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The Genetic Landscape of Renal Complications in Type 1 Diabetes.

ABSTRACT: Diabetes is the leading cause of ESRD. Despite evidence for a substantial heritability of diabetic kidney disease, efforts to identify genetic susceptibility variants have had limited success. We extended previous efforts in three dimensions, examining a more comprehensive set of genetic variants in larger numbers of subjects with type 1 diabetes characterized for a wider range of cross-sectional diabetic kidney disease phenotypes. In 2843 subjects, we estimated that the heritability of diabetic kidney disease was 35% (P=6.4×10-3). Genome-wide association analysis and replication in 12,540 individuals identified no single variants reaching stringent levels of significance and, despite excellent power, provided little independent confirmation of previously published associated variants. Whole-exome sequencing in 997 subjects failed to identify any large-effect coding alleles of lower frequency influencing the risk of diabetic kidney disease. However, sets of alleles increasing body mass index (P=2.2×10-5) and the risk of type 2 diabetes (P=6.1×10-4) associated with the risk of diabetic kidney disease. We also found genome-wide genetic correlation between diabetic kidney disease and failure at smoking cessation (P=1.1×10-4). Pathway analysis implicated ascorbate and aldarate metabolism (P=9.0×10-6), and pentose and glucuronate interconversions (P=3.0×10-6) in pathogenesis of diabetic kidney disease. These data provide further evidence for the role of genetic factors influencing diabetic kidney disease in those with type 1 diabetes and highlight some key pathways that may be responsible. Altogether these results reveal important biology behind the major cause of kidney disease.

SUBMITTER: Sandholm N

PROVIDER: S-EPMC5280020 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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The Genetic Landscape of Renal Complications in Type 1 Diabetes.

Sandholm Niina N Van Zuydam Natalie N Ahlqvist Emma E Juliusdottir Thorhildur T Deshmukh Harshal A HA Rayner N William NW Di Camillo Barbara B Forsblom Carol C Fadista Joao J Ziemek Daniel D Salem Rany M RM Hiraki Linda T LT Pezzolesi Marcus M Trégouët David D Dahlström Emma E Valo Erkka E Oskolkov Nikolay N Ladenvall Claes C Marcovecchio M Loredana ML Cooper Jason J Sambo Francesco F Malovini Alberto A Manfrini Marco M McKnight Amy Jayne AJ Lajer Maria M Harjutsalo Valma V Gordin Daniel D Parkkonen Maija M Tuomilehto Jaakko J Lyssenko Valeriya V McKeigue Paul M PM Rich Stephen S SS Brosnan Mary Julia MJ Fauman Eric E Bellazzi Riccardo R Rossing Peter P Hadjadj Samy S Krolewski Andrzej A Paterson Andrew D AD Florez Jose C JC Hirschhorn Joel N JN Maxwell Alexander P AP Dunger David D Cobelli Claudio C Colhoun Helen M HM Groop Leif L McCarthy Mark I MI Groop Per-Henrik PH

Journal of the American Society of Nephrology : JASN 20160919 2

Diabetes is the leading cause of ESRD. Despite evidence for a substantial heritability of diabetic kidney disease, efforts to identify genetic susceptibility variants have had limited success. We extended previous efforts in three dimensions, examining a more comprehensive set of genetic variants in larger numbers of subjects with type 1 diabetes characterized for a wider range of cross-sectional diabetic kidney disease phenotypes. In 2843 subjects, we estimated that the heritability of diabetic ...[more]

