Dataset Information

Hypothyroidism and Kidney Function: A Mendelian Randomization Study.

ABSTRACT: 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 (eGFR_crea), eGFR from cystatin C (eGFR_cys), 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 eGFR_crea (N?=?567,460), eGFR_cys (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 eGFR_crea [beta (standard error, SE): -0.024 (0.009) ln(mL/min/1.73?m²), p?=?0.01]. By MR, hypothyroidism was associated with decreased eGFR_crea 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 eGFR_crea 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 eGFR_cys 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 eGFR_crea [beta (SE): -0.041 (0.009), p?=?6.2?×?10^-6] and decreased eGFR_cys [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 eGFR_crea and increased CKD.

SUBMITTER: Ellervik C

PROVIDER: S-EPMC7074918 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Hypothyroidism and Kidney Function: A Mendelian Randomization Study.

Ellervik Christina C Mora Samia S Ridker Paul M PM Chasman Daniel I DI

Thyroid : official journal of the American Thyroid Association 20200214 3

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 stud ...[more]

PMID: 31910748

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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.

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Hypothyroidism and Kidney Function: A Mendelian Randomization Study.

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Hypothyroidism and Kidney Function: A Mendelian Randomization Study.

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