Mendelian randomization reveals causal effects of kidney function on various biochemical parameters.
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ABSTRACT:
SUBMITTER: Park S
PROVIDER: S-EPMC9293908 | biostudies-literature | 2022 Jul
REPOSITORIES: biostudies-literature
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Mendelian randomization reveals causal effects of kidney function on various biochemical parameters.
Park Sehoon S Lee Soojin S Kim Yaerim Y Cho Semin S Huh Hyeok H Kim Kwangsoo K Kim Yong Chul YC Han Seung Seok SS Lee Hajeong H Lee Jung Pyo JP Joo Kwon Wook KW Lim Chun Soo CS Kim Yon Su YS Kim Dong Ki DK
Communications biology 20220718 1
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) stu ...[more]
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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:Blood homocysteine level and related vitamin levels are associated with various health outcomes. We aimed to assess causal effects of blood homocysteine, folate, and cobalamin on kidney function in the general population by performing Mendelian randomization (MR) analysis. Genetic instruments for blood homocysteine, folate, and cobalamin levels were introduced from a previous genome-wide association (GWAS) meta-analysis of European individuals. Summary-level MR analysis was performed for the estimated glomerular filtration rate (eGFR) from the CKDGen consortium GWAS that included 567,460 European ancestry individuals. For replication, allele-score-based MR was performed with an independent U.K. Biobank cohort of 337,138 individuals of white British ancestry. In summary-level MR for the CKDGen data, high genetically predicted homocysteine levels were significantly associated with low eGFR (per 1 standard deviation, beta for eGFR change -0.95 (-1.21, -0.69) %), supported by pleiotropy-robust MR sensitivity analysis. Genetically predicted high folate levels were significantly associated with high eGFR change (0.86 (0.30, 1.42) %); however, causal estimates from cobalamin were nonsignificant (-0.11 (-0.33, 0.11) %). In the U.K. Biobank data, the results were consistently identified. Therefore, a high blood homocysteine level causally decreases eGFR. Future trials with appropriate homocysteine-lowering interventions may be helpful for the primary prevention of kidney function impairment.
| S-EPMC8001564 | biostudies-literature
Project description:Blood pressure and kidney function have a bidirectional relation. Hypertension has long been considered as a risk factor for kidney function decline. However, whether intensive blood pressure control could promote kidney health has been uncertain. The kidney is known to have a major role in affecting blood pressure through sodium extraction and regulating electrolyte balance. This bidirectional relation makes causal inference between these two traits difficult. Therefore, to examine the causal relations between these two traits, we performed two-sample Mendelian randomization analyses using summary statistics of large-scale genome-wide association studies. We selected genetic instruments more likely to be specific for kidney function using meta-analyses of complementary kidney function biomarkers (glomerular filtration rate estimated from serum creatinine [eGFRcr], and blood urea nitrogen from the CKDGen Consortium). Systolic and diastolic blood pressure summary statistics were from the International Consortium for Blood Pressure and UK Biobank. Significant evidence supported the causal effects of higher kidney function on lower blood pressure. Based on the mode-based Mendelian randomization method, the effect estimates for one standard deviation (SD) higher in log-transformed eGFRcr was -0.17 SD unit (95 % confidence interval: -0.09 to -0.24) in systolic blood pressure and -0.15 SD unit (95% confidence interval: -0.07 to -0.22) in diastolic blood pressure. In contrast, the causal effects of blood pressure on kidney function were not statistically significant. Thus, our results support causal effects of higher kidney function on lower blood pressure and suggest preventing kidney function decline can reduce the public health burden of hypertension.
| S-EPMC7784392 | biostudies-literature
Project description:BackgroundCausal research concerning the consumption of tea and the risk of chronic kidney disease (CKD) is limited. This study identified the potential causal effects of tea intake on CKD, the estimated glomerular filtration rate (eGFR), and albuminuria.MethodsGenome-wide association studies (GWASs) from UK Biobank were able to identify single-nucleotide polymorphisms (SNPs) associated with an extra cup of tea each day. The summary statistics for the kidney function from the CKDGen consortium include 11,765 participants (12,385 cases of CKD) and 54,116 participants for the urinary albumin-to-creatinine ratio who were mostly of European descent. A two-sample Mendelian randomization (MR) analysis was performed to test the relationship between the selected SNPs and the risk of CKD.ResultsA total of 2,672 SNPs associated with tea consumption (p < 5 × 10-8) were found, 45 of which were independent and usable in CKDGen. Drinking more cups of tea per day indicates a protective effect for CKD G3-G5 [odds ratio (OR) = 0.803; p = 0.004] and increases eGFR (β = 0.019 log ml/min/1.73 m2 per cup per day; p = 2.21 × 10-5). Excluding two SNPs responsible for directional heterogeneity (Cochran Q p = 0.02), a high consumption of tea was also negatively correlated with a lower risk of albuminuria (OR = 0.758; p = 0.002).ConclusionFrom the perspective of genes, causal relationships exist between daily extra cup of tea and the reduced risk of CKD and albuminuria and increased eGFR.
