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Abstract: FR-PO431

Exome Wide Association Study Identifies a Rare Coding Variant in Cubilin Gene and Suggestive Variants in Additional Genes Associated with Albuminuria Among 33,985 Europeans with and Without Diabetes

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Ahluwalia, Tarunveer S., Steno Diabetes Center Copenhagen, Gentofte, Denmark
  • Schulz, Christina-Alexandra, Lund University, Malmö, Sweden
  • Skaaby, Tea, Center for Clinical Research and Prevention, Bipebjerg and Frederiksberg Hospital, The Capital Region, Copenhagen, Denmark
  • Sandholm, Niina, Folkhalsan Institute of Genetics, Folkhalsan Research Center, Helsinki, Finland
  • Bork-Jensen, Jette, Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, University of Copenhagen, Copenhagen, Denmark
  • Van zuydam, Natalie R., Wellcome Center Human Genetics, University of Oxford, Oxford, United Kingdom
  • Almgren, Peter, Lund University, Malmö, Sweden
  • Thuesen, Betina H., Center for Clinical Research and Prevention, Bipebjerg and Frederiksberg Hospital, The Capital Region, Copenhagen, Denmark
  • Jørgensen, Marit Eika, Steno Diabetes Center Copenhagen, Gentofte, Denmark
  • Brandslund, Ivan, Lillebaelt hospital,University of South Denmark, Vejle, Denmark
  • Christensen, Cramer Kjeldahl, Lillebaelt Hospital, Horsens, Denmark
  • Linneberg, Allan, Center for Clinical Research and Prevention, Bipebjerg and Frederiksberg Hospital, The Capital Region, Copenhagen, Denmark
  • Ahlqvist, Emma, Lund University, Malmö, Sweden
  • Groop, Per-Henrik, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
  • Hadjadj, Samy, CHU Poitiers, CIC and Endocrinology Department, Poitiers, France
  • Groop, Leif, Lund University, Malmö, Sweden
  • Grarup, Niels, Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, University of Copenhagen, Copenhagen, Denmark
  • Orho-Melander, Marju, Lund University, Malmö, Sweden
  • McCarthy, Mark, Wellcome Center Human Genetics, University of Oxford, Oxford, United Kingdom
  • Melander, Olle, Lund University, Malmö, Sweden
  • Rossing, Peter, Steno Diabetes Center Copenhagen, Gentofte, Denmark
  • Kilpelainen, Tuomas O., Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, University of Copenhagen, Copenhagen, Denmark
  • Hansen, Torben, Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, University of Copenhagen, Copenhagen, Denmark
Background

Identification of rare coding variants associated with albuminuria may provide new options for preventing chronic kidney disease (CKD) and end-stage renal failure, especially in diabetic patients. With the increasing burden of CKD reaching about 15% in the US, efforts to identify underlying genetic factors for albuminuria have been limited, majority focusing just common variants.

Methods


We performed an exome-wide association study to identify coding variants in a two-phase (discovery and replication) approach employing 33,985 individuals of European ancestry (15,872 with and 18,111 without diabetes). Additive genetic models using linear regression on natural log transformed Albuminuria levels was performed for 263,894 single nucleotide polymorphisms (SNPs), adjusted for age, sex, and population substructure. Meta analyses conducted using fixed effects inverse variance method.

Results

We identify a rare (MAF: 0.8%) missense variant in Cubilin gene (CUBN, p=1.3 × 10-11) associated with albuminuria in the combined European (EUR) meta-analyses. The rare CUBN variant had 3 times stronger effect in individuals with diabetes compared to those without (pinteraction: 5.4 × 10-4, βDM: 0.69, βnonDM: 0.20) in the discovery meta-analyses. This CUBN rare variant is an independent signal for albuminuria after conditional analyses with the previously known albuminuria common SNP (LD: r2 = 0.0002, D’ = 1.0, pcondition: 8.5 × 10-7). Gene-aggregate tests based on rare (MAF<0.01) and common variants suggest three additional genes associated with albuminuria (HES1, CDC73, and GRM5) after correction for multiple testing (p_bonferroni<2.7 × 10-6).

Conclusion

The current study identifies a rare coding variant in the CUBN locus and suggestive variants in 3 other genes associated with albuminuria in individuals with and without diabetes, implicated in renal dysfunction. These highlight novel genes and pathways as potential targets towards diabetes related kidney disease prevention.

Funding

  • Private Foundation Support