Whole-body water mass and kidney function: a Mendelian randomization study
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PROVIDER: S-EPMC11022284 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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| S-EPMC11232203 | biostudies-literature
Project description:BackgroundObservational studies have found an association between increased whole body water mass (BWM) and atrial fibrillation (AF). However, the causality has yet to be confirmed. To provide feasible protective measures on disease development, we performed Mendelian randomization (MR) design to estimate the potential causal relationship between increased BWM and AF.MethodsWe implemented a two-sample MR study to assess whether increased BWM causally influences AF incidence. For exposure, 61 well-powered genetic instruments extracted from UK Biobank (N = 331,315) were used as the proxies of BWM. Summary genetic data of AF were obtained from FinnGen (Ncase = 22,068; Ncontrol = 116,926). Inverse-variance weighted (IVW), MR-Egger and weighted median methods were selected to infer causality, complemented with a series of sensitivity analyses. MR-Pleiotropy Residual Sum and Outlier (MR-PRESSO) and Radial MR were employed to identify outliers. Furthermore, risk factor analyses were performed to investigate the potential mechanisms between increased BWM and AF.ResultsGenetic predisposition to increased BWM was demonstrated to be significantly associated with AF in the IVW model (OR = 2.23; 95% CI = 1.47-3.09; p = 1.60 × 10-7), and the result was consistent in other MR approaches. There was no heterogeneity or pleiotropy detected in sensitivity analysis. MR-PRESSO identified no outliers with potential pleiotropy after excluding outliers by Radial MR. Furthermore, our risk factor analyses supported a positive causal effect of genetic predicted increased BWM on edematous diseases.ConclusionsMR estimates showed that a higher BWM could increase the risk of AF. Pathological edema is an important intermediate link mediating this causal relationship.
| S-EPMC9966889 | biostudies-literature
Project description:Background: Uncertainty in the mechanism and directionality of observational associations between thyroid function and kidney function may be addressed by genetic analysis with an instrumental variable method termed bidirectional Mendelian randomization (MR). Methods: In the Women's Genome Health Study (WGHS), observational associations between thyroid measures and kidney function were evaluated. Genetic instruments for MR were from recent genome-wide association studies (GWAS) of hypothyroidism, thyrotropin (TSH), and free thyroxine (fT4) concentrations within the reference range, thyroid peroxidase antibodies (TPOAb), estimated glomerular filtration rate from creatinine (eGFRcrea), eGFR from cystatin C (eGFRcys), and chronic kidney disease (CKD). In WGHS individual-level data, these instruments were used for bidirectional MR between thyroid (N = 3336) and kidney (N = 23,186) functions. To increase power, MR was also performed using GWAS summary statistics from the Chronic Kidney Disease Genetics Consortium (CKDGen) for eGFRcrea (N = 567,460), eGFRcys (N = 24,063), CKD [N(total) = 480,698, N(cases) = 41,395], and urinary albumin/creatinine ratio (UACR/N = 54,450). Results: In the WGHS, hypothyroidism was observationally associated with decreased eGFRcrea [beta (standard error, SE): -0.024 (0.009) ln(mL/min/1.73 m2), p = 0.01]. By MR, hypothyroidism was associated with decreased eGFRcrea in the WGHS [beta (SE): -0.007 (0.002) per doubled odds hypothyroidism, p = 1.7 × 10-3] and in CKDGen [beta (SE): -0.004 (0.0005), p = 2.0 × 10-22], and robust to sensitivity analysis. Hypothyroidism was also associated by MR with increased CKD in CKDGen (odds ratio, OR [confidence interval, CI]: 1.05 [1.03-1.08], p = 3.3 × 10-5), but not in the WGHS (OR [CI]: 1.02 [0.95-1.10], p = 0.57). Increased TSH within the reference range had an MR association with increased eGFRcrea in the WGHS [beta (SE): -0.018 (0.007) ln(mL/min/1.73 m2)/standard deviation, SD, p = 6.5 × 10-3] and CKDGen [beta (SE): -0.008 (0.001) ln(mL/min/1.73 m2)/SD, p = 6.8 × 10-17], and with CKD in CKDGen (OR [CI]: 1.10 [1.04-1.15], p = 3.1 × 10-4). There were no MR associations of hypothyroidism or TSH with eGFRcys or UACR, and MR associations of fT4 in the reference range with kidney function were inconsistent in both the WGHS and CKDGen. However, by MR in CKDGen, TPOAb were robustly associated with decreased eGFRcrea [beta (SE): -0.041 (0.009), p = 6.2 × 10-6] and decreased eGFRcys [beta (SE): -0.294 (0.065), p = 6.2 × 10-6]. TPOAb were less robustly associated with CKD but not associated with UACR. In reverse MR in the WGHS, kidney function was not consistently associated with thyroid function. Conclusions: Bidirectional MR supports a directional association from hypothyroidism, increased TSH, and TPOAb, but not fT4, to decreased eGFRcrea and increased CKD.