| S-EPMC9002236 | 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: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:BackgroundPoor socio-economic status, including low education attainment, has been reported in chronic kidney disease (CKD) patients. We aimed to investigate the causal effects of education attainment on the risk of CKD.MethodsThe study was an observational cohort study including Mendelian randomization (MR) analysis. First, the clinical association between education attainment years as the exposure and prevalent CKD Stages 3-5 as the outcome was investigated by multivariable logistic regression in 308 741 individuals 40-69 years of age from the UK Biobank. MR analysis was performed with a previously reported genetic instrument from a genome-wide association meta-analysis of education attainment. Two-sample MR was performed with summary statistics for CKD in 567 460 individuals with European ancestry in the CKDGen genome-wide association meta-analysis. The findings were replicated by allele score-based MR in 321 260 individuals of white British ancestry in the UK Biobank with quality-controlled genetic data.ResultsHigher education attainment was significantly associated with lower adjusted odds for CKD in the clinical analysis {>17 years versus <16 years, adjusted odds ratio [OR] 0.910 [95% confidence interval (CI) 0.849-0.975]}. The causal estimates obtained by the inverse variance method in the two-sample MR indicated that higher genetically predicted education attainment causally reduced the risk of CKD [OR 0.934 (95% CI 0.873-0.999)]. Allele score-based MR also supported that higher education attainment was causally linked to a decreased risk of CKD [adjusted OR 0.944 (95% CI 0.922-0.966)].ConclusionThe study suggests that higher education attainment causally reduces the risk of CKD development in the general population.
| S-EPMC8323131 | biostudies-literature
Project description:Salt restriction was recommended in clinical practice guideline for chronic kidney disease (CKD) treatment, but its effect on kidney outcomes remains conflicting. We aimed to test the causal effect of salt intake, using estimated 24-h sodium excretion from spot urinary sodium/urinary creatinine (UNa/UCr) ratio as a surrogate, on renal function using two-sample Mendelian randomization (MR). Genetic instruments for UNa/UCr were derived from a recent genome-wide association study of 218,450 European-descent individuals in the UK Biobank. Kidney outcomes were creatinine-based estimated glomerular filtration rate (eGFRcrea) (N = 567,460) and CKD (eGFRcrea < 60 ml/min/1.73 m2, N cases = 41,395, N controls = 439,303) from the CKDGen consortium. Cystatin C-based eGFR (eGFRcys) and eGFRcrea single-nucleotide polymorphisms associated with blood urea nitrogen (BUN) were used for sensitivity analyses. MR revealed a causal effect of UNa/UCr on higher eGFRcrea [β = 0.14, unit change in log ml/min/1.73 m2 per UNa/UCr ratio; 95% confidence interval (CI) = 0.07 - 0.20, P = 2.15 × 10-5] and a protective effect against CKD risk (odds ratio = 0.24, 95% CI = 0.14 to 0.41, P = 1.20 × 10-7). The MR findings were confirmed by MR-Egger regression, weighted median MR, and mode estimate MR, with less evidence of existence of horizontal pleiotropy. Consistent positive causal effect of UNa/UCr on eGFRcys was also detected. On the other hand, bidirectional MR suggested inconclusive results of CKD, eGFRcrea, eGFRcrea (BUN associated), and eGFRcys on UNa/UCr. The average 24-h sodium excretion was estimated to be approximately 2.6 g per day for women and 3.7 g per day for men. This study provides evidence that sodium excretion, well above the recommendation of <2 g per day of sodium intake, might not have a harmful effect on kidney function. Clinical trials are warranted to evaluate the sodium restriction target on kidney function.
| S-EPMC7358605 | biostudies-literature
Project description:BackgroundWhile targeted systemic inflammatory modulators show promise in preventing chronic kidney disease (CKD) progression, the causal link between specific inflammatory factors and CKD remains uncertain.MethodsUsing a genome-wide association study of 41 serum cytokines from 8,293 Finnish individuals, we conducted a bidirectional two-sample Mendelian randomization (MR) analysis. In addition, we genetically predicted causal associations between inflammatory factors and 5 phenotypes, including CKD, estimated glomerular filtration rate (eGFR), dialysis, rapid progression of CKD, and rapid decline in eGFR. Inverse variance weighting (IVW) served as the primary MR method, while MR-Egger, weighted median, and MR-pleiotropy residual sum and outlier (MR-PRESSO) were utilized for sensitivity analysis. Cochrane's Q test for heterogeneity. Leave-one-out method ensured stability of MR results, and Bonferroni correction assessed causal relationship strength.ResultsSeventeen cytokines were associated with diverse renal outcomes. Among them, after Bonferroni correction test, higher tumor necrosis factor alpha levels were associated with a rapid decrease in eGFR (OR = 1.064, 95% CI 1.028 - 1.103, P = 0.001), higher interleukin-4 levels were associated with an increase in eGFR (β = 0.003, 95% CI 0.001 - 0.005, P = 0.002), and higher growth regulated oncogene alpha (GROα) levels were associated with an increased risk of CKD (OR=1.035, 95% CI 1.012 - 1.058, P = 0.003). In contrast, genetic susceptibility to CKD was associated with an increase in GROa, and a decrease in eGFR may lead to an increase in stem cell factor. We did not find the presence of horizontal pleiotropy during the analysis.ConclusionWe discovered causally related inflammatory factors that contribute to the initiation and progression of CKD at the genetic prediction level.
| S-EPMC10498994 | biostudies-literature