprehensively provide modifiable risk factors for the prevention of nephrolithiasis. Genome-wide association studies with larger sample sizes are needed to verify these causal associations in the future further.
10.1186/s12920-023-01520-z
Genetic susceptibility of urolithiasis: comprehensive results from genome-wide analysis.
World journal of urology
BACKGROUND:The pathogenesis of urolithiasis is multi-factorial and genetic factors have been shown to play a significant role in the development of urolithiasis. We tried to apply genome-wide Mendelian randomization (MR) analysis and figure out reliable gene susceptibility of urolithiasis from the largest samples to date in two independent genome-wide association studies (GWAS) database of European ancestry. METHODS:We extracted summary statistics of expression quantitative trait locus (eQTL) from eQTLGen consortium. Urolithiasis phenotype information was obtained from both FinnGen Biobank and UK Biobank. Multiple two-sample MR analysis with a Bonferroni-corrected P threshold (P < 2.5e-06) was conducted. The primary endpoint was the causal effect calculated by random-effect inverse variance weighted (IVW) method. Sensitivity analysis, volcano plots, scatter plots, and regional plots were also performed and visualized. RESULTS:After multiple MR tests between 19942 eQTLs and urolithiasis phenotype from both cohorts, 30 common eQTLs with consistent effect size direction were found to be causally associated with urolithiasis risk. Finally only one gene (LMAN2) was simultaneously identified among all top significant eQTLs from both FinnGen Biobank (beta = 0.6758, se = 0.0327, P = 6.775e-95) and UK Biobank (beta = 0.0044, se = 0.0009, P = 2.417e-06). We also found that LMAN2 was with the largest beta effect size on urolithiasis phenotype from the two cohorts. CONCLUSION:We for the first time implemented genome-wide MR analysis to investigate the genetic susceptibility of urolithiasis in general population of European ancestry. Our results provided novel insights into common genetic variants of urinary stone disease, which was of great help to subsequent researches.
10.1007/s00345-024-04937-y
Causal effects of circulating lipids and lipid-lowering drugs on the risk of urinary stones: a Mendelian randomization study.
Frontiers in endocrinology
Background:Previous studies have yielded conflicting findings regarding the association between circulating lipids and lipid-lowering drugs with urinary stones, and the causal relationship between the two remains inconclusive. Objective:This study aimed to assess the causal relationship between circulating lipids (Triglycerides [TG], low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], apolipoprotein A [APOA], apolipoprotein B [APOB] and Pure hypercholesterolaemia), lipid-lowering drugs (HMGCR [HMG-CoA reductase] inhibitors and PCSK9[Proprotein Convertase Subtilisin/Kexin Type 9] inhibitors) and the risk of urinary stones, using genetic data. Methods:Genetic instrumental variables (GIVs) for circulating lipids and lipid-lowering drugs were obtained from the UK Biobank and existing literature. Outcome data were extracted from a genetic association database with 3,625 urinary stone cases and 459,308 controls. Two-sample MR analysis, employing the TwoSampleMR software package in R 4.2.3, was conducted to assess the associations between multiple exposures. The primary outcome was determined using the inverse variance weighted (IVW) method for the causal relationship between exposure and outcome, while additional methods such as MR-Egger, weighted median, simple mode, and weighted mode were utilized as supplementary analyses. Robustness of the Mendelian Randomization (MR) analysis results was assessed through leave-one-out analysis and funnel plots. Results:The MR analysis revealed a significant association between elevated TG levels per 1 standard deviation and the occurrence of urinary stones (odds ratio [OR]: 1.002, 95% confidence interval [CI]: 1.000-1.003, P = 0.010). However, no significant association was observed between factors other than TG exposure and the risk of urinary stone occurrence across all methods(LDL-C: [OR], 1.001; 95% [CI], 1.000-1.003, P=0.132;HDL-C: [OR], 0.999; 95% [CI], 0.998-1.000, P=0.151;APOA:[OR] being 1.000 (95% [CI], 0.999-1.001, P=0.721;APOB: [OR] of 1.001 (95% [CI], 1.000-1.002, P=0.058;Pure hypercholesterolaemia: [OR] of 1.015 (95% [CI], 0.976-1.055, P=0.455) and lipid-lowering drugs (HMGCR inhibitors: [OR], 0.997; 95% [CI], 0.990-1.003, P=0.301 and PCSK9 inhibitors:[OR], 1.002; 95% [CI], 1.000-1.005, P=0.099). Conclusion:Our findings provide conclusive evidence supporting a causal relationship between an increased risk of urinary stones and elevated serum TG levels. However, we did not find a significant association between urinary stone occurrence and the levels of LDL-C, HDL-C, APOA, APOB, Pure hypercholesterolaemia and lipid-lowering drugs.