| S-EPMC7074918 | biostudies-literature
Project description:Obesity is a highly prevalent risk factor for cardiometabolic diseases. Observational studies suggest that obesity is associated with psychiatric traits, but causal inference from such studies has several limitations. We used two-sample Mendelian randomization methods (inverse variance weighting, weighted median and MR-Egger regression) to evaluate the association of body mass index (BMI) with three psychiatric traits using data from the Genetic Investigation of Anthropometric Traits and Psychiatric Genomics consortia. Causal odds ratio estimates per 1-standard deviation increment in BMI ranged from 0.88 (95% CI: 0.62; 1.25) to 1.23 (95% CI: 0.65; 2.31) for bipolar disorder; 0.93 (0.78; 1.11) to 1.41 (0.87; 2.27) for schizophrenia; and 1.15 (95% CI: 0.92; 1.44) to 1.40 (95% CI: 1.03; 1.90) for major depressive disorder. Analyses removing potentially influential SNPs suggested that the effect estimates for depression might be underestimated. Our findings do not support the notion that higher BMI increases risk of bipolar disorder and schizophrenia. Although the point estimates for depression were consistent in all sensitivity analyses, the overall statistical evidence was weak. However, the fact that SNP-depression associations were estimated in relatively small samples reduced power to detect causal effects. This should be re-addressed when SNP-depression associations from larger studies become available.
| S-EPMC5013405 | biostudies-literature
Project description:The aim of this study is to apply a Mendelian randomization (MR) design to investigate the potential causal associations between the body mass index (BMI), body fat mass such as trunk fat mass and waist circumference (WC), and diabetic kidney disease (DKD). A two-sample MR study was conducted to obtain exposure and outcome data from previously published studies. The instrumental variables for BMI, trunk fat mass, and WC were selected from genome-wide association study datasets based on summary-level statistics. The random-effects inverse-variance weighted (IVW) method was used for the main analyses, and the weighted median and MR-Egger approaches were complementary. In total, three MR methods suggested that genetically predicted BMI, trunk fat mass, and WC were positively associated with DKD. Using IVW, we found evidence of causal relationships between BMI [odds ratio (OR) = 1.99; 95% confidence interval (CI), 1.47-2.69; p = 7.89 × 10-6], trunk fat mass (OR = 1.80; 95% CI, 1.28-2.53; p = 6.84 × 10-4), WC (OR = 2.48; 95% CI, 1.40-4.42; p = 1.93 × 10-3), and DKD. MR-Egger and weighted median regression also showed directionally similar estimates. Both funnel plots and MR-Egger intercepts showed no directional pleiotropic effects involving the aforementioned variables and DKD. Our MR analysis supported the causal effect of BMI, trunk fat mass, and WC on DKD. Individuals can substantially reduce DKD risk by reducing body fat mass and modifying their body fat distribution.
