A Mendelian randomization study found causal linkage between telomere attrition and chronic kidney disease

Park, Sehoon; Lee, Soo Jin; Kim, Yaerim; Cho, Semin; Kim, Kwangsoo; Kim, Yong Chul; Han, Seung Seok; Lee, Hajeong; Lee, Jung Pyo; Joo, Kwon Wook; Lim, Chun Soo; Kim, Yon Su

doi:10.1016/j.kint.2021.06.041

Cited by 52 publications

(59 citation statements)

References 40 publications

(54 reference statements)

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“…In humans, telomeres in the renal cortex shorten in an age-dependent manner [53,54], and telomere attrition has been described as a causal factor for CKD [42]. In contrast, we found no evidence of telomere shortening in the kidneys of senior cats without CKD, despite evaluating a large number of samples here and elsewhere [14].…”

Section: Discussioncontrasting

confidence: 76%

“…Specifically in cats, normal tubules contain large amounts of lipid, and when damage occurs, lipid is released into the interstitium, thus becoming a nidus for inflammation [3]. When considered together with similar observations in human CKD patients [38][39][40][41][42], it is not surprising that telomeres are shortened in cats with CKD, a scenario that would eventually result in critically short telomeres and the triggering of replicative senescence [36,37,[43][44][45].…”

Section: Discussionmentioning

confidence: 94%

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Renal Senescence, Telomere Shortening and Nitrosative Stress in Feline Chronic Kidney Disease

Quimby

Erickson

McLeland

et al. 2021

Veterinary Sciences

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Kidney tissues from cats with naturally occurring chronic kidney disease (CKD) and adult and senior cats without CKD were assessed to determine whether telomere shortening and nitrosative stress are associated with senescence in feline CKD. The histopathologic assessment of percent global glomerulosclerosis, inflammatory infiltrate, and fibrosis was performed. Senescence and nitrosative stress were evaluated utilizing p16 and iNOS immunohistochemistry, respectively. Renal telomere length was evaluated using telomere fluorescent in situ hybridization combined with immunohistochemistry. CKD cats were found to have significantly increased p16 staining in both the renal cortex and corticomedullary junction compared to adult and senior cats. Senior cats had significantly increased p16 staining in the corticomedullary junction compared to adult cats. p16 staining in both the renal cortex and corticomedullary junction were found to be significantly correlated with percent global glomerulosclerosis, cortical inflammatory infiltrate, and fibrosis scores. p16 staining also correlated with age in non-CKD cats. Average telomere length was significantly decreased in CKD cats compared to adult and senior cats. CKD cats had significantly increased iNOS staining compared to adult cats. Our results demonstrate increased renal senescence, telomere shortening, and nitrosative stress in feline CKD, identifying these patients as potential candidates for senolytic therapy with translational potential.

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Section: Discussioncontrasting

confidence: 76%

Section: Discussionmentioning

confidence: 94%

Renal Senescence, Telomere Shortening and Nitrosative Stress in Feline Chronic Kidney Disease

Quimby

Erickson

McLeland

et al. 2021

Veterinary Sciences

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“…The standard inverse variance-weighted (IVW) method was applied to primarily analyze the causal relationships between obesity (BMI, waist, and hip circumference) and POAG ( Brumpton et al, 2020 ; Park et al, 2021 ). This method calculated the Wald ratio of each SNP to assess the causal effects of each SNP on outcome, and finally, the inverse variances of SNPs were used as weights for meta-analysis to evaluate the combined causal effect.…”

