A bidirectional Mendelian randomization study supports causal effects of kidney function on blood pressure.
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ABSTRACT:
SUBMITTER: Yu Z
PROVIDER: S-EPMC7784392 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThe causal nature of the observed associations between serum lipids and apolipoproteins and kidney function are unclear.MethodsUsing two-sample and multivariable Mendelian randomization (MR), we examined the causal effects of serum lipids and apolipoproteins on kidney function, indicated by the glomerular-filtration rate estimated using creatinine (eGFRcrea) or cystatin C (eGFRcys) and the urinary albumin-to-creatinine ratio (UACR). We obtained lipid- and apolipoprotein-associated genetic variants from the Global Lipids Genetics Consortium (n = 331 368) and UK Biobank (n = 441 016), respectively, and kidney-function markers from the Trøndelag Health Study (HUNT; n = 69 736) and UK Biobank (n = 464 207). The reverse causal direction was examined using variants associated with kidney-function markers selected from recent genome-wide association studies.ResultsThere were no strong associations between genetically predicted lipid and apolipoprotein levels with kidney-function markers. Some, but inconsistent, evidence suggested a weak association of higher genetically predicted atherogenic lipid levels [indicated by low-density lipoprotein cholesterol (LDL-C), triglycerides and apolipoprotein B] with increased eGFR and UACR. For high-density lipoprotein cholesterol (HDL-C), results differed between eGFRcrea and eGFRcys, but neither analysis suggested substantial effects. We found no clear evidence of a reverse causal effect of eGFR on lipid or apolipoprotein traits, but higher UACR was associated with higher LDL-C, triglyceride and apolipoprotein B levels.ConclusionOur MR estimates suggest that serum lipid and apolipoprotein levels do not cause substantial changes in kidney function. A possible weak effect of higher atherogenic lipids on increased eGFR and UACR warrants further investigation. Processes leading to higher UACR may lead to more atherogenic lipid levels.
| S-EPMC8580277 | biostudies-literature
Project description:BackgroundDespite the potential demonstrated by targeted plasma metabolite modulators in halting the progression of chronic kidney disease (CKD), a lingering uncertainty persists concerning the causal relationship between distinct plasma metabolites and the onset and progression of CKD.MethodsA genome-wide association study was conducted on 1,091 metabolites and 309 metabolite ratios derived from a cohort of 8,299 unrelated individuals of European descent. Employing a bidirectional two-sample Mendelian randomization (MR) analysis in conjunction with colocalization analysis, we systematically investigated the associations between these metabolites and three phenotypes: CKD, creatinine-estimated glomerular filtration rate (creatinine-eGFR), and urine albumin creatinine ratio (UACR). In the MR analysis, the primary analytical approach employed was inverse variance weighting (IVW), and sensitivity analysis was executed utilizing the MR-Egger method and MR-pleiotropy residual sum and outlier (MR-PRESSO). Heterogeneity was carefully evaluated through Cochrane's Q test. To ensure the robustness of our MR results, the leave-one-out method was implemented, and the strength of causal relationships was subjected to scrutiny via Bonferroni correction.ResultsOur thorough MR analysis involving 1,400 plasma metabolites and three clinical phenotypes yielded a discerning identification of 21 plasma metabolites significantly associated with diverse outcomes. Specifically, in the forward MR analysis, 6 plasma metabolites were determined to be causally associated with CKD, 16 with creatinine-eGFR, and 7 with UACR. Substantiated by robust evidence from colocalization analysis, 6 plasma metabolites shared causal variants with CKD, 16 with creatinine-eGFR, and 7 with UACR. In the reverse analysis, a diminished creatinine-eGFR was linked to elevated levels of nine plasma metabolites. Notably, no discernible associations were observed between other plasma metabolites and CKD, creatinine-eGFR, and UACR. Importantly, our analysis detected no evidence of horizontal pleiotropy.ConclusionThis study elucidates specific plasma metabolites causally associated with CKD and renal functions, providing potential targets for intervention. These findings contribute to an enriched understanding of the genetic underpinnings of CKD and renal functions, paving the way for precision medicine applications and therapeutic strategies aimed at impeding disease progression.
