Exploring the association between multiple factors and urolithiasis: A retrospective study and Mendelian randomization analysis.

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.

Basal metabolic rate and the risk of urolithiasis: a two-sample Mendelian randomization study.

OBJECTIVE: Few studies have investigated the impact of basal metabolic rate (BMR) on the development of urolithiasis, and the causal relationship is yet to be established. In this study, a two-sample Mendelian randomization (MR) analysis was utilized to identify the causal relationship between BMR and risk of urolithiasis. METHOD: Genetic instruments for BMR were drawn from a public genome-wide association study (GWAS). Summary dates on BMR and urolithiasis were obtained from a GWAS meta-analysis with sample sizes of 454,874 and 212,453, respectively. The inverse-variance weighted (IVW) method was provided as the main approach to estimate the causal relationship. The weighted-median method and the MR-Egger method were used as supplements to the IVW method. In addition, we conducted sensitivity analyses, including heterogeneity tests, pleiotropy tests and leave-one-out analysis, to assess the robustness of the outcomes. Furthermore, the funnel plot asymmetry was visually inspected to evaluate possible bias. RESULTS: The inverse-variance weighted data revealed that genetically predicted BMR significantly decreased the risk of urolithiasis [beta coefficient (beta): - 0.2366, odds ratio (OR): 0.7893, 95% confidence interval (CI) 0.6504-0.9579, p = 0.0166]. CONCLUSIONS: BMR has causal effects on urolithiasis in an MR study, and the risk of urolithiasis in patients with lower levels of BMR is higher.

Risk relationship between inflammatory bowel disease and urolithiasis: A two-sample Mendelian randomization study.

BACKGROUND: The causal genetic relationship between common parenteral manifestations of inflammatory bowel disease (IBD) and urolithiasis remains unclear because their timing is difficult to determine. This study investigated the causal genetic association between IBD and urolithiasis using Mendelian randomization (MR) based on data from large population-based genome-wide association studies (GWASs). METHODS: A two-sample MR analysis was performed to assess the potential relationship between IBD and urolithiasis. Specific single nucleotide polymorphism data were obtained from GWASs, including IBD (n = 59957) and its main subtypes, Crohn's disease (CD) (n = 40266) and ulcerative colitis (UC) (n = 45975). Summarized data on urolithiasis (n = 218792) were obtained from different GWAS studies. A random-effects model was analyzed using inverse-variance weighting, MR-Egger, and weighted medians. RESULTS: Genetic predisposition to IBD and the risk of urolithiasis were significantly associated [odds ratio (OR), 1.04 (95% confidence interval [CI], 1.00-.08), P = 0.01]. Consistently, the weighted median method yielded similar results [OR, 1.06 (95% CI, 1.00-1.12), P = 0.02]. The MR-Egger method also demonstrated comparable findings [OR, 1.02 (95% CI, 0.96-1.08), P = 0.45]. Both funnel plots and MR-Egger intercepts indicated no directional pleiotropic effects between IBD and urolithiasis. CD was strongly associated with it in its subtype analysis [OR, 1.04 (95% CI, 1.01-1.07), P = 0.01], and UC was also causally associated with urolithiasis, although the association was not significant [OR, 0.99 (95% CI, 0.95-1.03), P = 0.71]. CONCLUSION: A unidirectional positive causal correlation was identified between IBD and urolithiasis, with varying degrees of association observed among the different subtypes of IBD. Recognizing the increased incidence of urolithiasis in patients with IBD is crucial in clinical practice. Early detection and surveillance of IBD, improved patient awareness, adoption of preventive strategies, and promotion of collaborative efforts among healthcare providers regarding treatment methodologies are vital for improving patient outcomes.

Genetic susceptibility of urolithiasis: comprehensive results from genome-wide analysis.

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.

Impact of habitual intake of glucosamine, fresh fruit, and tea on the risk of urolithiasis: A two-sample Mendelian randomization study.

