Dataset Information

Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline.

ABSTRACT: Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m²/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m² at follow-up among those with eGFRcrea 60 mL/min/1.73m² or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.

SUBMITTER: Gorski M

PROVIDER: S-EPMC8010357 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline.

Gorski Mathias M Jung Bettina B Li Yong Y Matias-Garcia Pamela R PR Wuttke Matthias M Coassin Stefan S Thio Chris H L CHL Kleber Marcus E ME Winkler Thomas W TW Wanner Veronika V Chai Jin-Fang JF Chu Audrey Y AY Cocca Massimiliano M Feitosa Mary F MF Ghasemi Sahar S Hoppmann Anselm A Horn Katrin K Li Man M Nutile Teresa T Scholz Markus M Sieber Karsten B KB Teumer Alexander A Tin Adrienne A Wang Judy J Tayo Bamidele O BO Ahluwalia Tarunveer S TS Almgren Peter P Bakker Stephan J L SJL Banas Bernhard B Bansal Nisha N Biggs Mary L ML Boerwinkle Eric E Bottinger Erwin P EP Brenner Hermann H Carroll Robert J RJ Chalmers John J Chee Miao-Li ML Chee Miao-Ling ML Cheng Ching-Yu CY Coresh Josef J de Borst Martin H MH Degenhardt Frauke F Eckardt Kai-Uwe KU Endlich Karlhans K Franke Andre A Freitag-Wolf Sandra S Gampawar Piyush P Gansevoort Ron T RT Ghanbari Mohsen M Gieger Christian C Hamet Pavel P Ho Kevin K Hofer Edith E Holleczek Bernd B Xian Foo Valencia Hui VH Hutri-Kähönen Nina N Hwang Shih-Jen SJ Ikram M Arfan MA Josyula Navya Shilpa NS Kähönen Mika M Khor Chiea-Chuen CC Koenig Wolfgang W Kramer Holly H Krämer Bernhard K BK Kühnel Brigitte B Lange Leslie A LA Lehtimäki Terho T Lieb Wolfgang W Loos Ruth J F RJF Lukas Mary Ann MA Lyytikäinen Leo-Pekka LP Meisinger Christa C Meitinger Thomas T Melander Olle O Milaneschi Yuri Y Mishra Pashupati P PP Mononen Nina N Mychaleckyj Josyf C JC Nadkarni Girish N GN Nauck Matthias M Nikus Kjell K Ning Boting B Nolte Ilja M IM O'Donoghue Michelle L ML Orho-Melander Marju M Pendergrass Sarah A SA Penninx Brenda W J H BWJH Preuss Michael H MH Psaty Bruce M BM Raffield Laura M LM Raitakari Olli T OT Rettig Rainer R Rheinberger Myriam M Rice Kenneth M KM Rosenkranz Alexander R AR Rossing Peter P Rotter Jerome I JI Sabanayagam Charumathi C Schmidt Helena H Schmidt Reinhold R Schöttker Ben B Schulz Christina-Alexandra CA Sedaghat Sanaz S Shaffer Christian M CM Strauch Konstantin K Szymczak Silke S Taylor Kent D KD Tremblay Johanne J Chaker Layal L van der Harst Pim P van der Most Peter J PJ Verweij Niek N Völker Uwe U Waldenberger Melanie M Wallentin Lars L Waterworth Dawn M DM White Harvey D HD Wilson James G JG Wong Tien-Yin TY Woodward Mark M Yang Qiong Q Yasuda Masayuki M Yerges-Armstrong Laura M LM Zhang Yan Y Snieder Harold H Wanner Christoph C Böger Carsten A CA Köttgen Anna A Kronenberg Florian F Pattaro Cristian C Heid Iris M IM

Kidney international 20201031 4

Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 m ...[more]

PMID: 33137338

Similar Datasets

Project description:Background and objectivesThe relationship of depressive symptoms with kidney function remains poorly investigated. We aimed to evaluate the prospective association between depressive symptoms and rapid decline in kidney function in Chinese adults with normal kidney function.Design, setting, participants, & measurementsA total of 4763 participants with eGFR≥60 ml/min per 1.73 m2 at baseline were enrolled from the China Health and Retirement Longitudinal Study. Baseline depressive symptoms were determined using a ten-item Center for Epidemiologic Studies Depression scale with a cutoff score of greater than or equal to ten to define high depressive symptoms. The GFR was estimated by a combination of serum creatinine and cystatin C. The primary outcome was rapid decline in kidney function, defined as an annualized decline in eGFR of ≥5 ml/min per 1.73 m2. Secondary outcome was defined as an annualized decline in eGFR of ≥5 ml/min per 1.73 m2 and to a level of <60 ml/min per 1.73 m2 at the exit visit.ResultsDuring a median follow-up of 4 years (interquartile range, 3.92-4.00), 260 (6%) participants developed rapid decline in kidney function. Overall, there was a significant positive association between baseline depressive symptoms and rapid decline in kidney function (per five-scores increment; adjusted odds ratio, 1.15; 95% confidence interval, 1.03 to 1.28) after adjustments for major demographic, clinical, or psychosocial covariates. Consistently, compared with participants with low depressive symptoms (total Center for Epidemiologic Studies Depression scale score less than ten), a significantly higher risk of rapid decline in kidney function was found among those with high depressive symptoms (total Center for Epidemiologic Studies Depression scale score greater than or equal to ten; adjusted odds ratio, 1.39; 95% confidence interval, 1.03 to 1.88). Similar results were found for the secondary outcome (per five-scores increment; adjusted odds ratio, 1.26; 95% confidence interval, 1.06 to 1.51).ConclusionsHigh depressive symptoms were significantly associated with a higher risk of rapid kidney function decline among Chinese adults with normal kidney function.