| S-EPMC11310041 | biostudies-literature
Project description:BackgroundObservational studies have investigated the effect of serum lipids on kidney function, but these findings are limited by confounding, reverse causation and have reported conflicting results. Mendelian randomization (MR) studies address this confounding problem. However, they have been conducted mostly in European ancestry individuals. We, therefore, set out to investigate the effect of lipid traits on the estimated glomerular filtration rate (eGFR) based on serum creatinine in individuals of African ancestry.MethodsWe used the two-sample and multivariable Mendelian randomization (MVMR) approaches; in which instrument variables (IV's) for the predictor (lipid traits) were derived from summary-level data of a meta-analyzed African lipid GWAS (MALG, n = 24,215) from the African Partnership for Chronic Disease Research (APCDR) (n = 13,612) & the Africa Wits-IN-DEPTH partnership for Genomics studies (AWI-Gen) dataset (n = 10,603). The outcome IV's were computed from the eGFR summary-level data of African-ancestry individuals within the Million Veteran Program (n = 57,336). A random-effects inverse variance method was used in our primary analysis, and pleiotropy was adjusted for using robust and penalized sensitivity testing. The lipid predictors for the MVMR were high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides (TG).FindingsWe found a significant causal association between genetically predicted low-density lipoprotein (LDL) cholesterol and eGFR in African ancestry individuals β = 1.1 (95% CI [0.411-1.788]; p = 0.002). Similarly, total cholesterol (TC) showed a significant causal effect on eGFR β = 1.619 (95% CI [0.412-2.826]; p = 0.009). However, the IVW estimate showed that genetically predicted HDL-C β = -0.164, (95% CI = [-1.329 to 1.00]; p = 0.782), and TG β = -0.934 (CI = [-2.815 to 0.947]; p = 0.33) were not significantly causally associated with the risk of eGFR. In the multivariable analysis inverse-variance weighted (MVIVW) method, there was evidence for a causal association between LDL and eGFR β = 1.228 (CI = [0.477-1.979]; p = 0.001). A significant causal effect of Triglycerides (TG) on eGFR in the MVIVW analysis β = -1.3 ([-2.533 to -0.067]; p = 0.039) was observed as well. All the causal estimates reported reflect a unit change in the outcome per a 1 SD increase in the exposure. HDL showed no evidence of a significant causal association with eGFR in the MVIVW method (β = -0.117 (95% CI [-1.252 to 0.018]; p = 0.840)). We found no evidence of a reverse causal impact of eGFR on serum lipids. All our sensitivity analyses indicated no strong evidence of pleiotropy or heterogeneity between our instrumental variables for both the forward and reverse MR analysis.InterpretationIn this African ancestry population, genetically predicted higher LDL-C and TC are causally associated with higher eGFR levels, which may suggest that the relationship between LDL, TC and kidney function may be U-shaped. And as such, lowering LDL_C does not necessarily improve risk of kidney disease. This may also imply the reason why LDL_C is seen to be a poorer predictor of kidney function compared to HDL. In addition, this further supports that more work is warranted to confirm the potential association between lipid traits and risk of kidney disease in individuals of African Ancestry.FundingWellcome (220740/Z/20/Z).
| S-EPMC10070509 | biostudies-literature
Project description:BackgroundIncreasing 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.MethodsWe obtained instrumental variables related to each exposure at the genome-wide significant threshold (P < 5 × 10-8). 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.ResultsAmong 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.ConclusionsOur 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.
