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

• Published in: Diabetologia
• Main Authors: Ahluwalia, Tarunveer, Schulz, Christina-Alexandra, Waage, Johannes, Skaaby, Tea, Sandholm, Niina, Van Zuydam, Natalie, Charmet, Romain, Bork-Jensen, Jette, Almgren, Peter, Thuesen, Betina, Bedin, Mathilda, Brandslund, Ivan, Christensen, Cramer, Linneberg, Allan, Ahlqvist, Emma, Groop, Per-Henrik, Hadjadj, Samy, Trégouët, David-Alexandre, Jorgensen, Marit, Grarup, Niels, Pedersen, Oluf, Simons, Matias, Groop, Leif, Orho-Melander, Marju, McCarthy, Mark, Melander, Olle, Rossing, Peter, Kilpeläinen, Tuomas, Hansen, Torben
• Other Authors: IT University of Copenhagen, Lund University Lund, University of Helsinki, Nuffield Department of Medicine Oxford, UK (Big Data Institute), University of Oxford Oxford, The Wellcome Trust Centre for Human Genetics Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière AP-HP, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Monash University Melbourne, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre hospitalier universitaire de Nantes (CHU Nantes), University of Southern Denmark (SDU), Institute for Molecular Medicine Finland Helsinki (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki-University of Helsinki
• Format: Article in Journal/Newspaper
• Language: English
• Published: HAL CCSD 2019
• Subjects: Genome-wide association study; Kidney disease; Genetics; Albuminuria; DKD; Diabetes; Exome chip; GWAS; Rare variant; SKAT; Type 2 diabetes; [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics; [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE]; [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism; Skat; greenlander*
• Online Access: https://hal.sorbonne-universite.fr/hal-01976819; https://hal.sorbonne-universite.fr/hal-01976819/document; https://hal.sorbonne-universite.fr/hal-01976819/file/Ahluwalia2019_Article_ANovelRareCUBNVariantAndThreeA.pdf; https://doi.org/10.1007/s00125-018-4783-z

International audience 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.