Dietary patterns have a significant impact on the occurrence of urolithiasis. This study aimed to investigate the causal relationships between the consumption of glucosamine, fresh fruits, and tea, and the predisposition to urinary stones using a Mendelian randomization (MR) approach. Genetic proxies for these dietary factors were obtained from the UK Biobank, while the summary data for urolithiasis genome-wide association analyses were sourced from the FinnGen consortium. Five MR methodologies, namely inverse variance weighted (IVW), MR-Egger regression, weighted median, weighted mode, and simple mode, were employed in the analysis. To validate the findings, sensitivity evaluations such as the MR-PRESSO disruption test and Cochran Q test for heterogeneity were performed. The IVW method showed that glucosamine consumption had a strong inverse association with urolithiasis risk (Odds Ratio [OR] = 0.006, 95% Confidence Interval [CI] 0.0001-0.287, P = .009), surpassing the associations of fresh fruits (OR = 0.464, 95% CI 0.219-0.983, P = .045) and tea (OR = 0.550, 95% CI 0.345-0.878, P = .012). These findings were consistent when verified using alternative MR techniques, and the sensitivity analyses further supported their credibility. The results of this MR analysis demonstrate that regular consumption of glucosamine, fresh fruits, and tea is inversely correlated with the risk of developing urolithiasis.

Blood metabolites mediate the impact of lifestyle factors on the risk of urolithiasis: a multivariate, mediation Mendelian randomization study.

Urolithiasis is closely linked to lifestyle factors. However, the causal relationship and underlying mechanisms remain unclear. This study aims to investigate the relationship between lifestyle factors and the onset of urolithiasis and explore potential blood metabolite mediators and their role in mediating this relationship. In this study, we selected single nucleotide polymorphisms (SNPs) as instrumental variables if they exhibited significant associations with our exposures in genome-wide association studies (GWAS) (p < 5.0 × 10-8). Summary data for urolithiasis came from the FinnGen database, including 8597 cases and 333,128 controls. We employed multiple MR analysis methods to assess causal links between genetically predicted lifestyle factors and urolithiasis, as well as the mediating role of blood metabolites. A series of sensitivity and pleiotropy analyses were also conducted. Our results show that cigarettes smoked per day (odds ratio [OR] = 1.159, 95% confidence interval [CI] = 1.004-1.338, p = 0.044) and alcohol intake frequency (OR = 1.286, 95% CI = 1.056-1.565, p = 0.012) were positively associated with increased risk of urolithiasis, while tea intake (OR = 0.473, 95% CI = 0.299-0.784, p = 0.001) was positively associated with reduced risk of urolithiasis. Mediation analysis identifies blood metabolites capable of mediating the causal relationship between cigarettes smoked per day, tea intake and urolithiasis. We have come to the conclusion that blood metabolites serve as potential causal mediators of urolithiasis, underscoring the importance of early lifestyle interventions and metabolite monitoring in the prevention of urolithiasis.

Association Between Klotho Gene Polymorphisms and Urolithiasis: A Meta-Analysis.

Former studies have suggested that urolithiasis is related to Klotho gene polymorphisms. The aim of this meta-analysis was to investigate this relationship. Studies on the association between urolithiasis susceptibility and Klotho gene polymorphisms were systematically searched for in databases. Odds ratios and 95% confidence intervals were pooled as the effect size. This meta-analysis incorporated ten articles. Klotho rs1207568 adenine (A) may be related to a decreased urolithiasis risk in Caucasians. The results showed that Klotho rs3752472 may not be related to urolithiasis risk in the Han Asian subgroup. Klotho rs564481 may not be related to urolithiasis risk in Asians or Caucasians, and Klotho rs650439 may not be related to urolithiasis risk in Asians. Key Words: Klotho, Single-nucleotide polymorphism, Urolithiasis, Meta-analysis.

Genes polymorphism as risk factor of recurrent urolithiasis: a systematic review and meta-analysis.