| S-EPMC10116718 | biostudies-literature
Project description:Introduction Many observational studies imply elevated blood pressure (BP) as a leading risk factor for incident myocardial infarction (MI), but whether this relationship is causal remains unknown. In this study, we used bidirectional Mendelian randomization (MR) to investigate the potential causal association of BP levels with the risk of MI. Methods Genetic variants associated with BP and MI traits were retrieved from the International Consortium of Blood Pressure (N = 7,57,601) and UKB (N = 3,61,194), obtaining 1,26,40,541 variants. We used two-sample MR (TSMR) analyses to examine the potential bidirectional causal association of systolic BP (SBP), diastolic BP (DBP) and pulse pressure (PP) with MI. Results The forward MR analysis identified a potentially causal association between MI and BP except PP[odds ratio (OR) SBP: 1.0008, P = 1.911 × 10−22; ORDBP: 1.0014, P = 1.788 × 10−28;odds ratio (OR)pp: 1.0092, P = 0.179]. However, the reverse analysis suggested no causal relation (betaSBP: 5.469, P = 0.763; betaDBP: 3.624, P = 0.588; betaPP: −0.074, P = 0.912). These findings were robust in sensitivity analyses such as the MR–Egger method, the maximum likelihood method and the MR pleiotropy residual sum and outlier test (MR-PRESSO). No horizontal pleiotropy (p = 0.869 for SBP, p = 0.109 for DBP and p = 0.978 for PP in the forward results and p = 0.168 for SBP, P = 0.892 for DBP and p = 0.989 for PP in the reverse results) was observed. Conclusions Elevated SBP or DBP levels increase the risk of MI, but there is no causal relationship between MI and changes in BP including PP. Independent of other risk factors, optimal BP control might represent an important therapeutic target for MI prevention in the general population.
| S-EPMC9686852 | biostudies-literature
Project description:The kidney is a vital organ with diverse biological effects and the burden of kidney function impairment is increasing in modern medicine. As the effects from kidney function on diverse biochemical parameters are yet fully understood, additional investigation to reveal the causal effects is warranted. Here we show the causal estimates from kidney function parameter, estimated glomerular filtration rate (eGFR), on 60 biochemical parameters by performing two-sample Mendelian randomization (MR) study in 337,138 white British UK Biobank participants. A higher genetically predicted eGFR was significantly associated with higher lymphocyte percentage, HDL cholesterol, and alanine aminotransferase. The causal estimates indicated that a higher genetically predicted eGFR was associated with lower urea, urate, insulin growth factor-1, and triglycerides levels. The parameters with significant but non-linear causal estimates were hemoglobin concentration, calcium, vitamin D, and urine creatinine values, identified by non-linear MR. Healthcare providers should understand that changes in eGFR may affect the identified biochemical parameters in diverse patterns. Future study is warranted to expand the knowledge of the mechanisms and clinical implications of the causal effects of eGFR on various biochemical parameters.
| S-EPMC9293908 | biostudies-literature
Project description:BackgroundHeart Failure (HF) is a widespread condition that affects millions of people, and it is caused by issues with the heart and blood vessels. Even though we know hypertension, coronary artery disease, obesity, diabetes, and genetics can increase the risk of HF and Chronic Kidney Disease (CKD), the exact cause of these conditions remains a mystery. To bridge this gap, we adopted Mendelian Randomization (MR), which relies on genetic variants as proxies.MethodsWe used data from European populations for our Bidirectional Two-Sample MR Study, which included 930,014 controls and 47,309 cases of HF from the HERMES consortium, as well as 736,396 controls and 51,256 cases of CKD. We also employed several MR variations, including MR-Egger, Inverse Variance Weighted (IVW), and Weighted Median Estimator (WME), to guarantee the results were accurate and comprehensive.).ResultsIn this study, the MR analysis found that individuals with a genetic predisposition for HF have an elevated risk of CKD. Our study revealed a significant association between the genetic prediction of HF and the risk of CKD, as evidenced by the IVW method [with an odds ratio (OR) of 1.12 (95% CI, 1.03-1.21), p = 0.009] and the WME [with an OR of 1.14 (95% CI, 1.03-1.26), p = 0.008]. This causal relationship remained robust even after conducting MR analysis while adjusting for the effects of diabetes and hypertension, yielding ORs of 1.13 (IVW:95% CI, 1.03-1.23), 1.12 (MR-Egger: 95% CI, 0.85-1.48), and 1.15 (WME:95% CI, 1.04-1.27) (p = 0.008). However, in the reverse analysis aiming to explore CKD and renal function as exposures and HF as the outcome, we did not observe a statistically significant causal link between CKD and HF.ConclusionOur study demonstrates the significance of HF in CKD progression, thus having meaningful implications for treatment and the potential for discovering new therapies. To better understand the relationship between HF and CKD, we need to conduct research in a variety of populations.