10.3389/fendo.2023.1301163
Causal effects of gut microbiota on the risk of urinary tract stones: A bidirectional two-sample mendelian randomization study.
Heliyon
Background:Recent studies increasingly suggest notable changes in both the quantity and types of gut microbiota among individuals suffering from urinary tract stones. However, the causal relationship between GMB and urinary tract stone formation remains elusive, which we aim to further investigate in this research through Mendelian Randomization (MR) analysis. Materials and methods:Single nucleotide polymorphisms (SNPs) associated with the human GMB were selected from MiBioGen International Consortium GWAS dataset. Data on urinary tract stone-related traits and associated SNPs were sourced from the IEU Open GWAS database. To investigate the causal relationships between gut microbiota and urinary tract stones, Mendelian Randomization (MR) was applied using genetic variants as instrumental variables, utilizing a bidirectional two-sample MR framework. This analysis incorporated various statistical techniques such as inverse variance weighting, weighted median analysis, MR-Egger, and the maximum likelihood method. To ensure the reliability of the findings, a range of sensitivity tests were conducted, including Cochran's Q test, the MR-Egger intercept, leave-one-out cross-validation, and examination of funnel plots. Results:The results revealed the causal relationship between the increase in the abundance of 10 microbial taxa, including Genus-Barnesiella (IVW OR = 0.73, 95%CI 0.73-0.89, P = 2.29 × 10-3) and Genus-Flavonifractor (IVW OR = 0.69, 95%CI 0.53-0.91, P = 8.57 × 10-3), and the decreased risk of urinary tract stone formation. Conversely, the development of urinary tract stones was observed to potentially instigate alterations in the abundance of 13 microbial taxa, among which Genus-Ruminococcus torques group was notably affected (IVW OR = 1.07, 95%CI 0.64-0.98, P = 1.86 × 10-3). In this context, Genus-Clostridium sensustricto1 exhibited a bidirectional causal relationship with urinary tract stones, while the remaining significant microbial taxa demonstrated unidirectional causal effects in the two-sample MR analysis. Sensitivity analyses did not identify significant estimates of heterogeneity or pleiotropy. Conclusion:To summarize, the results of this study suggest a likely causative link between gut microbiota and the incidence of urinary tract stones. This insight opens up potential pathways for discovering biomarkers and therapeutic targets in the management and prevention of urolithiasis. However, further in-depth research is warranted to investigate these associations.
10.1016/j.heliyon.2024.e25704
Lifestyle factors, serum parameters, metabolic comorbidities, and the risk of kidney stones: a Mendelian randomization study.
Frontiers in endocrinology
Background and objective:The early identification of modifiable risk factors is important for preventing kidney stones but determining causal associations can be difficult with epidemiological data. We aimed to genetically assess the causality between modifiable factors (lifestyle factors, serum parameters, and metabolic comorbidities) and the risk of kidney stones. Additionally, we aimed to explore the causal impact of education on kidney stones and its potential mediating pathways. Methods:We conducted a two-sample Mendelian randomization (MR) study to explore the causal association between 44 modifiable risk factors and kidney stones. The FinnGen dataset initially explored the causal relationship of risk factors with kidney stones and the UK Biobank dataset was used as the validation set. Then, a meta-analysis was conducted by combining discovery and validation datasets. We used two-step MR to assess potential mediators and their mediation proportions between education and kidney stones. Results:The combined results indicated that previous exposures may increase the risk of kidney stones, including sedentary behavior, urinary sodium, the urinary sodium/potassium ratio, the urinary sodium/creatinine ratio, serum calcium, 25-hydroxyvitamin D (25OHD), the estimated creatinine-based glomerular filtration rate (eGFRcrea), GFR estimated by serum cystatin C (eGFRcys), body mass index (BMI), waist circumference, type 2 diabetes mellitus (T2DM), fasting insulin, glycated hemoglobin, and hypertension. Coffee intake, plasma caffeine levels, educational attainment, and the urinary potassium/creatinine ratio may decrease the risk of kidney stones. Ranked by mediation proportion, the effect of education on the risk of kidney stones was mediated by five modifiable risk factors, including sedentary behavior (mediation proportion, 25.7%), smoking initiation (10.2%), BMI (8.2%), T2DM (5.8%), and waist circumference (3.2%). Conclusion:This study provides MR evidence supporting causal associations of many modifiable risk factors with kidney stones. Sedentary lifestyles, obesity, smoking, and T2DM are mediating factors in the causal relationship between educational attainment and kidney stones. Our results suggest more attention should be paid to these modifiable factors to prevent kidney stones.
