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Inhibition of interleukin 6 signalling and renal function: A Mendelian randomization study.

ABSTRACT: Inhibition of interleukin 6 (IL-6) signalling has been proposed as a potential cardioprotective strategy for patients with chronic kidney disease (CKD), but the direct effects of IL-6 inhibition on renal function are not known. A Mendelian randomization (MR) study was performed to investigate the association of genetically proxied inhibition of IL-6 signalling with estimated glomerular filtration rate (eGFR), CKD and blood urea nitrogen (BUN). Inverse-variance weighted MR was used as the main analysis, with sensitivity analyses performed using simple median, weighted median and MR-Egger methods. There was no evidence for an association of genetically proxied inhibition of IL-6 signalling (scaled per standard deviation unit decrease in C-reactive protein) with log eGFR (0.001, 95% confidence interval -0.004-0.007), BUN (0.009, 95% confidence interval -0.003-0.021) and CKD (odds ratio 0.948, 95% confidence interval 0.822-1.094). These findings do not raise concerns for IL-6 signalling having large adverse effects on renal function.

SUBMITTER: Ryan DK

PROVIDER: S-EPMC8327328 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Inhibition of interleukin 6 signalling and renal function: A Mendelian randomization study.

Ryan David K DK Karhunen Ville V Walker Drew J DJ Gill Dipender D

British journal of clinical pharmacology 20210210 7

Inhibition of interleukin 6 (IL-6) signalling has been proposed as a potential cardioprotective strategy for patients with chronic kidney disease (CKD), but the direct effects of IL-6 inhibition on renal function are not known. A Mendelian randomization (MR) study was performed to investigate the association of genetically proxied inhibition of IL-6 signalling with estimated glomerular filtration rate (eGFR), CKD and blood urea nitrogen (BUN). Inverse-variance weighted MR was used as the main an ...[more]

PMID: 33393675

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Project description:BackgroundPrevious observational studies have found a potential link between prostate disease, particularly prostate cancer (PCa), and kidney disease, specifically chronic renal disease (CKD), in relation to erectile dysfunction (ED), yet the causal relationship between these factors remains uncertain.AimThe study sought to explore the potential causal association between prostate diseases, renal diseases, renal function, and risk of ED.MethodsIn this study, 5 analytical approaches were employed to explore the causal relationships between various prostate diseases (PCa and benign prostatic hyperplasia), renal diseases (CKD, immunoglobulin A nephropathy, membranous nephropathy, nephrotic syndrome, and kidney ureter calculi), as well as 8 renal function parameters, with regard to ED. All data pertaining to exposure and outcome factors were acquired from publicly accessible genome-wide association studies. The methods used encompassed inverse variance weighting, MR-Egger, weighted median, simple mode, and weighted mode residual sum and outlier techniques. The MR-Egger intercept test was utilized to assess pleiotropy, while Cochran's Q statistic was employed to measure heterogeneity.OutcomesWe employed inverse variance weighting MR as the primary statistical method to assess the causal relationship between exposure factors and ED.ResultsGenetically predicted PCa demonstrated a causal association with an elevated risk of ED (odds ratio, 1.125; 95% confidence interval, 1.066-1.186; P < .0001). However, no compelling evidence was found to support associations between genetically determined benign prostatic hyperplasia, CKD, immunoglobulin A nephropathy, membranous nephropathy, nephrotic syndrome, kidney ureter calculi, and the renal function parameters investigated, and the risk of ED.Clinical implicationsThe risk of ED is considerably amplified in patients diagnosed with PCa, thereby highlighting the importance of addressing ED as a significant concern for clinicians treating individuals with PCa.Strengths and limitationsThis study's strength lies in validating the PCa-ED association using genetic analysis, while its limitation is the heterogeneity in study results.ConclusionThe results of this study suggest a potential link between PCa and a higher risk of ED.

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.

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Inhibition of interleukin 6 signalling and renal function: A Mendelian randomization study.

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Inhibition of interleukin 6 signalling and renal function: A Mendelian randomization study.

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