| S-EPMC10712866 | biostudies-literature
Project description:ContextChronic kidney disease (CKD) is a public health burden worldwide. Epidemiological studies observed an association between sex hormones, including estradiol, and kidney function.ObjectiveWe conducted a Mendelian randomization (MR) study to assess a possible causal effect of estradiol levels on kidney function in males and females.DesignWe performed a bidirectional two-sample MR using published genetic associations of serum levels of estradiol in men (n = 206,927) and women (n = 229,966), and of kidney traits represented by estimated glomerular filtration rate (eGFR, n = 567,460), urine albumin-to-creatinine ratio (UACR, n = 547,361), and CKD (n = 41,395 cases and n = 439,303 controls) using data obtained from the CKDGen Consortium. Additionally, we conducted a genome-wide association study using UK Biobank cohort study data (n = 11,798 men and n = 6,835 women) to identify novel genetic associations with levels of estradiol, and then used these variants as instruments in a one-sample MR.ResultsThe two-sample MR indicated that genetically predicted estradiol levels are significantly associated with eGFR in men (beta = 0.077; p = 5.2E-05). We identified a single locus at chromosome 14 associated with estradiol levels in men being significant in the one-sample MR on eGFR (beta = 0.199; p = 0.017). We revealed significant results with eGFR in postmenopausal women and with UACR in premenopausal women, which did not reach statistical significance in the sensitivity MR analyses. No causal effect of eGFR or UACR on estradiol levels was found.ConclusionsWe conclude that serum estradiol levels may have a causal effect on kidney function. Our MR results provide starting points for studies to develop therapeutic strategies to reduce kidney disease.
| S-EPMC10758447 | biostudies-literature
Project description:Purpose We conducted a bidirectional two-sample Mendelian randomization (MR) study to determine whether genetically predicted basal metabolic rate (BMR) was a causal risk factor for colorectal cancer (CRC) or whether a genetically predicted CRC risk can influence the BMR level (i.e., reverse causation). Methods We employed 1,040 genetic variants as proxies for BMR to obtain effect estimates on CRC risk. Another 58 CRC-associated variants were used to estimate effects on BMR levels. Stratified analysis by tumor site was used to examine the causal associations between BMR and colon/rectal cancer risk. Results The inverse variance weighted (IVW) method indicated a significant causal effect of genetically determined BMR on CRC risk (ORSD = 1.27, 95% CI = 1.07–1.51). No significant reverse causal association was identified between genetically increased CRC risk and BMR levels [IVW (β = 0, 95% CI = -0.01 to 0)]. The results of MR-Egger and the weighted median method were consistent with the IVW method. Stratified analysis by CRC sites identified significant causal associations between BMR and colon cancer [IVW (ORSD = 1.45, 95% CI = 1.16-1-80)], and null evidence of a causal association between BMR and rectal cancer risk was found (p > 0.05). Conclusion Our findings add to the current literature by validating a positive relationship between high BMR levels and CRC risk instead of reverse causality. The genetically predicted BMR level was causally associated with colon cancer risk but not rectal cancer risk.
| S-EPMC9394792 | 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