INTRODUCTION: Urolithiasis is one of the most prevalent diseases worldwide. Its prevalence is rising, both in developing and developed countries. It is known that genetic factors play big roles in the development of urolithiasis. One of the suspected factors is gene polymorphism. This study aims to find an accurate estimate of the association between genetic polymorphism and the risk of recurrent urolithiasis. METHODS: A systematic review and meta-analysis were performed on 12 studies from 3 databases that investigated gene polymorphism as an risk factor of urolithiasis. The review was done using Review Manager® version 5.3. RESULTS: Insignificant heterogenicity was found in this study. Populations from Asia and the Middle East are more likely to experience recurrent urolithiasis. Additionally, variation in the VDR and urokinase genes, particularly in the Asian population, increases the risk of developing recurrent urolithiasis. CONCLUSIONS: Gene polymorphisms have significant roles in the development of urolithiasis, especially in the Middle Eastern region.

Alterations in urinary microbiota composition in urolithiasis patients: insights from 16S rRNA gene sequencing.

Objectives: To investigate the urinary microbiota composition in urolithiasis patients compared to healthy controls and to identify potential microbial markers and their association with clinical parameters. Methods: A total of 66 samples, comprising 45 from urolithiasis patients and 21 from healthy controls, were analyzed. 16S rRNA gene sequencing was employed to determine the microbiota composition. Various statistical and bioinformatics tools, including ANOVA, PCoA, and LEfSe, were utilized to analyze the sequencing data and identify significant differences in microbial abundance. Results: No significant demographic differences were observed between the two groups. Post-quality control, clean tags ranged from 60,979 to 68,736. Significant differences in α-diversity were observed between the two groups. ß-diversity analysis revealed distinct clustering of the urinary microbiota in urolithiasis patients and controls. Notably, Ruminococcaceae was predominant in urolithiasis samples, while Proteobacteria was more prevalent in healthy samples. Lactobacillus was significantly overrepresented in samples from healthy females. Conclusion: The urinary microbiota composition in urolithiasis patients is distinct from that of healthy controls. Specific microbial taxa, such as Ruminococcaceae and Proteobacteria, could serve as potential biomarkers for urolithiasis. The findings pave the way for further exploration of the role of microbiota in urolithiasis and the development of microbiome-based therapeutic strategies.

Mendelian randomization analysis reveals fresh fruit intake as a protective factor for urolithiasis.

OBJECTIVE: Previous studies have proposed that food intakes are associated with the risk of urolithiasis. Here, we conducted a two-sample Mendelian randomization (MR) study to evaluate the causal effects of different food intakes on urolithiasis. METHODS: Independent genetic variants associated with different food intakes at a genome-wide significant level were selected from summary-level statistics of genome-wide association studies from the UK Biobank. The association of these instrumental variables with urolithiasis was studied in a cohort from FinnGen Consortium. RESULTS: Among the 15 studied food intake exposures, tea intake (odds ratio [OR] = 0.433, 95% confidence interval [CI] = 0.281-0.667, p value = 1.470 × 10-4) and fresh fruit intake (OR = 0.358, 95% CI = 0.185-0.694, p value = 0.002) were found to significantly reduce the risk of the calculus of kidney and ureter. The association remained consistent in the sensitivity analyses. After adjusting for the effects of vitamin D and vitamin C, fresh fruit intake remained the reverse causal association with the calculus of kidney and ureter. CONCLUSIONS: Genetically proxied fresh fruit intake is causally associated with a reduced risk of the calculus of kidney and ureter.

Polymorphic variations and mRNA expression of the genes encoding interleukins as well as enzymes of oxidative and nitrative stresses as a potential risk of nephrolithiasis development.

