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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

Ahluwalia, Tarunveer S.; Schulz, Christina Alexandra LU ; Waage, Johannes; Skaaby, Tea; Sandholm, Niina; van Zuydam, Natalie; Charmet, Romain; Bork-Jensen, Jette; Almgren, Peter LU and Thuesen, Betina H., et al. (2019) In Diabetologia 62(2). p.292-305
Abstract

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... (More)

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.

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published
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keywords
Albuminuria, Diabetes, DKD, Exome chip, Genetics, Genome-wide association study, GWAS, Kidney disease, Rare variant, SKAT, Type 2 diabetes
in
Diabetologia
volume
62
issue
2
pages
292 - 305
publisher
Springer
external identifiers
  • scopus:85058467890
ISSN
0012-186X
DOI
10.1007/s00125-018-4783-z
language
English
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yes
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91eb011c-d9bd-48d6-809b-e1ae5024a452
date added to LUP
2019-01-10 12:17:11
date last changed
2019-02-20 11:42:33
@article{91eb011c-d9bd-48d6-809b-e1ae5024a452,
  abstract     = {<p>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<sup>−11</sup>) 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<sub>interaction</sub> = 7.0 × 10<sup>−4</sup>, 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 (p<sub>Bonferroni</sub> &lt; 2.7 × 10<sup>−6</sup>). 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.</p>},
  author       = {Ahluwalia, Tarunveer S. and Schulz, Christina Alexandra and Waage, Johannes and Skaaby, Tea and Sandholm, Niina and van Zuydam, Natalie and Charmet, Romain and Bork-Jensen, Jette and Almgren, Peter and Thuesen, Betina H. and Bedin, Mathilda and Brandslund, Ivan and Christensen, Cramer K. and Linneberg, Allan and Ahlqvist, Emma and Groop, Per Henrik and Hadjadj, Samy and Tregouet, David Alexandre and Jørgensen, Marit E. and Grarup, Niels and Pedersen, Oluf and Simons, Matias and Groop, Leif and Orho-Melander, Marju and McCarthy, Mark I. and Melander, Olle and Rossing, Peter and Kilpeläinen, Tuomas O. and Hansen, Torben},
  issn         = {0012-186X},
  keyword      = {Albuminuria,Diabetes,DKD,Exome chip,Genetics,Genome-wide association study,GWAS,Kidney disease,Rare variant,SKAT,Type 2 diabetes},
  language     = {eng},
  number       = {2},
  pages        = {292--305},
  publisher    = {Springer},
  series       = {Diabetologia},
  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},
  url          = {http://dx.doi.org/10.1007/s00125-018-4783-z},
  volume       = {62},
  year         = {2019},
}