PMID: 27647854

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Project description:Background and objectivesWe investigated the association of urinary potassium and sodium excretion with the incidence of renal failure and cardiovascular disease in patients with type 2 diabetes.Design, setting, participants, & measurementsA total of 623 Japanese type 2 diabetic patients with eGFR≥60 ml/min per 1.73 m(2) were enrolled in this observational follow-up study between 1996 and 2003 and followed-up until 2013. At baseline, a 24-hour urine sample was collected to estimate urinary potassium and sodium excretion. The primary end point was renal and cardiovascular events (RRT, myocardial infarction, angina pectoris, stroke, and peripheral vascular disease). The secondary renal end points were the incidence of a 50% decline in eGFR, progression to CKD stage 4 (eGFR<30 ml/min per 1.73 m(2)), and the annual decline rate in eGFR.ResultsDuring the 11-year median follow-up period, 134 primary end points occurred. Higher urinary potassium excretion was associated with lower risk of the primary end point, whereas urinary sodium excretion was not. The adjusted hazard ratios for the primary end point in Cox proportional hazards analysis were 0.56 (95% confidence interval [95% CI], 0.33 to 0.95) in the third quartile of urinary potassium excretion (2.33-2.90 g/d) and 0.33 (95% CI, 0.18 to 0.62) in the fourth quartile (>2.90 g/d) compared with the lowest quartile (<1.72 g/d). Similar associations were observed for the secondary renal end points. The annual decline rate in eGFR in the fourth quartile of urinary potassium excretion (-1.3 ml/min per 1.73 m(2)/y; 95% CI, -1.5 to -1.0) was significantly slower than those in the first quartile (-2.2; 95% CI, -2.4 to -1.8).ConclusionsHigher urinary potassium excretion was associated with the slower decline of renal function and the lower incidence of cardiovascular complications in type 2 diabetic patients with normal renal function. Interventional trials are necessary to determine whether increasing dietary potassium is beneficial.

Project description:Adherence to evidence-based cardiovascular risk factor targets in patients with type 2 diabetes and microalbuminuria has shown long-term reduction in mortality and morbidity. Strategies to achieve such adherence have been delivered at individual patient level and are not cost-effective. Health care professional-level intervention has the potential to promote better adherence at lower cost.The aim of this study was to assess the effectiveness of a multifactorial technology-driven intervention comprising health care professional training, a software prompt installed on practice systems, clinician email support, and enhanced performance and feedback reporting.A cluster randomized trial will be performed where the primary outcome is the proportion of eligible patients meeting tight cardiovascular risk factor targets, including systolic and diastolic blood pressure (BP; BP<130/80 mm Hg) and total cholesterol (TC; TC<3.5 mmol/L) at 24 months. Secondary outcomes include proportion of patients with glycated hemoglobin (HbA1c) <58 mmol/mol (7.5%), change in medication prescribing, changes in microalbuminuria and renal function (estimated glomerular filtration rate, eGFR), incidence of major adverse CV events and mortality, and coding accuracy. Cost-effectiveness of the intervention will also be assessed.Among 2721 eligible patients, mean age was 62.9 (SD 10.0) years, and duration of diabetes was 10.46 (SD 7.22) years. Mean HbA1c was 59.3 (SD 17.4) mmol/mol; mean systolic and diastolic BP (mm Hg) were 134.3 (SD 14.6) and 76.1 (SD 9.5) mm Hg, respectively; and mean TC was 4.1 (SD 0.98) mmol/L. Overall, 131 out of 2721 (4.81%) patients achieved all 3 "tight" cardiovascular risk factor targets. Cardiovascular risk factor burden increased two-fold in those with eGFR<60 mL/min/1.73 m2 compared with those with eGFR≥60 mL/min/1.73 m2. Prevalence of microalbuminuria was 22.76%. In total, 1076 out of 2721 (39.54%) patients were coded for microalbuminuria or proteinuria on their primary care medical record.The general practitioner prompt study is the largest UK primary care-based, technology-driven, randomized controlled trial to support intensive intervention in high-risk group of multiethnic individuals with type 2 diabetes and microalbuminuria. This paper provides contemporary estimates for prevalent cardiovascular disease and adherence to evidence-based cardiovascular risk factor targets at baseline in a population with type 2 diabetes and microalbuminuria. The main trial results, including cost-effectiveness data, will be submitted for publication in 2018.International Standard Randomized Controlled Trial Number ISRCTN14918517; http://www.isrctn.com/ISRCTN14918517 (Archived by WebCite at http://www.webcitation.org/6zqm53wNA).RR1-10.2196/9588.

Dataset Information

The Genetic Landscape of Renal Complications in Type 1 Diabetes.

Publications

The Genetic Landscape of Renal Complications in Type 1 Diabetes.

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