Serum uric acid and risk of diabetic neuropathy: a genetic correlation and mendelian randomization study
Ontology highlight
ABSTRACT:
SUBMITTER: Zhang Y
PROVIDER: S-EPMC10684953 | biostudies-literature | 2023 Jan
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:BackgroundObservational studies have linked hyperuricemia with venous thromboembolism (VTE). We aimed to investigate whether there are causal relationships between uric acid levels and VTE and its subtypes, including deep venous thrombosis (DVT) of the lower extremities and pulmonary embolism (PE).MethodsWe utilized Mendelian randomization (MR) analysis to estimate the causal association in European individuals. We extracted two sets of polygenic instruments strongly associated (p < 5 × 10-8) with uric acid from the CKDGen consortium and UK biobank, respectively. Genetic associations with the risk of VTE, DVT, and PE were obtained from the FinnGen biobank. We used the inverse-variance weighted method as the preliminary estimate. Additionally, we employed MR-Egger, weighted median, and Mendelian randomization pleiotropy residual sum and outlier method as complementary assessments. Sensitivity analyses were performed to test for pleiotropic bias.ResultsThe genetically instrumented serum uric acid levels had no causal effects on VTE, DVT, and PE. Two sets of polygenic instruments used for exposure, along with three complementary MR methods, also yielded no significant association.ConclusionsOur MR analysis provided no compelling evidence for a causal relationship of serum uric acid with the risk of VTE. This suggests that uric acid-lowering therapies in patients with hyperuricemia may not be effective in reducing the likelihood of developing VTE.
| S-EPMC10354911 | biostudies-literature
Project description:Background and objectivesResearch suggests that diabetic peripheral neuropathy (DPN) is related to high serum uric acid (SUA) level, although its correlation with low SUA level has not been reported. Here, diabetic patients with hyperuricemia were excluded, and the correlation between low SUA level and DPN was explored.Subjects and methodsThis prospective observational clinical study enrolled 525 type 2 diabetes mellitus (T2DM) patients without hyperuricemia, who were divided into the diabetes with symptomatic neuropathy (150 cases), diabetes with asymptomatic neuropathy (125 cases) and diabetes with no neuropathy (250 cases) groups.ResultsThe SUA slightly decreased in subjects with asymptomatic DPN compared with those with no neuropathy and greatly decreased in subjects with symptomatic DPN compared with those without (P < 0.001). The association of the SUA with diabetic neuropathy was independent of the hyperglycemic state and other potential confounders (odds ratio 0.985 [0.981-0.988], P < 0.001). The SUA was closely correlated with the means of motor/sensory nerve amplitude and CV (all P < 0.001). The optimal cut-off point for SUA to distinguish patients with diabetic neuropathy from those without was 324 umol/L, with a sensitivity of 76.0% and a specificity of 79.2% (AUC = 0.806).ConclusionsThe low SUA level is closely associated with DPN. Future studies are warranted to clarify the relationship.
| S-EPMC10238292 | biostudies-literature
Project description:Previous observational studies have shown that the serum uric acid (UA) level is decreased in persons with multiple sclerosis (MS). We used the two-sample Mendelian randomization (MR) method to determine whether the serum UA level is causally associated with the risk of MS. We screened 26 single-nucleotide polymorphisms (SNPs) in association with serum UA level (p < 5 × 10-8) from a large genome-wide meta-analysis involving 110,347 individuals. The SNP outcome effects were obtained from two large international genetic studies of MS involving 38,589 individuals and 27,148 individuals. A total of 18 SNPs, including nine proxy SNPs, were included in the MR analysis. The estimate based on SNP rs12498742 that explained the largest proportion of variance showed that the odds ratio (OR) of UA (per mg/dl increase) for MS was 1.00 [95% confidence interval (CI) 0.90-1.11; p = 0.96]. The main MR analysis based on the random effects inverse variance weighted method showed that the pooled OR was 1.05 (95% CI 0.92-1.19; p = 0.50). Although there was no evidence of net horizontal pleiotropy in MR-Egger regression (p = 0.48), excessive heterogeneity was found via Cochran's Q statistic (p = 9.6 × 10-4). The heterogeneity showed a substantial decrease after exclusion of two outlier SNPs (p = 0.17). The pooled ORs for the other MR methods ranged from 0.89 (95% CI 0.65-1.20; p = 0.45) to 1.05 (95% CI 0.96-1.14; p = 0.29). The results of sensitivity analyses and additional analyses all showed similar pooled estimates. MR analyses by using 81 MS -associated SNPs as instrumental variables showed that genetically predicted risk of MS was not significantly associated with serum UA level. The pooled OR was 1.00 (95% CI 0.99-1.02; p = 0.74) for the main MR analysis. This MR study does not support a causal effect of genetically determined serum UA level on the risk of MS, nor does it support a causal effect of genetically determined risk of MS on serum UA level.