| S-EPMC9557077 | biostudies-literature
Project description:BackgroundFurther investigation is needed to determine the causal effects of serum bilirubin on the risk of chronic kidney disease (CKD).MethodsThis study is a Mendelian randomization (MR) analysis. Among the well-known single-nucleotide polymorphisms (SNPs) related to serum bilirubin levels, rs4149056 in the SLCO1B1 gene was selected as the genetic instrument for single-variant MR analysis, as it was found to be less related to possible confounders than other SNPs. The association between genetic predisposition for bilirubin levels and estimated glomerular filtration rate (eGFR) or CKD was assessed in 337 129 individuals of white British ancestry from the UK Biobank cohort. Two-sample MR based on summary-level data was also performed. SNPs related to total or direct bilirubin levels were collected from a previous genome-wide association study and confounder-associated SNPs were discarded. The independent CKDGen meta-analysis data for CKD were employed as the outcome summary statistics.ResultsThe alleles of rs4149056 associated with higher bilirubin levels were associated with better kidney function in the UK Biobank data. In the summary-level MR, both of the genetically predicted total bilirubin {per 5 µmol/L increase; odds ratio [OR] 0.931 [95% confidence interval (CI) 0.871-0.995]} and direct bilirubin [per 1 µmol/L increase; OR 0.910 (95% CI 0.834-0.993)] levels were significantly associated with a lower risk of CKD, supported by the causal estimates from various MR sensitivity analyses.ConclusionGenetic predisposition for higher serum bilirubin levels is associated with better kidney function. This result suggests that higher serum bilirubin levels may have causal protective effects against kidney function impairment.
| S-EPMC9394720 | biostudies-literature
Project description:BackgroundHigh body mass index (BMI) is consistently linked to increased risk of colorectal cancer for men, whereas the association is less clear for women. As risk estimates from observational studies may be biased and/or confounded, we conducted a Mendelian randomization study to estimate the causal association between BMI and colorectal cancer.MethodsWe used data from 10,226 colorectal cancer cases and 10,286 controls of European ancestry. The Mendelian randomization analysis used a weighted genetic risk score, derived from 77 genome-wide association study-identified variants associated with higher BMI, as an instrumental variable (IV). We compared the IV odds ratio (IV-OR) with the OR obtained using a conventional covariate-adjusted analysis.ResultsIndividuals carrying greater numbers of BMI-increasing alleles had higher colorectal cancer risk [per weighted allele OR, 1.31; 95% confidence interval (CI), 1.10-1.57]. Our IV estimation results support the hypothesis that genetically influenced BMI is directly associated with risk for colorectal cancer (IV-OR per 5 kg/m(2), 1.50; 95% CI, 1.13-2.01). In the sex-specific IV analyses higher BMI was associated with higher risk of colorectal cancer among women (IV-OR per 5 kg/m(2), 1.82; 95% CI, 1.26-2.61). For men, genetically influenced BMI was not associated with colorectal cancer (IV-OR per 5 kg/m(2), 1.18; 95% CI, 0.73-1.92).ConclusionsHigh BMI was associated with increased colorectal cancer risk for women. Whether abdominal obesity, rather than overall obesity, is a more important risk factor for men requires further investigation.ImpactOverall, conventional epidemiologic and Mendelian randomization studies suggest a strong association between obesity and the risk of colorectal cancer.
| S-EPMC4490960 | biostudies-literature
Project description:Traditional observational studies have reported a positive association between higher body mass index (BMI) and the risk of colorectal cancer (CRC). However, evidence from other approaches to pursue the causal relationship between BMI and CRC is sparse. A two-sample Mendelian randomization (MR) study was undertaken using 68 single nucleotide polymorphisms (SNPs) from the Japanese genome-wide association study (GWAS) and 654 SNPs from the GWAS catalogue for BMI as sets of instrumental variables. For the analysis of SNP-BMI associations, we undertook a meta-analysis with 36 303 participants in the Japanese Consortium of Genetic Epidemiology studies (J-CGE), comprising normal populations. For the analysis of SNP-CRC associations, we utilized 7636 CRC cases and 37 141 controls from five studies in Japan, and undertook a meta-analysis. Mendelian randomization analysis of inverse-variance weighted method indicated that a one-unit (kg/m2 ) increase in genetically predicted BMI was associated with an odds ratio of 1.13 (95% confidence interval, 1.06-1.20; P value <.001) for CRC using the set of 68 SNPs, and an odds ratio of 1.07 (1.03-1.11, 0.001) for CRC using the set of 654 SNPs. Sensitivity analyses robustly showed increased odds ratios for CRC for every one-unit increase in genetically predicted BMI. Our MR analyses strongly support the evidence that higher BMI influences the risk of CRC. Although Asians are generally leaner than Europeans and North Americans, avoiding higher BMI seems to be important for the prevention of CRC in Asian populations.