Urolithiasis is one of the most common urological diseases worldwide with an unclear aetiology. However, a growing body of evidence suggests the potential role of molecular disturbances of the inflammation as well as oxidative and nitrative stresses, in the pathogenesis of urolithiasis. Therefore, we aimed to detect the potential association between six selected single-nucleotide polymorphisms (SNPs) and the development of nephrolithiasis. Moreover, we verified the association of urolithiasis development and mRNA expression of IL-6, IL-8, SOD2, and NOS2 in peripheral blood mononuclear cells (PBMCs). Total genomic DNA and mRNA were isolated from the peripheral blood of 112 patients with urolithiasis and 114 healthy subjects. Using Taq-Man® probes, we genotyped the following SNPs: rs1800797 and rs2069845 in IL-6, rs2227307 in IL-8, rs4880 in SOD2, rs2297518 and rs2779249 in NOS2. In turn, the evaluation of mRNA expression was performed using real-time PCR and 2-ΔCt methods. We found that the C/T genotype of the c.47 T>C-SOD2 SNP increased the frequency of urolithiasis occurrence whereas the T/T homozygote of the same polymorphism decreased the risk of urolithiasis development in the Polish population. Moreover, our study confirmed that patients with urolithiasis were characterised by decreased IL-6, IL-8, and SOD2 mRNA expression levels compared to the controls. In conclusion, our results suggest that polymorphic variants and changes in mRNA expression of IL-6, IL8, SOD2, and NOS2 may be involved in the pathophysiology of urolithiasis.

Urinary stone disease: closing the heritability gap by challenging conventional Mendelian inheritance.

Urinary stone disease is based on gene-environment interaction with an almost 50% heritability. Despite all efforts from exome-sequencing and genome-wide association studies, the genetic factors making up for observed heritability have been incompletely characterized. The study by Sadeghi-Alavijeh et al. leverages the invaluable resources of the 100,000 Genomes Project and the UK Biobank to identify heterozygous rare variants in the phosphate transporter SLC34A3 as a significant factor of urinary stone disease, challenging the traditional concept of Mendelian inheritance.

Univariable and multivariable mendelian randomization study revealed the modifiable risk factors of urolithiasis.

BACKGROUND: Urolithiasis is a common urological disease with increasing incidence worldwide, and preventing its risk poses significant challenges. Here, we used Mendelian randomization (MR) framework to genetically assess the causal nature of multifaceted risk factors on urolithiasis. METHODS: 17 potential risk factors associated with urolithiasis were collected from recently published observational studies, which can be categorized basically into lifestyle factors and circulating biomarkers. The instrumental variables of risk factors were selected from large-scale genome-wide association studies (N ≤ 607,291). Summary-level data on urolithiasis were obtained from UK Biobank (UKB) (3,625 cases and 459,308 noncases) and the FinnGen consortium (5,347 cases and 213,445 noncases). The univariable and multivariable MR analyses were applied to evaluate the causal, independent effect of these potential risk factors upon urolithiasis. Effects from the two consortia were combined by the meta-analysis methods. RESULTS: Higher genetically predicted sex hormone-binding globulin (SHBG, OR, 0.708; 95% CI, 0.555 to 0.903), estradiol (OR, 0.179; 95% CI, 0.042 to 0.751), tea intake (OR, 0.550; 95% CI, 0.345 to 0.878), alcoholic drinks per week (OR, 0.992; 95% CI, 0.987 to 0.997), and some physical activity (e.g., swimming, cycling, keeping fit, and bowling, OR, 0.054; 95% CI, 0.008 to 0.363) were significantly associated with a lower risk of urolithiasis. In the Multivariate Mendelian Randomization (MVMR) analyses, the significant causal associations between estradiol, SHBG, tea intake, and alcoholic drinks per week with urolithiasis were robust even after adjusting for potential confounding variables. However, the previously observed causal association between other exercises and urolithiasis was no longer significant after adjusting for these factors. CONCLUSIONS: The univariable and multivariable MR findings highlight the independent and significant roles of estradiol, SHBG, tea intake, and alcoholic drinks per week in the development of urolithiasis, which might provide a deeper insight into urolithiasis risk factors and supply potential preventative strategies.

Adenine phosphoribosyl transferase (APRT) deficiency and a novel sequence variant in APRT with phenotypic diversity and a literature review.