10.3389/fendo.2023.1240171
Association between tea consumption and risk of kidney stones: results from dose-response meta-analysis of prospective studies and Mendelian randomization analysis.
International urology and nephrology
PURPOSE:The association between tea consumption and kidney stones is inconsistent in observational studies. Thus, we performed a dose-response meta-analysis of prospective cohort studies and a two-sample Mendelian randomization (MR) analysis to identify this association. METHODS:The prospective cohort studies reporting the relationship between tea consumption and kidney stones were searched from PubMed, the Cochrane Library, EMBASE, and Web of Science from inception to December 1, 2023. For MR analysis, the summary-level data for tea consumption and kidney stones were extracted from the UK Biobank available data and the 8th release of the FinnGen consortium, respectively. The inverse-variance weighted (IVW) method was the primary analytical method. RESULTS:In our dose-response meta-analysis, four prospective cohort studies involving 1,263,008 participants were included, and tea consumption was found to have significant associations with kidney stones (RR: 0.80, 95% CI: 0.73-0.87). We also observed a substantially linear negative relationship between tea consumption and the risk of kidney stones. In MR analysis, the IVW method indicated that tea consumption was inversely associated with kidney stones (OR: 0.71, 95% CI: 0.53-0.94). CONCLUSION:Our study confirmed a causal relationship between tea consumption and kidney stones, and higher tea consumption may reduce the risk of kidney stones.
10.1007/s11255-023-03918-1
The impact of anxiety on the risk of kidney stone disease: Insights into eGFR-mediated effects.
Journal of affective disorders
BACKGROUND:Previous studies have linked kidney stone disease (KSD) with depression, but there are no reports on the relationship between anxiety and KSD, and the mechanism underlying the potential relationship remains unclear. METHODS:Associations of anxiety and incident KSD were assessed in the National Health and Nutrition Examination Survey (NHENES) using multivariate logistic regression. Two-sample bidirectional Mendelian randomization studies and a two-step two-sample MR was used to estimate the mediating factors that influence KSD risk. RESULTS:Examinations of NHANES data revealed that a rise in the frequency and intensity of anxiety were independently associated with incident KSD. In MR analysis, anxiety (uk-a-51 and uk-b-6519) were from the UK Biobank, with sample sizes of 328,717 and 450,765 respectively. KSD data were from the FinnGen, including 8597 cases and 333,128 controls. In the IVW analysis, genetically predicted anxieties (ukb-a-51 and ukb-b-6519) were found to be causally associated with a higher risk of KSD, with odds ratios of 6.18 (95 % CI 2.54-15.04) and 3.44 (95 % CI 1.67-7.08), respectively. There were no reverse causal effects. Further mediation analysis indicated that anxiety increases the risk of KSD by raising eGFR, through which 11.8 % of the effect of anxiety on KSD risk was mediated. LIMITATIONS:The research was confined to individuals of European heritage, and there could be specific genetic variances among diverse ethnicities. CONCLUSION:The current study suggests anxiety as an independent causal risk factor for KSD and unveils a new pathogenic mechanism, showing that anxiety raises eGFR, thereby increasing the risk of KSD.
10.1016/j.jad.2024.08.061
Inflammatory factors and the risk of urolithiasis: a bidirectional Mendelian randomization study.
