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PMID: 23028342 Published · ppublish English Journal Article Meta-Analysis Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

New susceptibility loci associated with kidney disease in type 1 diabetes.

PLoS genetics ·Vol. 8 ·No. 9 ·2012-09-00 ·Pages e1002921

Sandholm N, Salem RM, McKnight AJ, Brennan EP, Forsblom C, Isakova T, McKay GJ, Williams WW, Sadlier DM, Mäkinen VP, Swan EJ, Palmer C, Boright AP, Ahlqvist E, Deshmukh HA, Keller BJ, Huang H, Ahola AJ, Fagerholm E, Gordin D, Harjutsalo V, He B, Heikkilä O, Hietala K, Kytö J, Lahermo P, Lehto M, Lithovius R, Osterholm AM, Parkkonen M, Pitkäniemi J, Rosengård-Bärlund M, Saraheimo M, Sarti C, Söderlund J, Soro-Paavonen A, Syreeni A, Thorn LM, Tikkanen H, Tolonen N, Tryggvason K, Tuomilehto J, Wadén J, Gill GV, Prior S, Guiducci C, Mirel DB, Taylor A, Hosseini SM, DCCT/EDIC Research Group, Parving HH, Rossing P, Tarnow L, Ladenvall C, Alhenc-Gelas F, Lefebvre P, Rigalleau V, Roussel R, Tregouet DA, Maestroni A, Maestroni S, Falhammar H, Gu T, Möllsten A, Cimponeriu D, Ioana M, Mota M, Mota E, Serafinceanu C, Stavarachi M, Hanson RL, Nelson RG, Kretzler M, Colhoun HM, Panduru NM, Gu HF, Brismar K, Zerbini G, Hadjadj S, Marre M, Groop L, Lajer M, Bull SB, Waggott D, Paterson AD, Savage DA, Bain SC, Martin F, Hirschhorn JN, Godson C, Florez JC, Groop PH, Maxwell AP

Abstract

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 genome-wide association studies (GWAS) of T1D DN comprising ~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 × 10(-8)) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0 × 10(-9)). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-β1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1 × 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.

MeSH Terms
Diabetes Mellitus, Type 1/complications,genetics Diabetic Nephropathies/etiology,genetics,pathology ErbB Receptors/genetics Fibrosis/genetics,metabolism Genetic Predisposition to Disease Genome-Wide Association Study Humans Kidney Failure, Chronic/etiology,genetics,pathology Kidney Tubules/metabolism,pathology Nuclear Proteins/genetics Polymorphism, Single Nucleotide Quantitative Trait Loci/genetics Receptor, ErbB-4 Transforming Growth Factor beta1/genetics,metabolism
Chemicals
AFF3 protein, human Nuclear Proteins Transforming Growth Factor beta1 ERBB4 protein, human ErbB Receptors Receptor, ErbB-4
Authors & Affiliations
93 authors, click to expand affiliations / ORCID
Sandholm Niina
Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland.
Salem Rany M
McKnight Amy Jayne
Brennan Eoin P
Forsblom Carol
Isakova Tamara
McKay Gareth J
Williams Winfred W
Sadlier Denise M
Mäkinen Ville-Petteri
Swan Elizabeth J
Palmer Cameron
Boright Andrew P
Ahlqvist Emma
Deshmukh Harshal A
Keller Benjamin J
Huang Huateng
Ahola Aila J
Fagerholm Emma
Gordin Daniel
Harjutsalo Valma
He Bing
Heikkilä Outi
Hietala Kustaa
Kytö Janne
Lahermo Päivi
Lehto Markku
Lithovius Raija
Osterholm Anne-May
Parkkonen Maija
Pitkäniemi Janne
Rosengård-Bärlund Milla
Saraheimo Markku
Sarti Cinzia
Söderlund Jenny
Soro-Paavonen Aino
Syreeni Anna
Thorn Lena M
Tikkanen Heikki
Tolonen Nina
Tryggvason Karl
Tuomilehto Jaakko
Wadén Johan
Gill Geoffrey V
Prior Sarah
Guiducci Candace
Mirel Daniel B
Taylor Andrew
Hosseini S Mohsen
DCCT/EDIC Research Group
Parving Hans-Henrik
Rossing Peter
Tarnow Lise
Ladenvall Claes
Alhenc-Gelas François
Lefebvre Pierre
Rigalleau Vincent
Roussel Ronan
Tregouet David-Alexandre
Maestroni Anna
Maestroni Silvia
Falhammar Henrik
Gu Tianwei
Möllsten Anna
Cimponeriu Danut
Ioana Mihai
Mota Maria
Mota Eugen
Serafinceanu Cristian
Stavarachi Monica
Hanson Robert L
Nelson Robert G
Kretzler Matthias
Colhoun Helen M
Panduru Nicolae Mircea
Gu Harvest F
Brismar Kerstin
Zerbini Gianpaolo
Hadjadj Samy
Marre Michel
Groop Leif
Lajer Maria
Bull Shelley B
Waggott Daryl
Paterson Andrew D
Savage David A
Bain Stephen C
Martin Finian
Hirschhorn Joel N
Godson Catherine
Florez Jose C
Groop Per-Henrik
Maxwell Alexander P
Conflict of Interest

JC Florez has received consulting honoraria from Novartis, Lilly, and Pfizer. M Kretzler received grant support from Hoffman La Roche and Fibrotech. P-H Groop has received lecture honorariums from Abbot, Boehringer Ingelheim, Cebix, Eli Lilly, Genzyme, Novartis, Novo Nordisk, MSD, and research grants from Eli Lilly and Roche. P-H Groop is also an advisory board member of Boehringer Ingelheim and Novartis.

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Article Info
Journal
PLoS genetics
Abbr.
PLoS Genet
ISSN
1553-7404
DOI
10.1371/journal.pgen.1002921
Published
2012-09-00
Epub
2012-00-20
Pages
e1002921
Language
English
Region
United States
NLM ID
101239074
PMCID
PMC3447939
Subset
IM
Grants
Medical Research Council · MR/K003364/1 · United Kingdom
NIDDK NIH HHS · R01 DK077510 · United States
NIDDK NIH HHS · R01 DK081923 · United States
Diabetes UK · 10/0004154 · United Kingdom
NIDDK NIH HHS · R01-DK-077510 · United States
NIDDK NIH HHS · N01-DK-6-2204 · United States
CIHR · Canada
PHS HHS · NIH NIDDK R01 DK081923 · United States
NIDDK NIH HHS · K23 DK087858 · United States
Corrections
CommentIn
PMID: 23028380
External Links
PubMed source DOI: 10.1371/journal.pgen.1002921 PMC Full Text View journal details
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