Adenine phosphoribosyl transferase (APRT) deficiency is an autosomal recessive disorder and a rare cause of urolithiasis due to mutations in APRT (OMIM #102600). APRT deficiency results in increased urinary excretion of 2,8-dihydroxyadenine (DHA) which can cause urolithiasis and kidney failure. However, with prompt diagnosis, patients with APRT deficiency can be treated with xanthine oxidoreductase inhibitors which decrease urinary DHA excretion and improve outcomes. We report a pair of siblings, an 11-year-old brother and his 14-year-old sister with compound heterozygous variants c.270del (p.Lys91Serfs*46) and c.484_486del (p.Leu162del) in APRT with variable clinical presentation of APRT deficiency. The brother presented at 17 months of age with urolithiasis and severe acute kidney injury. His elder sister remained well and asymptomatic with normal kidney function and did not develop renal calculi. Brownish disk or sphere-like crystals with both concentric and radial markings were reported on urine microscopy in the sister on screening. The sister's diagnosis was confirmed with further laboratory evidence of absent red cell lysate APRT activity with corresponding elevated levels of urinary DHA. In conclusion, we identified a novel mutation in the APRT gene in a pair of siblings with greater phenotypic severity in the male.

Association between alcohol and urolithiasis: a mendelian randomization study.

The causal relationship between alcohol and urolithiasis remains uncertain, despite previous observational studies reporting an association between the two. To determine the causality, we conducted a two-sample Mendelian randomization (MR) analysis. In this study, we aimed to investigate the causal relationship between alcohol and kidney stones using a two-sample MR approach. Two sets of genetic instruments were utilized in the analysis, both of which were derived from publicly available genetic summary data. The first set consisted of 73 single-nucleotide polymorphisms (SNPs) robustly linked to alcohol intake frequency (AIF) and the second set was comprised of 69 SNPs associated with alcohol consumption (AC). Our MR analysis was performed using several methods including the inverse-variance weighted (IVW) method, weighted median method, MR-Egger regression, MR Pleiotropy RESidual Sum and Outlier test. Our results from the MR analysis revealed a borderline significant association between AIF and the risk of urolithiasis. This was established through the use of the IVW method (OR (95% CI) = 1.29 (1.02, 1.65), p = 0.036) and the weighted median approach (OR (95% CI) = 1.44 (1.10, 1.89), p = 0.008). The MR-Egger model also yielded similar risk estimates (OR (95% CI) = 1.39 (0.66, 2.93), p = 0.386), although the relationship was not statistically significant. Sixty-eight SNPs were identified as having a substantial and independent link with AC. However, the IVW approach revealed no significant effect of AC on the risk of urolithiasis (OR (95% CI) = 0.74 (0.48, 1.14), p = 0.173). The MR analysis suggested a potential causal association between alcohol intake frequency and the risk of urolithiasis, but not alcohol consumption.

Rare variants in the sodium-dependent phosphate transporter gene SLC34A3 explain missing heritability of urinary stone disease.

Urinary stone disease (USD) is a major health burden affecting over 10% of the United Kingdom population. While stone disease is associated with lifestyle, genetic factors also strongly contribute. Common genetic variants at multiple loci from genome-wide association studies account for 5% of the estimated 45% heritability of the disorder. Here, we investigated the extent to which rare genetic variation contributes to the unexplained heritability of USD. Among participants of the United Kingdom 100,000-genome project, 374 unrelated individuals were identified and assigned diagnostic codes indicative of USD. Whole genome gene-based rare variant testing and polygenic risk scoring against a control population of 24,930 ancestry-matched controls was performed. We observed (and replicated in an independent dataset) exome-wide significant enrichment of monoallelic rare, predicted damaging variants in the SLC34A3 gene for a sodium-dependent phosphate transporter that were present in 5% cases compared with 1.6% of controls. This gene was previously associated with autosomal recessive disease. The effect on USD risk of having a qualifying SLC34A3 variant was greater than that of a standard deviation increase in polygenic risk derived from GWAS. Addition of the rare qualifying variants in SLC34A3 to a linear model including polygenic score increased the liability-adjusted heritability from 5.1% to 14.2% in the discovery cohort. We conclude that rare variants in SLC34A3 represent an important genetic risk factor for USD, with effect size intermediate between the fully penetrant rare variants linked with Mendelian disorders and common variants associated with USD. Thus, our findings explain some of the heritability unexplained by prior common variant genome-wide association studies.

