New Susceptibility Loci Associated with Kidney Disease in Type 1 Diabetes

Niina Sandholm; Rany M. Salem; Amy Jayne McKnight; Eoin P. Brennan; Carol Forsblom; Tamara Isakova; Gareth J. McKay; Winfred W. Williams; Denise M. Sadlier; Ville-Petteri Makinen; Elizabeth J. Swan; Cameron Palmer; Andrew P. Boright; Emma Ahlqvist; Harshal A. Deshmukh; Benjamin J. Keller; Huateng Huang; Aila J. Ahola; Emma Fagerholm; Daniel Gordin; Valma Harjutsalo; Bing He; Outi Heikkila; Kustaa Hietala; Janne Kyto; Paivi Lahermo; Markku Lehto; Raija Lithovius; Anne-May Osterholm; Maija Parkkonen; Janne Pitkaniemi; Milla Rosengard-Barlund; Markku Saraheimo; Cinzia Sarti; Jenny Soderlund; Aino Soro-Paavonen; Anna Syreeni; Lena M. Thorn; Heikki Tikkanen; Nina Tolonen; Karl Tryggvason; Jaakko Tuomilehto; Johan Waden; Geoffrey V. Gill; Sarah Prior; Candace Guiducci; Daniel B. Mirel; Andrew Taylor; S. Mohsen Hosseini; Hans-Henrik Parving; Peter Rossing; Lise Tarnow; Claes Ladenvall; Francois Alhenc-Gelas; Pierre Lefebvre; Vincent Rigalleau; Ronan Roussel; David-Alexandre Tregouet; Anna Maestroni; Silvia Maestroni; Henrik Falhammar; Tianwei Gu; Anna Mollsten; Danut Cimponeriu; Mihai Ioana; Maria Mota; Eugen Mota; Cristian Serafinceanu; Monica Stavarachi; Robert L. Hanson; Robert G. Nelson; Matthias Kretzler; Helen M. Colhoun; Nicolae Mircea Panduru; Harvest F. Gu; Kerstin Brismar; Gianpaolo Zerbini; Samy Hadjadj; Michel Marre; Leif Groop; Maria Lajer; Shelley B. Bull; Daryl Waggott; Andrew D. Paterson; David A. Savage; Stephen C. Bain; Finian Martin; Joel N. Hirschhorn; Catherine Godson; Jose C. Florez; Per-Henrik Groop; Alexander P. Maxwell; DCCT-EDIC Res Grp

doi:10.1371/journal.pgen.1002921

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New Susceptibility Loci Associated with Kidney Disease in Type 1 Diabetes

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New Susceptibility Loci Associated with Kidney Disease in Type 1 Diabetes

Niina Sandholm, Rany M. Salem, Amy Jayne McKnight, Eoin P. Brennan, Carol Forsblom, Tamara Isakova, Gareth J. McKay, Winfred W. Williams, Denise M. Sadlier, Ville-Petteri Makinen, …

PLoS genetics, Vol.8(9), pp.e1002921-e1002921

01/09/2012

DOI: https://doi.org/10.1371/journal.pgen.1002921

PMID: 23028342

Abstract

Genetics & Heredity

Life Sciences & Biomedicine

Science & Technology

Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genomewide association studies (GWAS) of T1D DN comprising similar to 2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2 x 10(-8)) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0 x 10(-9)). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-beta 1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1 x 10(-7)), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN.

