Dataset Information

Genetic variations in HMGCR and PCSK9 and kidney function: a Mendelian randomization study.

ABSTRACT:

Background

The genetically predicted lipid-lowering effect of HMGCR or PCSK9 variant can be used to assess drug proxy effects on kidney function.

Methods

Mendelian randomization (MR) analysis-identified HMGCR and PCSK9 genetic variants were used to predict the low-density lipoprotein (LDL) cholesterol-lowering effects of medications targeting related molecules. Primary summary-level outcome data for log-estimated glomerular filtration rate (eGFR; creatinine) were provided by the CKDGen Consortium (n = 1,004,040 European) from a meta-analysis of CKDGen and UK Biobank data. We also conducted a separate investigation of summary-level data from CKDGen (n = 567,460, log-eGFR [creatinine]) and UK Biobank (n = 436,581, log-eGFR [cystatin C]) samples. Summary-level MRs using an inverse variance weighted method and pleiotropy-robust methods were performed.

Results

Summary-level MR analysis indicated that the LDL-lowering effect predicted genetically by HMGCR variants (50-mg/dL decrease) was significantly associated with a decrease in eGFR (-1.67%; 95% confidence interval [CI], -2.20% to -1.13%). Similar significance was found in results from the pleiotropy-robust MR methods when the CKDGen and UK Biobank data were analyzed separately. However, the LDL-lowering effect predicted genetically by PCSK9 variants was significantly associated with an increase in eGFR (+1.17%; 95% CI, 0.10%-2.25%). The results were similarly supported by the weighted median method and in each CKDGen and UK Biobank dataset, but the significance obtained by MR-Egger regression was attenuated.

Conclusion

Genetically predicted HMG-CoA reductase inhibition was associated with low eGFR, while genetically predicted PCSK9 inhibition was associated with high eGFR. Clinicians should consider that the direct effect of different types of lipid-lowering medication on kidney function can vary.

SUBMITTER: Park S

PROVIDER: S-EPMC10407636 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Publications

Genetic variations in HMGCR and PCSK9 and kidney function: a Mendelian randomization study.

Park Sehoon S Kim Seong Geun SG Lee Soojin S Kim Yaerim Y Cho Semin S 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

Kidney research and clinical practice 20230522 4

<h4>Background</h4>The genetically predicted lipid-lowering effect of HMGCR or PCSK9 variant can be used to assess drug proxy effects on kidney function.<h4>Methods</h4>Mendelian randomization (MR) analysis-identified HMGCR and PCSK9 genetic variants were used to predict the low-density lipoprotein (LDL) cholesterol-lowering effects of medications targeting related molecules. Primary summary-level outcome data for log-estimated glomerular filtration rate (eGFR; creatinine) were provided by the C ...[more]

PMID: 37448291

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Project description:Background & aimsObservational studies have linked lipid-lowering drug targets pro-protein convertase subtilisin/kexin 9 (PCSK9) and HMG-CoA reductase (HMGCR) with adverse liver outcomes; however, liver disease incidence varies across diverse populations, and the long-term hepatic impact of these lipid-lowering drugs among non-white Europeans remains largely unknown.MethodsWe use single nucleotide polymorphisms (SNPs) in PCSK9 and HMGCR loci from genome-wide association study data of low-density lipoprotein cholesterol in 4 populations (East Asian [EAS], South Asian [SAS], African [AFR], and European [EUR]) to perform drug-target Mendelian randomization investigating relationships between PCSK9 and HMGCR inhibition and alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), and bilirubin.ResultsAnalyses of PCSK9 instruments, including functional variants R46L and E670G, failed to find evidence for relationships of low-density lipoprotein cholesterol lowering via PCSK9 variants and adverse effects on ALT, AST, GGT, or ALP among the cohorts. PCSK9 inhibition was associated with increased direct bilirubin levels in EUR (β = 0.089; P value = 5.69 × 10-6) and, nominally, in AFR (β = 0.181; P value = .044). HMGCR inhibition was associated with reduced AST in SAS (β = -0.705; P value = .005) and, nominally, reduced AST in EAS (β = -0.096; P value = .03), reduced ALP in EUR (β = -2.078; P value = .014), and increased direct bilirubin in EUR (β = 0.071; P value = .032). Sensitivity analyses using genetic instruments derived from circulating PCSK9 protein levels, tissue-specific PCSK9 expression, and HMGCR expression were in alignment, strengthening causal inference.ConclusionsWe did not find ALT, AST, GGT, or ALP associated with genetically proxied PCSK9 and HMGCR inhibition across ancestries. We identified possible relationships in several ancestries between PCSK9 and increased direct and total bilirubin and between HMGCR and reduced AST. These findings support long-term safety profiles and low hepatotoxic risk of PCSK9 and HMGCR inhibition in diverse populations.