| S-EPMC7133767 | biostudies-literature
Project description:The relationship between serum uric acid (UA) levels and cancer risk remains controversial. Here, a two-sample Mendelian randomization analysis was performed to identify a causal effect of serum UA levels on cancer risk. Twenty-six single nucleotide polymorphisms strongly associated with serum UA levels were screened as genetic variants from large-scale meta-analysis data of a genome-wide association study of 110,347 European individuals. Genetic associations with eight common site-specific cancers were subsequently explored. A total of six Mendelian randomization methods were used to estimate the potential effect of serum UA levels on cancer risk, including random effects inverse variance weighting, fix effects inverse variance weighting, MR-Egger, median weighting, mode weighting, and simple mode analysis. Our primary random effects inverse variance weighted analysis revealed that no significant associations with cancers was found (all p > 0.05). Sensitivity analyses and additional analyses also showed similar pooled results. In conclusion, no significant causality between serum UA levels and cancer risk was evidenced.
| S-EPMC7985250 | biostudies-literature
Project description:Limited Mendelian randomization (MR) studies have assessed the causal relationship between serum uric acid levels and diabetes risk. Here we investigated causality between the serum uric acid concentration and diabetes risk in Chinese population. The observational analysis, based on the Dongfeng-Tongji prospective cohort (n=15 195) we tested the association of serum uric acid levels with incident diabetes risk. In the instrumental variable analysis, we examined the association of the genetic risk score (GRS) of serum uric acid with diabetes risk in case-control design (2539 cases and 4595 controls) via MR analysis. During a mean (SD) follow-up of 4.5 (0.5) years, 1156 incident diabetes cases were identified. Compared with those in the lowest quintile of serum uric acid levels, the HRs of incident diabetes were 1.19 (95% CI 0.96 to 1.48), 1.12 (95% CI 0.90 to 1.40), 1.38 (95% CI 1.12 to 1.70), and 1.51 (95% CI 1.23 to 1.87) for Q2, Q3, Q4 and Q5, respectively (P-trend <0.001). The GRS was strongly associated with serum uric acid levels (β=0.17, 95% CI 0.15 to 0.19; P=2.81×10-67). However, no significant association was observed between the GRS and diabetes risk (OR=1.01, 95 CI 0.95 to 1.06; P=0.75). Even though serum uric acid levels were significantly associated with increased incident diabetes risk, the results did not provide evidence for a causal relationship between them.
| S-EPMC7050304 | biostudies-literature
Project description:ObjectiveThe effects of coffee consumption on serum uric acid (SUA) levels and gout risk are controversial. There have hitherto been no reports based on Mendelian randomization (MR) analysis of its effects that consider pleiotropy. Here, we evaluated the effects of coffee consumption across ancestry populations, taking pleiotropy into account.MethodsWe performed the first MR analyses for coffee consumption on SUA levels and gout, considering pleiotropy. We used the following summary statistics of genome-wide association studies from a Japanese population: habitual coffee consumption (152,634 subjects), gout (3053 cases and 4554 controls), and SUA levels (121,745 subjects). In addition to fixed-effect inverse variance weighted (IVW) meta-analysis, we performed a robust evaluation of heterogeneity and removed several instruments for reasons of possible pleiotropy. Previous European datasets were also reevaluated while heterogeneity was considered.ResultsHabitual coffee consumption was significantly and inversely associated with gout (odds ratio [OR] = 0.29, 95% confidence interval [95% CI]: 0.16-0.51, P = 1.9 × 10-5 ) in random-effect IVW (Phet = 5.5 × 10-19 ). Excluding pleiotropic instruments, the protective effect on gout was confirmed in fixed-effect IVW analysis (OR = 0.75, 95% CI: 0.58-0.97, P = 0.026) without heterogeneity (Phet = 0.39). However, we observed no significance in the previous European datasets when heterogeneity was considered. Associations were not observed between coffee consumption and SUA levels in either ancestry in MR analyses that considered pleiotropy. Multivariable MR analysis showed that increased coffee consumption significantly reduced gout risk, even after adjusting for SUA levels (OR = 0.50, 95% CI: 0.31-0.81, P = 0.0046).ConclusionWith pleiotropy taken into account, our MR analyses revealed that coffee consumption can causally reduce gout risk, and that it may reduce gout risk independently of SUA levels.
| S-EPMC9190218 | biostudies-literature
Project description:BackgroundAlthough recent animal experiments have revealed that tea intake improves elevated serum uric acid (SUA) levels, a causal link between the consumption of different types of tea and SUA levels remains undetermined.MethodsBidirectional Mendelian randomization (MR) analysis based on genome-wide association studies was used to assess the causal relationship between consumption of different types of tea and the risk of elevated SUA levels in European and Asian populations.ResultsForward MR analysis showed that tea intake was significantly associated with lower SUA levels (p = 0.0013). The estimated effect value ( β$$ \beta $$ =$$ = $$ -0.0440) suggests that for every 1-unit increase in tea intake, there is a 0.044-unit decrease in SUA levels. However, there is no reverse causality between SUA and tea intake (p = 0.2824). No causal relationship was found between the consumption of different types of tea and risk of elevated SUA levels (p > 0.05).ConclusionAlthough this bidirectional MR study provided evidence of a causal relationship between tea intake and SUA levels, however, due to limitations associated with the sample size and strength of instrumental variables, a definite conclusion was not possible.