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Title: New Susceptibility Loci Associated with Kidney Disease in Type 1 Diabetes
Creators - without role: Niina Sandholm - Biomedicum Helsinki, Folkhalsan Res Ctr, Folkhalsan Inst Genet, Helsinki, Finland
Rany M. Salem - Broad Institute
Amy Jayne McKnight - Queens University
Eoin P. Brennan - Supreme Council Of Health
Carol Forsblom - Biomedicum Helsinki, Folkhalsan Res Ctr, Folkhalsan Inst Genet, Helsinki, Finland
Tamara Isakova - University of Miami
Gareth J. McKay - Queens University
Winfred W. Williams - Harvard University
Denise M. Sadlier - Supreme Council Of Health
Ville-Petteri Makinen - Biomedicum Helsinki, Folkhalsan Res Ctr, Folkhalsan Inst Genet, Helsinki, Finland
Elizabeth J. Swan - Queens University
Cameron Palmer - Broad Institute
Andrew P. Boright - University of Toronto
Emma Ahlqvist - Lund University
Harshal A. Deshmukh - University of Dundee
Benjamin J. Keller - Eastern Michigan University
Huateng Huang - Univ Michigan, Div Nephrol, Ann Arbor, MI 48109 USA
Aila J. Ahola - Biomedicum Helsinki, Folkhalsan Res Ctr, Folkhalsan Inst Genet, Helsinki, Finland
Emma Fagerholm - Biomedicum Helsinki, Folkhalsan Res Ctr, Folkhalsan Inst Genet, Helsinki, Finland
Daniel Gordin - Biomedicum Helsinki, Folkhalsan Res Ctr, Folkhalsan Inst Genet, Helsinki, Finland
Valma Harjutsalo - Biomedicum Helsinki, Folkhalsan Res Ctr, Folkhalsan Inst Genet, Helsinki, Finland
Bing He - Karolinska Institutet
Outi Heikkila - Biomedicum Helsinki, Folkhalsan Res Ctr, Folkhalsan Inst Genet, Helsinki, Finland
Kustaa Hietala - Biomedicum Helsinki, Folkhalsan Res Ctr, Folkhalsan Inst Genet, Helsinki, Finland
Janne Kyto - Biomedicum Helsinki, Folkhalsan Res Ctr, Folkhalsan Inst Genet, Helsinki, Finland
Paivi Lahermo - College Station Medical Center
Markku Lehto - Biomedicum Helsinki, Folkhalsan Res Ctr, Folkhalsan Inst Genet, Helsinki, Finland
Raija Lithovius - Biomedicum Helsinki, Folkhalsan Res Ctr, Folkhalsan Inst Genet, Helsinki, Finland
Anne-May Osterholm - Karolinska Institutet
Maija Parkkonen - Biomedicum Helsinki, Folkhalsan Res Ctr, Folkhalsan Inst Genet, Helsinki, Finland
Janne Pitkaniemi - University of Helsinki
Milla Rosengard-Barlund - Biomedicum Helsinki, Folkhalsan Res Ctr, Folkhalsan Inst Genet, Helsinki, Finland
Markku Saraheimo - Biomedicum Helsinki, Folkhalsan Res Ctr, Folkhalsan Inst Genet, Helsinki, Finland
Cinzia Sarti - University of Helsinki
Jenny Soderlund - Biomedicum Helsinki, Folkhalsan Res Ctr, Folkhalsan Inst Genet, Helsinki, Finland
Aino Soro-Paavonen - Biomedicum Helsinki, Folkhalsan Res Ctr, Folkhalsan Inst Genet, Helsinki, Finland
Anna Syreeni - Biomedicum Helsinki, Folkhalsan Res Ctr, Folkhalsan Inst Genet, Helsinki, Finland
Lena M. Thorn - Biomedicum Helsinki, Folkhalsan Res Ctr, Folkhalsan Inst Genet, Helsinki, Finland
Heikki Tikkanen - University of Helsinki
Nina Tolonen - Biomedicum Helsinki, Folkhalsan Res Ctr, Folkhalsan Inst Genet, Helsinki, Finland
Karl Tryggvason - Karolinska Institutet
Jaakko Tuomilehto - Natl Inst Hlth & Welf, Diabet Prevent Unit, Helsinki, Finland
Johan Waden - Biomedicum Helsinki, Folkhalsan Res Ctr, Folkhalsan Inst Genet, Helsinki, Finland
Geoffrey V. Gill - University of Liverpool
Sarah Prior - Swansea University
Candace Guiducci - Broad Institute
Daniel B. Mirel - Broad Institute
Andrew Taylor - Broad Institute
S. Mohsen Hosseini - University of Toronto
Hans-Henrik Parving - University of Copenhagen
Peter Rossing - Univ Aarhus, Fac Hlth Sci, Aarhus, Denmark
Lise Tarnow - Univ Aarhus, Fac Hlth Sci, Aarhus, Denmark
Claes Ladenvall - Lund University
Francois Alhenc-Gelas - Paris Descartes University
Pierre Lefebvre - CHU Sart Tilman, B-4000 Liege, Belgium
Vincent Rigalleau - CHU Bordeaux, Bordeaux, France
Ronan Roussel - Assistance Publique – Hôpitaux de Paris
David-Alexandre Tregouet - Université Paris Cité