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.

Project description:To investigate the use of lipid-lowering drugs and abnormal serum lipid levels in patients at risk of sleep apnea syndrome. Three types of Mendelian randomization (MR) analyses were used. First, a 2-sample Mendelian randomization (TSMR) analysis was used to investigate the association between sleep apnea syndrome risk and serum lipid levels. Multivariate Mendelian randomization (MVMR) analysis was subsequently used to investigate the effects of confounding variables on SAS incidence of sleep apnea syndrome. Finally, drug-target Mendelian randomization (DMR) analysis was used to analyze the association between lipid-lowering drug use and sleep apnea syndrome risk. According to the TSMR analysis, the serum HDL-C concentration was negatively correlated with sleep apnea syndrome (OR = 0.904; 95% CI = 0.845-0.967; P = .003). Serum TG levels were positively correlated with sleep apnea syndrome (OR = 1.081; 95% CI = 1.003-1.163; P = .039). The association between serum HDL-C levels and sleep apnea syndrome in patients with MVMR was consistent with the results in patients with TSMR (OR = 0.731; 95% CI = 0.500-1.071; P = 3.94E-05). According to our DMR analysis, HMGCR and PCSK9, which act by lowering serum LDL-C levels, were inversely associated with the risk of sleep apnea syndrome (OR = 0.627; 95% CI = 0.511-0.767; P = 6.30E-06) (OR = 0.775; 95% CI = 0.677-0.888; P = .0002). LPL, that lowered serum TG levels, was positively associated with the risk of sleep apnea syndrome (OR = 1.193; 95% CI = 1.101-1.294; P = 1.77E-05). Our analysis suggested that high serum HDL-C levels may reduce the risk of sleep apnea syndrome. Low serum TG levels have a protective effect against sleep apnea syndrome. The DMR results suggested that the use of HMGCR lipid-lowering drugs (such as statins) and PCSK9 inhibitors has a protective effect against sleep apnea syndrome. However, LPL-based lipid-lowering drugs may increase the risk of sleep apnea syndrome.

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.

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.

Project description:BackgroundObesity and type 2 diabetes (T2D) are correlated risk factors for chronic kidney disease (CKD).MethodsUsing summary data from GIANT (Genetic Investigation of Anthropometric Traits), DIAGRAM (DIAbetes Genetics Replication And Meta-analysis), and CKDGen (CKD Genetics), we examined causality and directionality of the association between obesity and kidney function. Bidirectional 2-sample Mendelian randomization (MR) estimated the total causal effects of body mass index (BMI) and waist-to-hip ratio (WHR) on kidney function, and vice versa. Effects of adverse obesity and T2D were examined by stratifying BMI variants by their association with WHR and T2D. Multivariable MR estimated the direct causal effects of BMI and WHR on kidney function. The inverse variance weighted random-effects MR for Europeans was the main analysis, accompanied by several sensitivity MR analyses.ResultsOne standard deviation (SD ≈ 4.8 kg/m2) genetically higher BMI was associated with decreased estimated glomerular filtration rate (eGFR) [β=-0.032 (95% confidence intervals: -0.036, -0.027) log[eGFR], P = 1 × 10-43], increased blood urea nitrogen (BUN) [β = 0.010 (0.005, 0.015) log[BUN], P = 3 × 10-6], increased urinary albumin-to-creatinine ratio [β = 0.199 (0.067, 0.332) log[urinary albumin-to-creatinine ratio (UACR)], P = 0.003] in individuals with diabetes, and increased risk of microalbuminuria [odds ratios (OR) = 1.15 [1.04-1.28], P = 0.009] and CKD [1.13 (1.07-1.19), P = 3 × 10-6]. Corresponding estimates for WHR and for trans-ethnic populations were overall similar. The associations were driven by adverse obesity, and for microalbuminuria additionally by T2D. While genetically high BMI, unlike WHR, was directly associated with eGFR, BUN, and CKD, the pathway to albuminuria was likely through T2D. Genetically predicted kidney function was not associated with BMI or WHR.ConclusionsGenetically high BMI is associated with impaired kidney function, driven by adverse obesity, and for albuminuria additionally by T2D.

Dataset Information

Genetic variations in HMGCR and PCSK9 and kidney function: a Mendelian randomization study.

Background

Methods

Results

Conclusion

Publications

Genetic variations in HMGCR and PCSK9 and kidney function: a Mendelian randomization study.

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