Research progress on renal calculus associate with inborn error of metabolism. / é—ä¼ æ€§ä»£è°¢ç¼ºé™·æ‰€è‡´è‚¾ç»“çŸ³ç ”ç©¶è¿›å±•.

Renal calculus is a common disease with complex etiology and high recurrence rate. Recent studies have revealed that gene mutations may lead to metabolic defects which are associated with the formation of renal calculus, and single gene mutation is involved in relative high proportion of renal calculus. Gene mutations cause changes in enzyme function, metabolic pathway, ion transport, and receptor sensitivity, causing defects in oxalic acid metabolism, cystine metabolism, calcium ion metabolism, or purine metabolism, which may lead to the formation of renal calculus. The hereditary conditions associated with renal calculus include primary hyperoxaluria, cystinuria, Dent disease, familial hypomagnesemia with hypercalciuria and nephrocalcinosis, Bartter syndrome, primary distal renal tubular acidosis, infant hypercalcemia, hereditary hypophosphatemic rickets with hypercalciuria, adenine phosphoribosyltransferase deficiency, hypoxanthine-guanine phosphoribosyltransferase deficiency, and hereditary xanthinuria. This article reviews the research progress on renal calculus associated with inborn error of metabolism, to provide reference for early screening, diagnosis, treatment, prevention and recurrence of renal calculus.

Inflammatory bowel disease increases the levels of albuminuria and the risk of urolithiasis: a two-sample Mendelian randomization study.

BACKGROUND: Alterations in kidney function and increased risk of kidney diseases in patients with inflammatory bowel disease (IBD) have been reported, but the causal relationship remains unclear. Herein, Mendelian randomization was employed to identify the causal effect of inflammatory bowel disease on kidney function and the risk of chronic kidney disease (CKD), urolithiasis, and IgA nephropathy. METHODS: The International Inflammatory Bowel Disease Genetics Consortium provided the summary-level genome-wide association study (GWAS) data that correlates with Crohn's disease (CD) and ulcerative colitis (UC). GWAS data for estimated glomerular filtration rate from serum creatinine (eGFRcrea), urine albumin-creatinine ratio (uACR), and CKD were obtained from the CKDGen Consortium, and GWAS data for urolithiasis were obtained from the FinnGen consortium. The summary-level GWAS data for IgA nephropathy were obtained from the meta-analysis of UK-biobank, FinnGen, and Biobank Japan. Inverse-variance weighted was used as the primary estimate. Furthermore, the Steiger test was used to validate the direction of causality. RESULTS: The inverse-variance weighted data revealed that genetically predicted UC significantly increased uACR levels, while genetically predicted CD significantly increased the risk of urolithiasis. CONCLUSIONS: UC increases the levels of uACR, and CD increases the risk of urolithiasis.

Maternal family history of urolithiasis is associated with earlier age of onset of stone disease.

PURPOSE: To evaluate the impact of detailed family history on the severity of disease and age of onset in patients with urolithiasis. METHODS: Prospectively collected data from a single institution between October 2015 and December 2020 were analyzed. Our primary endpoint was the number of patients experiencing at least one recurrent stone during the follow-up period. RESULTS: Of 1566 patients analyzed, 603 (39%) reported at least one family member with a history of stones. The percentage of patients experiencing at least one recurrent stone event was higher in patients with a family history of stones (38%) compared to those without a family history of stones (28%) over a median follow-up period of 8 months (p = 0.001). On multivariate analysis, the presence of any family history of urolithiasis increased risk of recurrent stone events (odds ratio [OR] 1.62, p < 0.001). The presence of both a first- and a second-degree relative with urolithiasis was associated with higher odds for a recurrent stone event (OR 2.17; p = 0.003) and a younger age of onset for stones, (OR 3.32; < 0.001). A maternal-side relative with stones conferred a higher odds ratio for younger age of first onset of stones (OR 2.93; p < 0.001). CONCLUSION: Any family history of kidney stone disease imparts an increased risk of recurrent stone event and an earlier age of onset for urolithiasis. The presence of both first- and second-degree relatives or a maternal-side relative with kidney stones may be a predictor for an earlier age of onset for urolithiasis.