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

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...

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Bibliographic Details
Published in:Diabetologia
Main Authors: 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
Other Authors: 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
Format: Article in Journal/Newspaper
Language:English
Published: Springer 2019
Subjects:
DKD
Online Access:http://hdl.handle.net/10138/298740
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Summary: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) Peer reviewed