| S-EPMC11829186 | biostudies-literature
Project description:The causal link between serum uric acid (SUA) levels and gastric cancer susceptibility remains inadequately elucidated. This investigation employed a two-sample Mendelian randomization (MR) framework to assess the potential causative link between SUA concentrations and the propensity for developing gastric cancer. To further explore potential racial differences, this MR analysis was conducted on cohorts of both European and East Asian descent. Data from a large-scale GWAS in 343,836 Europeans and 92,615 East Asians were screened for 206 and 45 SNPs significantly linked to SUA levels, respectively, as genetic variants. Subsequently, four distinct MR methodologies were deployed to determine how SUA levels affected gastric cancer risk. Using the fixed-effects IVW approach, our analysis revealed no significant association between SUA levels and gastric cancer risk, with P-values exceeding the threshold of significance in both populations (European P = 0.778; East Asian P = 0.245). The findings were supported by three additional MR methods. The reliability of these results was substantiated by comprehensive sensitivity analyses. In summary, our data do not support a significant causal linkage between SUA levels and gastric cancer risk.
| S-EPMC11525654 | biostudies-literature
Project description:BackgroundObservational studies have established an association between serum uric acid and cardiovascular disease (CVD). However, these studies are susceptible to uncontrolled confounders and reverse causality bias. To overcome these challenges, we employed a two-sample Mendelian randomization (MR) approach to investigate the causal link between serum uric acid and CVD.MethodsWe utilized Genome-wide association study (GWAS) data for serum uric acid and six CVD: coronary artery disease (CAD), hypertension, myocardial infarction (MI), heart failure (HF), angina, and coronary heart disease (CHD). MR analyses employed inverse variance weighting (IVW), MR-Egger, weighted median, and weighted model. Sensitivity analyses were conducted to assess result reliability, including Cochrane's Q test, MR-Egger intercept, MR-PRESSO, and the leave-one-out approach.ResultsIVW analysis revealed that a genetic predisposition to elevated serum uric acid levels significantly increases the risk of CVD, with higher odds ratios (ORs) observed for CAD (OR: 1.227; 95 % CI: 1.107-1.360, P = 0.0002), hypertension (OR: 1.318, 95 %CI: 1.184-1.466, P = 2.13E-06), MI (OR: 1.184, 95 %CI: 1.108-1.266, P = 2.13E-06), HF (OR: 1.158, 95 %CI: 1.066-1.258, P = 2.13E-06), angina (OR: 1.150, 95 %CI: 1.074-1.231, P = 0.0002) and CHD (OR: 1.170, 95 %CI: 1.072-1.276, P = 0.0005). Sensitivity analysis research results have robustness.ConclusionThis MR study robustly demonstrates a significant causal relationship between genetically elevated serum uric acid and various cardiovascular diseases, suggesting that higher levels may enhance the risk of cardiovascular events. Consequently, patients with elevated uric acid levels warrant early and aggressive interventions to mitigate cardiovascular risks.
| S-EPMC11473680 | biostudies-literature
Project description:BackgroundAlthough the relationship between serum uric acid (SUA) and adiposity is well established, the direction of the causality is still unclear in the presence of conflicting evidences. We used a bidirectional Mendelian randomization approach to explore the nature and direction of causality between SUA and adiposity in a population-based study of Caucasians aged 35 to 75 years.Methods and findingsWe used, as instrumental variables, rs6855911 within the SUA gene SLC2A9 in one direction, and combinations of SNPs within the adiposity genes FTO, MC4R and TMEM18 in the other direction. Adiposity markers included weight, body mass index, waist circumference and fat mass. We applied a two-stage least squares regression: a regression of SUA/adiposity markers on our instruments in the first stage and a regression of the response of interest on the fitted values from the first stage regression in the second stage. SUA explained by the SLC2A9 instrument was not associated to fat mass (regression coefficient [95% confidence interval]: 0.05 [-0.10, 0.19] for fat mass) contrasting with the ordinary least square estimate (0.37 [0.34, 0.40]). By contrast, fat mass explained by genetic variants of the FTO, MC4R and TMEM18 genes was positively and significantly associated to SUA (0.31 [0.01, 0.62]), similar to the ordinary least square estimate (0.27 [0.25, 0.29]). Results were similar for the other adiposity markers.ConclusionsUsing a bidirectional Mendelian randomization approach in adult Caucasians, our findings suggest that elevated SUA is a consequence rather than a cause of adiposity.
| S-EPMC3378571 | biostudies-literature