| S-EPMC8019210 | biostudies-literature
Project description:BackgroundMany observational epidemiology studies discovered that kidney cancer and impaired kidney function have a bidirectional relationship. However, it remains unclear whether these two kinds of traits are causally linked. In this study, we aimed to investigate the bidirectional causal relation between kidney cancer and kidney function biomarkers (creatinine-based estimated glomerular filtration rate (eGFRcrea), cystatin C-based estimated glomerular filtration rate (eGFRcys), blood urea nitrogen (BUN), serum urate, and urinary albumin-to-creatinine ratio (UACR)).MethodsFor both directions, single-nucleotide polymorphisms (SNPs), as genetic instruments, for the five kidney function traits were selected from up to 1,004,040 individuals, and SNPs for kidney cancer were from 408,786 participants(1338 cases). In the main analysis, we applied two state-of-the-art MR methods, namely, contamination mixture and Robust Adjusted Profile Score to downweight the effect of weak instrument bias, pleiotropy, and extreme outliers. We additionally conducted traditional MR analyses as sensitivity analyses. Summary-level data of European ancestry were extracted from UK Biobank, Chronic Kidney Disease Genetics Consortium, and Kaiser Permanente.ResultsBased on 99 SNPs, we found that the eGFRcrea had a significant negative causal effect on the risk of kidney cancer (OR = 0.007, 95% CI:2.6 × 10-4 -0.569, p = 0.041). After adjusting for body composition or diabetes, urate had a significant negative causal effect on kidney cancer (OR <1, p < 0.05). For UACR, it showed a strong causal effect on kidney cancer, after adjusting for body composition (OR = 14.503, 95% CI: 2.546-96.001, p = 0.032). Due to lacking significant signals and effect power for the reverse MR, further investigations are warranted.ConclusionsOur study suggested a potential causal effect of damaged kidney function on kidney cancer. EGFRcrea and UACR might be causally associated with kidney cancer, especially when patients were comorbid with obesity or diabetes. We called for larger sample-size studies to further unravel the underlying causal relationship and the exact mechanism.
| S-EPMC9939186 | biostudies-literature
Project description:ObjectivesExtensive researches highlight the detrimental impact of sleep disorders such as insomnia and insufficient sleep duration on kidney function. However, establishing a clear causal relationship between insomnia, sleep duration, and kidney function remains challenging. This study aims to estimate this relationship using Mendelian randomization (MR).MethodsIndependent genetic variants strongly associated with insomnia (N = 462,341) and sleep duration (N = 460,099) were selected as instrumental variables from corresponding genome-wide association studies (GWAS). Kidney function parameters, including serum creatinine, estimated glomerular filtration rate by cystatin C (eGFRcys), acute renal failure (ARF), chronic renal failure (CRF), kidney injury molecule-1, neutrophil gelatinase associated lipocalin, microalbuminuria, cystatin C, and β2 microglobulin, were derived from GWAS databases. A two-sample MR study was conducted to assess the causal relationship between sleep disorders and kidney function, and multivariable MR was used to identify potential mediators. The inverse-variance weighted was used as the primary estimate.ResultsMR analysis found robust evidence indicating that insomnia and short sleep duration were associated with an increased risk of elevated serum creatinine, regardless of adjusting for obesity. Causal links between sleep duration and eGFRcys or cystatin C were also identified. While genetically predicted insomnia and sleep duration were found to potentially impact ARF, CRF, microalbuminuria, and β2 microglobulin, the p-values in multivariable MR analysis became nonsignificant. No pleiotropy was detected.ConclusionsThis study demonstrates a causal impact of insomnia on the risk of elevated serum creatinine and a positive effect of sleep duration on serum creatinine, eGFRcys, and cystatin C. Our findings also suggest their potential indirect effects on ARF, CRF, microalbuminuria, and β2 microglobulin mediated by obesity.
| S-EPMC11321106 | biostudies-literature