A novel rare CUBN variant and three additional genes identified in Europeans with and without diabetes : results from an exome-wide association study of albuminuria

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Ahluwalia , T S , Schulz , C-A , Waage , J , Skaaby , T , Sandholm , N , van Zuydam , N , Charmet , R , Bork-Jensen , J , Almgren , P , Thuesen , B H , Bedin , M , Brandslund , I , Christensen , C K , Linneberg , A , Ahlqvist , E , Groop , P-H , Hadjadj , S , Tregouet , D-A , Jorgensen , M E , Grarup , N , Pedersen , O , Simons , M , Groop , L , Orho-Melander , M , McCarthy , M I , Melander , O , Rossing , P , Kilpeläinen , T O & Hansen , T 2019 , ' A novel rare CUBN variant and three additional genes identified in Europeans with and without diabetes : results from an exome-wide association study of albuminuria ' , Diabetologia , vol. 62 , no. 2 , pp. 292-305 . https://doi.org/10.1007/s00125-018-4783-z

Title: A novel rare CUBN variant and three additional genes identified in Europeans with and without diabetes : results from an exome-wide association study of albuminuria
Author: Ahluwalia, Tarunveer S.; Schulz, Christina-Alexandra; Waage, Johannes; Skaaby, Tea; Sandholm, Niina; van Zuydam, Natalie; Charmet, Romain; Bork-Jensen, Jette; Almgren, Peter; Thuesen, Betina H.; Bedin, Mathilda; Brandslund, Ivan; Christensen, Cramer K.; Linneberg, Allan; Ahlqvist, Emma; Groop, Per-Henrik; Hadjadj, Samy; Tregouet, David-Alexandre; Jorgensen, Marit E.; Grarup, Niels; Pedersen, Oluf; Simons, Matias; Groop, Leif; Orho-Melander, Marju; McCarthy, Mark I.; Melander, Olle; Rossing, Peter; Kilpeläinen, Tuomas O.; Hansen, Torben
Contributor organization: Clinicum
Research Programs Unit
Nefrologian yksikkö
Diabetes and Obesity Research Program
Department of Medicine
Per Henrik Groop / Principal Investigator
Centre of Excellence in Complex Disease Genetics
Institute for Molecular Medicine Finland
University of Helsinki
HUS Abdominal Center
Date: 2019-02
Language: eng
Number of pages: 14
Belongs to series: Diabetologia
ISSN: 0012-186X
DOI: https://doi.org/10.1007/s00125-018-4783-z
URI: http://hdl.handle.net/10138/298740
Abstract: Aims/hypothesisIdentifying rare coding variants associated with albuminuria may open new avenues for preventing chronic kidney disease and end-stage renal disease, which are highly prevalent in individuals with diabetes. Efforts to identify genetic susceptibility variants for albuminuria have so far been limited, with the majority of studies focusing on common variants.MethodsWe performed an exome-wide association study to identify coding variants in a two-stage (discovery and replication) approach. Data from 33,985 individuals of European ancestry (15,872 with and 18,113 without diabetes) and 2605 Greenlanders were included.ResultsWe identified a rare (minor allele frequency [MAF]: 0.8%) missense (A1690V) variant in CUBN (rs141640975, =0.27, p=1.3x10(-11)) associated with albuminuria as a continuous measure in the combined European meta-analysis. The presence of each rare allele of the variant was associated with a 6.4% increase in albuminuria. The rare CUBN variant had an effect that was three times stronger in individuals with type 2 diabetes compared with those without (p(interaction)=7.0x10(-4), with diabetes=0.69, without diabetes=0.20) in the discovery meta-analysis. Gene-aggregate tests based on rare and common variants identified three additional genes associated with albuminuria (HES1, CDC73 and GRM5) after multiple testing correction (p(Bonferroni)
Subject: Albuminuria
Diabetes
DKD
Exome chip
Genetics
Genome-wide association study
Kidney disease
GWAS
Rare variant
SKAT
Type 2 diabetes
GENOME-WIDE
KIDNEY-DISEASE
RISK
REVEALS
LOCI
METAANALYSIS
PROTECTION
RECEPTORS
DISCOVERY
FRAMEWORK
3121 General medicine, internal medicine and other clinical medicine
3111 Biomedicine
1184 Genetics, developmental biology, physiology
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion


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