Anna Maestroni - Ist Sci San Raffaele, Complicat Diabet Unit, Div Metab & Cardiovasc Sci, I-20132 Milan, Italy
Silvia Maestroni - Ist Sci San Raffaele, Complicat Diabet Unit, Div Metab & Cardiovasc Sci, I-20132 Milan, Italy
Henrik Falhammar - Karolinska Institutet
Tianwei Gu - Karolinska Institutet
Anna Mollsten - Umeå University
Danut Cimponeriu - University of Bucharest
Mihai Ioana - College Station Medical Center
Maria Mota - College Station Medical Center
Eugen Mota - College Station Medical Center
Cristian Serafinceanu - College Station Medical Center
Monica Stavarachi - University of Bucharest
Robert L. Hanson - Phoenix
Robert G. Nelson - NIDDK, Diabet Epidemiol & Clin Res Sect, Phoenix, AZ USA
Matthias Kretzler - College Station Medical Center
Helen M. Colhoun - University of Dundee
Nicolae Mircea Panduru - College Station Medical Center
Harvest F. Gu - Karolinska Institutet
Kerstin Brismar - Karolinska Institutet
Gianpaolo Zerbini - Mylan
Samy Hadjadj - University of Poitiers
Michel Marre - Assistance Publique – Hôpitaux de Paris
Leif Groop - Lund University
Maria Lajer - Steno Diabet Ctr, DK-2820 Gentofte, Denmark
Shelley B. Bull - Lunenfeld-Tanenbaum Research Institute
Daryl Waggott - Lunenfeld-Tanenbaum Research Institute
Andrew D. Paterson - Sick
David A. Savage - Queens University
Stephen C. Bain - Swansea University
Finian Martin - Supreme Council Of Health
Joel N. Hirschhorn - Broad Institute
Catherine Godson - Supreme Council Of Health
Jose C. Florez - Broad Institute
Per-Henrik Groop - Biomedicum Helsinki, Folkhalsan Res Ctr, Folkhalsan Inst Genet, Helsinki, Finland
Alexander P. Maxwell - Queens University
DCCT-EDIC Res Grp
Publication Details: PLoS genetics, Vol.8(9), pp.e1002921-e1002921
Publisher: Public Library Science
Number of pages: 13
Grant note: Signe and Arne Gyllenberg Foundation General Clinical Research Center Program, NCRR Societe Francophone du Diabete Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) TEKES; Finnish Funding Agency for Technology & Innovation (TEKES) 3-2011-70 / Juvenile Diabetes Research Foundation post doctoral fellowship (JDRF) Finska Lakaresallskapet Juvenile Diabetes Research Foundation Novo Nordisk Foundation; Novocure Limited US Ireland R&D partnership award Fibrotech STL/3714/07 / Public Health Agency Diabetes UK Studentship; Diabetes UK Canadian Network of Centres of Excellence in Mathematics Family Erling-Persson Foundation Genome Canada through the Ontario Genomics Institute; Genome Canada Association Francaise des Diabetiques Northern Ireland Research Development office Danish Diabetes Association European Union's Seventh Framework Program (FP7) for the Innovative Medicine Initiative Sigrid Juselius Foundation N01-DK-6-2204; R01-DK-077510 / National Institute of Diabetes and Digestive and Kidney Diseases; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) Health Research Board Ireland; Health Research Board - Ireland National Institute of Diabetes, Endocrinology, and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Folkhalsan Research Foundation R01 DK081923 / NIH NIDDK; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) French Ministry of Health (Programmes Hospitaliers de Recherche Clinique) SFI/08/US/B1517 / Science Foundation Ireland Sehested Hansen Foundation Diabetes UK Hoffman La Roche Swedish Medical Research Council; Swedish Medical Research Council (SMRC) Wilhelm and Else Stockmann Foundation Knut and Alice Wallengberg Foundation ENGAGE 10/0004154 / Diabetes UK IMI/115006 / European Union's Seventh Framework Program (FP7) for the Innovative Medicine Initiative Orion-Farmos Research Foundation Swedish Diabetes Society Foundation QLG2-CT-2001-01669 / European Commission; European Commission Joint Research Centre Helsinki University Central Hospital Research Funds (EVO) Liv och Halsa Foundation
Identifiers: 9936968408331
Academic Unit: King Abdulaziz University
Language: English
Resource Type: Journal article