Frontiers in medicine
Background:Urolithiasis is a prevalent condition encountered in urology. Over the past decade, its global incidence has been on an upward trajectory; paired with a high recurrence rate, this presents considerable health and economic burdens. Although inflammatory factors are pivotal in the onset and progression of urolithiasis, their causal linkages remain elusive. Method:Mendelian randomization (MR) is predicated upon genome-wide association studies (GWASs). It integrates bioinformatics analyses to reveal causal relationships between exposures and outcomes, rendering it an effective method with minimized bias. Drawing from a publicly accessible GWAS meta-analysis comprising 8,293 samples, we identified 41 genetic variations associated with inflammatory cytokines as instrumental variables. Outcome data on upper urinary tract stones, which included renal and ureteral stones (9,713 cases and 366,693 controls), and lower urinary tract stones, including bladder and urethral stones (1,398 cases and 366,693 controls), were derived from the FinnGen Consortium R9 dataset. By leveraging the bidirectional MR methodology, we aimed to decipher the causal interplay between inflammatory markers and urolithiasis. Results:Our study comprehensively elucidated the association between genetic inflammatory markers and urolithiasis via bidirectional Mendelian randomization. Post-MR analysis of the 41 genetic inflammation markers revealed that elevated levels of circulating interleukin-2 (IL-2) (OR = 0.921, 95% CI = 0.848-0.999) suggest a reduced risk for renal stone disease, while heightened stem cell growth factor beta (SCGF-β) (OR = 1.150, 95% CI = 1.009-1.310) and diminished macrophage inflammatory protein 1 beta (MIP-1β) (OR = 0.863, 95% CI = 0.779-0.956) levels suggest an augmented risk for lower urinary tract stones. Furthermore, renal stone disease appeared to elevate IL-2 ( = 0.145, 95% CI = 0.013-0.276) and cutaneous T cell-attracting chemokine (CTACK) ( = 0.145, 95% CI = 0.013-0.276) levels in the bloodstream, whereas lower urinary tract stones were linked to a surge in interleukin-5 (IL-5) ( = 0.142, 95% CI = 0.057-0.226), interleukin-7 (IL-7) ( = 0.108, 95% CI = 0.024-0.192), interleukin-8 (IL-8) ( = 0.127, 95% CI = 0.044-0.210), growth regulated oncogene alpha (GRO-α) ( = 0.086, 95% CI = 0.004-0.169), monokine induced by interferon-gamma (MIG) ( = 0.099, 95% CI = 0.008-0.191) and macrophage inflammatory protein 1 alpha (MIP-1α) ( = 0.126, 95% CI = 0.044-0.208) levels. Conclusion:These discoveries intimate the instrumental role of IL-2 in the onset and progression of upper urinary tract stones. SCGF-β and MIP-1β influence the development of lower urinary tract stones. Urolithiasis also impacts the expression of cytokines such as IL-2, CTACK, IL-5, IL-7, IL-8, GRO-α, MIG, and MIP-1α. There is a pressing need for further investigation to ascertain whether these biomarkers can be harnessed to prevent or treat urolithiasis.
10.3389/fmed.2024.1432275
Plasma metabolites as potential markers and targets to prevent and treat urolithiasis: a Mendelian randomization study.
Frontiers in molecular biosciences
Background:Studies on the relationships between diseases of the urinary system and human plasma proteomes have identified several potential biomarkers. However, none of these studies have elucidated the causal relationships between plasma proteins and urolithiasis. Objective:The objective of the study was to investigate the potential risks of plasma metabolites in urolithiasis using a two-sample Mendelian randomization (MR) study. Methods:A total of 1,400 metabolites were identified in the most comprehensive genome-wide association study (GWAS) of plasma metabolomics in a European population to date, and single-nucleotide polymorphisms (SNPs) were used as the instrumental variables for the plasma metabolites. The European GWAS data for urinary calculi included 482,123 case samples and 6,223 control samples (ebi-a-GCST90018935). The associations between the plasma metabolites and risk of urolithiasis were evaluated by inverse variance weighting (IVW) and supplemented by sensitivity analyses of the MR-Egger and MR-PRESSO tests. Results:For the first time, we found a causal relationship between two plasma metabolites ( < 1.03 × 10) and urolithiasis ( < 0.05). The chemical 4-hydroxychlorothalonil, which is an intermediate product of the pesticide hydroxychlorothalonil, could promote urolithiasis (odds ratio (OR) = 1.12) as a risk factor. Moreover, 1-stearoyl-2-arachidonoyl-GPC, which is an important component of phospholipid metabolism in the human body, can inhibit urolithiasis (OR = 0.94). Conclusions:Our results suggest that blood metabolites can be used as blood markers and drug targets in the prevention, diagnosis, and treatment of urolithiasis; furthermore, our results can provide a basis for policy makers to formulate prevention and treatment policies for urolithiasis.
10.3389/fmolb.2024.1426575