Section: Methodsmentioning

confidence: 99%

The Causal Association Between Obesity and Primary Open-Angle Glaucoma: A Two-Sample Mendelian Randomization Study

et al. 2022

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The correlation between obesity and primary open-angle glaucoma (POAG) has not yet been fully established. The aim of this study was to investigate the causal relationship between obesity and POAG by a two-sample Mendelian randomization (MR) study. In this study, body mass index (BMI), an index to evaluate general obesity, and waist and hip circumference, indices to evaluate abdominal obesity, were selected as exposures in MR analysis. Single-nucleotide polymorphisms (SNPs) were chosen as instrumental variables (IVs). Summary data from genome-wide association studies (GWASs) based on a European ancestry by Locke et al., with regard to BMI, and Shungin et al., with regard to waist and hip circumference, were used. Genetic predictors of POAG were obtained from public GWAS summary data. To assess the causal effect of obesity on POAG, the inverse variance-weighted (IVW) method was used as the primary method, and other methods, such as MR–Egger, weighted median, simple mode, and weighted mode, were also used as complementary analyses. Finally, we performed Cochran’s Q statistic to assess heterogeneity, and sensitivity analysis was performed to evaluate the reliability and stability of the MR results. MR analysis showed that BMI has a positive effect on the risk of POAG, with 1 standard deviation (SD) increase in BMI; the risk of POAG increases by approximately 90.9% [OR = 1.909; 95% CI= (1.225, 2.975); p = 0.0042)] (analyzed by IVW); there were no heterogeneity and pleiotropy in the result; and waist circumference also had a positive effect on the risk of POAG [OR = 2.319; 95% CI= (1.071, 5.018); p = 0.033)] analyzed by weighted median. As hip circumference increases, with 1 SD increase in hip circumference, the risk of POAG increases by approximately 119% [OR = 2.199; 95% CI= (1.306, 3.703); p = 0.00305)] estimated by IVW, there were not heterogeneity and pleiotropy as for the result. Our study for the first time confirms that obesity might increase the risk of POAG using two-sample MR analysis. These results might provide guidance on the prevention and treatment of POAG.

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“…As there are strengths and weaknesses in each MR method, a replication analysis including multiple methods and datasets is desirable, 13 and the UK Biobank dataset, for individual-level MR, and the CKDGen data, for summary-level MR, are widely used for MR analysis towards kidney function traits. 11,[14][15][16] The strengths of investigating the individual-level data are that direct adjustment of clinical covariates is available and a subgroup analysis is possible. The advantage of analysing the summary-level data is the transparency as the results can be easily replicated from publicly available summarylevel data.…”

Section: Study Settingmentioning

confidence: 99%

Causal effects from non‐alcoholic fatty liver disease on kidney function: A Mendelian randomization study

Park

Lee

Kim

et al. 2021

Liver International

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Background and aims: An observational association between nonalcoholic fatty liver disease (NAFLD) and kidney function impairment has been reported. We aimed to investigate the causal effects from NAFLD on estimated glomerular filtration rate (eGFR) by a Mendelian randomization (MR) study. Methods: We first performed single-variant MR with rs738409 as a genetic instrument for NAFLD. Another genetic instrument was developed from a genome-wide association study for biopsy-confirmed NAFLD among individuals of European ancestry (1483 cases and 17 781 controls). The eGFR outcome was assessed in individuals of white British ancestry from the UK Biobank (N = 321 405). The associations were reassessed in the negative control subgroup (body mass index < 30 kg/m 2 , absence of central obesity, and serum alanine aminotransferase level ≤ 20 IU/mL) with a low probability of developing NAFLD. As a replication analysis, a summary-level MR was performed with the European ancestry CKDGen dataset (N = 567 460).Results: In the UK Biobank, a genetic predisposition for NAFLD, determined either by the single SNP rs738409 or by the group of variants, was significantly associated with a reduced eGFR even with adjustment for metabolic disorders. Although the associations were not significant in the negative control subgroup with a low probability of developing NAFLD, they were significant in the subgroup with a remaining risk of NAFLD, suggesting the absence of a horizontal pleiotropic pathway. The | 413 PARK et Al.

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A Mendelian randomization study found causal linkage between telomere attrition and chronic kidney disease

Cited by 52 publications

References 40 publications

Renal Senescence, Telomere Shortening and Nitrosative Stress in Feline Chronic Kidney Disease

Renal Senescence, Telomere Shortening and Nitrosative Stress in Feline Chronic Kidney Disease

The Causal Association Between Obesity and Primary Open-Angle Glaucoma: A Two-Sample Mendelian Randomization Study

Causal effects from non‐alcoholic fatty liver disease on kidney function: A Mendelian randomization study

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