Project description:Rationale & objectiveThe direct and indirect effects of the coronavirus disease 2019 (COVID-19) pandemic on kidney function in the chronic kidney disease (CKD) population are not well understood.Study designCohort study.Setting & participantsRetrospective study of kidney function trajectories using deidentified administrative claims and laboratory data for Medicare Advantage and commercially insured enrollees with CKD stages G3-4 between 2018 and 2021.PredictorsCOVID-19 infection.OutcomeRapid kidney function decline defined as annual estimated glomerular filtration rate (eGFR) decline of ≥40%.Analytical approachPropensity score matching was used to identify individuals without COVID-19 infection matched 1:1 to a COVID-19 infected cohort and indexed on the date of diagnosing COVID-19 infection, age, sex, race or ethnicity, and Charlson comorbidity index score. Outpatient kidney function was compared during the prepandemic period (January 1, 2018, to February 29, 2020) with the pandemic period (March 1, 2020, to August 31, 2021). Two creatinine measurements, after the infection date and ≥60 days apart, were required to reduce correlation with acute infection.ResultsOf 97,203 enrollees with CKD G3-4, 9% experienced a COVID-19 infection. Characteristics of 8,901 propensity matched enrollees include mean age 74 years, 58% women, 67% White, and 63% CKD G3a, 28% CKD G3b, and 9% CKD G4. Median overall annual eGFR change was -2.65 ml/min/1.73m2, with 76% of the cohort experiencing worsened eGFR in the pandemic period. Rapid kidney function decline was observed in 1.9% and 2.0% of enrollees in the prepandemic and pandemic periods, respectively. Rapid kidney function decline was observed in 2.5% of those with COVID-19 infection and 1.5% of those without COVID-19 infection (P < 0.05). Factors associated with increased odds of rapid kidney function decline during pandemic included Asian race, higher Charlson comorbidity index, advancing CKD stage, prepandemic rapid kidney function decline, and COVID-19 infection.LimitationsRetrospective study design with potential bias.ConclusionsCOVID-19 infection increased odds of rapid kidney function decline during the pandemic. The downstream impact of pandemic-related eGFR decline on health outcomes, such as kidney failure or mortality, requires further study.Plain-language summaryWe used a cohort of insured individuals with moderate-to-severe chronic kidney disease (CKD) to compare the rates of rapid kidney function decline in prepandemic and pandemic periods and to evaluate the impact of the coronavirus disease 19 (COVID-19) on kidney function decline. We found that overall rates of rapid kidney function decline did not change during the prepandemic and pandemic periods but were significantly higher in both periods among individuals with a COVID-19 infection. As CKD severity increased, rates of both rapid kidney function decline and COVID-19 increased. Advancing CKD, higher comorbid condition, Asian race, prepandemic rapid kidney function decline, and COVID-19 were all associated with higher odds of rapid kidney function decline in the pandemic. These findings suggest close monitoring is warranted for individuals with CKD and COVID-19.

Project description:Genome-wide association studies (GWASs) have reported numerous associations between risk variants and Alzheimer's disease (AD). However, these associations do not necessarily indicate a causal relationship. If the risk variants can be demonstrated to be biologically functional, the possibility of a causal relationship would be increased. In this article, we reviewed all of the published GWASs to extract the genome-wide significant (p < 5×10-8) and replicated associations between risk variants and AD or AD-biomarkers. The regulatory effects of these risk variants on the expression of a novel class of non-coding RNAs (piRNAs) and protein-coding RNAs (mRNAs), the alteration of proteins caused by these variants, the associations between AD and these variants in our own sample, the expression of piRNAs, mRNAs and proteins in human brains targeted by these variants, the expression correlations between the risk genes and APOE, the pathways and networks that the risk genes belonged to, and the possible long non-coding RNAs (LncRNAs) that might regulate the risk genes were analyzed, to investigate the potential biological functions of the risk variants and explore the potential mechanisms underlying the SNP-AD associations. We found replicated and significant associations for AD or AD-biomarkers, surprisingly, only at 17 SNPs located in 11 genes/snRNAs/LncRNAs in eight genomic regions. Most of these 17 SNPs enriched some AD-related pathways or networks, and were potentially functional in regulating piRNAs and mRNAs; some SNPs were associated with AD in our sample, and some SNPs altered protein structures. Most of the protein-coding genes regulated by the risk SNPs were expressed in human brain and correlated with APOE expression. We conclude that these variants were most robust risk markers for AD, and their contributions to AD risk was likely to be causal. As expected, APOE and the lipoprotein metabolism pathway possess the highest weight among these contributions.

Dataset Information

Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline.

Publications

Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets