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 & 31 others 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, Helen M. Colhoun, Andrew D. Paterson, DCCT-EDIC Res Grp

    Research output: Contribution to journalArticle

    134 Citations (Scopus)

    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.

    Original languageEnglish
    Article numbere1002921
    Number of pages13
    JournalPLoS Genetics
    Volume8
    Issue number9
    DOIs
    Publication statusPublished - 20 Sep 2012

    Keywords

    • GENE
    • RISK
    • NATURAL-HISTORY
    • GENOME-WIDE ASSOCIATION
    • COLLAGEN CHAINS
    • GROWTH-FACTOR
    • RENAL-FUNCTION
    • EXPRESSION
    • NEPHROPATHY
    • AF4/FMR2 FAMILY

    Cite this

    Sandholm, N., Salem, R. M., McKnight, A. J., Brennan, E. P., Forsblom, C., Isakova, T., ... DCCT-EDIC Res Grp (2012). New Susceptibility Loci Associated with Kidney Disease in Type 1 Diabetes. PLoS Genetics, 8(9), [e1002921]. https://doi.org/10.1371/journal.pgen.1002921
    Sandholm, Niina ; Salem, Rany M. ; McKnight, Amy Jayne ; Brennan, Eoin P. ; Forsblom, Carol ; Isakova, Tamara ; McKay, Gareth J. ; Williams, Winfred W. ; Sadlier, Denise M. ; Makinen, 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 ; Heikkila, Outi ; Hietala, Kustaa ; Kyto, Janne ; Lahermo, Paivi ; Lehto, Markku ; Lithovius, Raija ; Osterholm, Anne-May ; Parkkonen, Maija ; Pitkaniemi, Janne ; Rosengard-Barlund, Milla ; Saraheimo, Markku ; Sarti, Cinzia ; Soderlund, Jenny ; Soro-Paavonen, Aino ; Syreeni, Anna ; Thorn, Lena M. ; Tikkanen, Heikki ; Tolonen, Nina ; Tryggvason, Karl ; Tuomilehto, Jaakko ; Waden, Johan ; Gill, Geoffrey V. ; Prior, Sarah ; Guiducci, Candace ; Mirel, Daniel B. ; Taylor, Andrew ; Colhoun, Helen M. ; Paterson, Andrew D. ; DCCT-EDIC Res Grp. / New Susceptibility Loci Associated with Kidney Disease in Type 1 Diabetes. In: PLoS Genetics. 2012 ; Vol. 8, No. 9.
    @article{dbfc2ea44f8a44f9bc1173742253c7d9,
    title = "New Susceptibility Loci Associated with Kidney Disease in Type 1 Diabetes",
    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.",
    keywords = "GENE, RISK, NATURAL-HISTORY, GENOME-WIDE ASSOCIATION, COLLAGEN CHAINS, GROWTH-FACTOR, RENAL-FUNCTION, EXPRESSION, NEPHROPATHY, AF4/FMR2 FAMILY",
    author = "Niina Sandholm and Salem, {Rany M.} and McKnight, {Amy Jayne} and Brennan, {Eoin P.} and Carol Forsblom and Tamara Isakova and McKay, {Gareth J.} and Williams, {Winfred W.} and Sadlier, {Denise M.} and Ville-Petteri Makinen and Swan, {Elizabeth J.} and Cameron Palmer and Boright, {Andrew P.} and Emma Ahlqvist and Deshmukh, {Harshal A.} and Keller, {Benjamin J.} and Huateng Huang and Ahola, {Aila J.} and Emma Fagerholm and Daniel Gordin and Valma Harjutsalo and Bing He and Outi Heikkila and Kustaa Hietala and Janne Kyto and Paivi Lahermo and Markku Lehto and Raija Lithovius and Anne-May Osterholm and Maija Parkkonen and Janne Pitkaniemi and Milla Rosengard-Barlund and Markku Saraheimo and Cinzia Sarti and Jenny Soderlund and Aino Soro-Paavonen and Anna Syreeni and Thorn, {Lena M.} and Heikki Tikkanen and Nina Tolonen and Karl Tryggvason and Jaakko Tuomilehto and Johan Waden and Gill, {Geoffrey V.} and Sarah Prior and Candace Guiducci and Mirel, {Daniel B.} and Andrew Taylor and Colhoun, {Helen M.} and Paterson, {Andrew D.} and {DCCT-EDIC Res Grp}",
    year = "2012",
    month = "9",
    day = "20",
    doi = "10.1371/journal.pgen.1002921",
    language = "English",
    volume = "8",
    journal = "PLoS Genetics",
    issn = "1553-7390",
    publisher = "Public Library of Science",
    number = "9",

