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

Tarunveer S Ahluwalia, Christina-Alexandra Schulz, Johannes Waage, Tea Skaaby, Niina Sandholm, Natalie van Zuydam, Romain Charmet, Jette Bork-Jensen, Peter Almgren, Betina H Thuesen, Mathilda Bedin, Ivan Brandslund, Cramer K Christensen, Allan Linneberg, Emma Ahlqvist, Per-Henrik Groop, Samy Hadjadj, David-Alexandre Tregouet, Marit E Jørgensen, Niels GrarupOluf Pedersen, Matias Simons, Leif Groop, Marju Orho-Melander, Mark I McCarthy, Olle Melander, Peter Rossing, Tuomas O Kilpeläinen, Torben Hansen

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AIMS/HYPOTHESIS: Identifying 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.

METHODS: We 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.

RESULTS: We identified a rare (minor allele frequency [MAF]: 0.8%) missense (A1690V) variant in CUBN (rs141640975, β = 0.27, p = 1.3 × 10-11) 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 (pinteraction = 7.0 × 10-4, β with diabetes = 0.69, β 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 (pBonferroni < 2.7 × 10-6).

CONCLUSIONS/INTERPRETATION: The current study identifies a rare coding variant in the CUBN locus and other potential genes associated with albuminuria in individuals with and without diabetes. These genes have been implicated in renal and cardiovascular dysfunction. The findings provide new insights into the genetic architecture of albuminuria and highlight target genes and pathways for the prevention of diabetes-related kidney disease.

OriginalsprogEngelsk
TidsskriftDiabetologia
Vol/bind62
Udgave nummer2
Sider (fra-til)292-305
ISSN0012-186X
DOI
StatusUdgivet - feb. 2019

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