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Title: New Susceptibility Loci Associated with Kidney Disease in Type 1 Diabetes
Authors: Sandholm N.
Salem R.M.
McKnight A.J.
Brennan E.P.
Forsblom C.
Isakova T.
McKay G.J.
Williams W.W.
Sadlier D.M.
Mäkinen V.-P.
Swan E.J.
Palmer C.
Boright A.P.
Ahlqvist E.
Deshmukh H.A.
Keller B.J.
Huang H.
Ahola A.J.
Fagerholm E.
Gordin D.
Harjutsalo V.
He B.
Heikkilä O.
Hietala K.
Kytö J.
Lahermo P.
Lehto M.
Lithovius R.
Österholm A.-M.
Parkkonen M.
Pitkäniemi J.
Rosengård-Bärlund M.
Saraheimo M.
Sarti C.
Söderlund J.
Soro-Paavonen A.
Syreeni A.
Thorn L.M.
Tikkanen H.
Tolonen N.
Tryggvason K. 
Tuomilehto J.
Wadén J.
Gill G.V.
Prior S.
Guiducci C.
Mirel D.B.
Taylor A.
Hosseini S.M.
Parving H.-H.
Rossing P.
Tarnow L.
Ladenvall C.
Alhenc-Gelas F.
Lefebvre P.
Rigalleau V.
Roussel R.
Tregouet D.-A.
Maestroni A.
Maestroni S.
Falhammar H.
Gu T.
Möllsten A.
Cimponeriu D.
Ioana M.
Mota M.
Mota E.
Serafinceanu C.
Stavarachi M.
Hanson R.L.
Nelson R.G.
Kretzler M.
Colhoun H.M.
Panduru N.M.
Gu H.F.
Brismar K.
Zerbini G.
Hadjadj S.
Marre M.
Groop L.
Lajer M.
Bull S.B.
Waggott D.
Paterson A.D.
Savage D.A.
Bain S.C.
Martin F.
Hirschhorn J.N.
Godson C.
Florez J.C.
Groop P.-H.
Maxwell A.P.
Böger C.A.
Keywords: transforming growth factor beta1
AFF3 gene
chromosome 15q
diabetic nephropathy
ERBB4 gene
gene expression
gene locus
genetic association
genetic susceptibility
insulin dependent diabetes mellitus
kidney failure
kidney fibrosis
kidney tubule disorder
MCTP2 gene
quantitative trait locus
RGMA gene
single nucleotide polymorphism
Diabetes Mellitus, Type 1
Diabetic Nephropathies
Genetic Predisposition to Disease
Genome-Wide Association Study
Kidney Failure, Chronic
Kidney Tubules
Nuclear Proteins
Polymorphism, Single Nucleotide
Quantitative Trait Loci
Receptor, Epidermal Growth Factor
Transforming Growth Factor beta1
Issue Date: 2012
Citation: Sandholm N., Salem R.M., McKnight A.J., Brennan E.P., Forsblom C., Isakova T., McKay G.J., Williams W.W., Sadlier D.M., Mäkinen V.-P., Swan E.J., Palmer C., Boright A.P., Ahlqvist E., Deshmukh H.A., Keller B.J., Huang H., Ahola A.J., Fagerholm E., Gordin D., Harjutsalo V., He B., Heikkilä O., Hietala K., Kytö J., Lahermo P., Lehto M., Lithovius R., Österholm A.-M., Parkkonen M., Pitkäniemi J., Rosengård-Bärlund M., Saraheimo M., Sarti C., Söderlund J., Soro-Paavonen A., Syreeni A., Thorn L.M., Tikkanen H., Tolonen N., Tryggvason K., Tuomilehto J., Wadén J., Gill G.V., Prior S., Guiducci C., Mirel D.B., Taylor A., Hosseini S.M., Parving H.-H., Rossing P., Tarnow L., Ladenvall C., Alhenc-Gelas F., Lefebvre P., Rigalleau V., Roussel R., Tregouet D.-A., Maestroni A., Maestroni S., Falhammar H., Gu T., Möllsten A., Cimponeriu D., Ioana M., Mota M., Mota E., Serafinceanu C., Stavarachi M., Hanson R.L., Nelson R.G., Kretzler M., Colhoun H.M., Panduru N.M., Gu H.F., Brismar K., Zerbini G., Hadjadj S., Marre M., Groop L., Lajer M., Bull S.B., Waggott D., Paterson A.D., Savage D.A., Bain S.C., Martin F., Hirschhorn J.N., Godson C., Florez J.C., Groop P.-H., Maxwell A.P., Böger C.A. (2012). New Susceptibility Loci Associated with Kidney Disease in Type 1 Diabetes. PLoS Genetics 8 (9) : e1002921. ScholarBank@NUS Repository.
Rights: Attribution 4.0 International
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-?1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1×10-7), 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. © 2012 Sandholm et al.
Source Title: PLoS Genetics
ISSN: 15537390
DOI: 10.1371/journal.pgen.1002921
Rights: Attribution 4.0 International
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