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Public Library of Science, PLoS Genetics, 9(8), p. e1002921, 2012

DOI: 10.1371/journal.pgen.1002921

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New Susceptibility Loci Associated with Kidney Disease in Type 1 Diabetes

Journal article published in 2012 by Anne-May Österholm, Gianpaolo Zerbini, Rany M. Salem, Amy Jayne McKnight, Niina Sandholm, Gareth J. McKay, Winfred W. Williams, Denise M. Sadlier, Ville-Petteri Makinen, Salem Rm, Ville-Petteri Mäkinen, Elizabeth J. Swan, Benjamin J. Keller, Anne-May Osterholm, Janne Kytö and other authors.
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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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 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.