    }

    Sandholm, N, Salem, RM, McKnight, AJ, Brennan, EP, Forsblom, C, Isakova, T, McKay, GJ, Williams, WW, Sadlier, DM, Makinen, V-P, Swan, EJ, Palmer, C, Boright, AP, Ahlqvist, E, Deshmukh, HA, Keller, BJ, Huang, H, Ahola, AJ, Fagerholm, E, Gordin, D, Harjutsalo, V, He, B, Heikkila, O, Hietala, K, Kyto, J, Lahermo, P, Lehto, M, Lithovius, R, Osterholm, A-M, Parkkonen, M, Pitkaniemi, J, Rosengard-Barlund, M, Saraheimo, M, Sarti, C, Soderlund, J, Soro-Paavonen, A, Syreeni, A, Thorn, LM, Tikkanen, H, Tolonen, N, Tryggvason, K, Tuomilehto, J, Waden, J, Gill, GV, Prior, S, Guiducci, C, Mirel, DB, Taylor, A, Colhoun, HM, Paterson, AD & DCCT-EDIC Res Grp 2012, 'New Susceptibility Loci Associated with Kidney Disease in Type 1 Diabetes', PLoS Genetics, vol. 8, no. 9, e1002921. https://doi.org/10.1371/journal.pgen.1002921

    New Susceptibility Loci Associated with Kidney Disease in Type 1 Diabetes. / Sandholm, Niina; Salem, Rany M.; McKnight, Amy Jayne; Brennan, Eoin P.; Forsblom, Carol; Isakova, Tamara; McKay, Gareth J.; Williams, Winfred W.; Sadlier, Denise M.; Makinen, 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; Heikkila, Outi; Hietala, Kustaa; Kyto, Janne; Lahermo, Paivi; Lehto, Markku; Lithovius, Raija; Osterholm, Anne-May; Parkkonen, Maija; Pitkaniemi, Janne; Rosengard-Barlund, Milla; Saraheimo, Markku; Sarti, Cinzia; Soderlund, Jenny; Soro-Paavonen, Aino; Syreeni, Anna; Thorn, Lena M.; Tikkanen, Heikki; Tolonen, Nina; Tryggvason, Karl; Tuomilehto, Jaakko; Waden, Johan; Gill, Geoffrey V.; Prior, Sarah; Guiducci, Candace; Mirel, Daniel B.; Taylor, Andrew; Colhoun, Helen M.; Paterson, Andrew D.; DCCT-EDIC Res Grp.

    In: PLoS Genetics, Vol. 8, No. 9, e1002921, 20.09.2012.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - New Susceptibility Loci Associated with Kidney Disease in Type 1 Diabetes

    AU - Sandholm, Niina

    AU - Salem, Rany M.

    AU - McKnight, Amy Jayne

    AU - Brennan, Eoin P.

    AU - Forsblom, Carol

    AU - Isakova, Tamara

    AU - McKay, Gareth J.

    AU - Williams, Winfred W.

    AU - Sadlier, Denise M.

    AU - Makinen, Ville-Petteri

    AU - Swan, Elizabeth J.

    AU - Palmer, Cameron

    AU - Boright, Andrew P.

    AU - Ahlqvist, Emma

    AU - Deshmukh, Harshal A.

    AU - Keller, Benjamin J.

    AU - Huang, Huateng

    AU - Ahola, Aila J.

    AU - Fagerholm, Emma

    AU - Gordin, Daniel

    AU - Harjutsalo, Valma

    AU - He, Bing

    AU - Heikkila, Outi

    AU - Hietala, Kustaa

    AU - Kyto, Janne

    AU - Lahermo, Paivi

    AU - Lehto, Markku

    AU - Lithovius, Raija

    AU - Osterholm, Anne-May

    AU - Parkkonen, Maija

    AU - Pitkaniemi, Janne

    AU - Rosengard-Barlund, Milla

    AU - Saraheimo, Markku

    AU - Sarti, Cinzia

    AU - Soderlund, Jenny

    AU - Soro-Paavonen, Aino

    AU - Syreeni, Anna

    AU - Thorn, Lena M.

    AU - Tikkanen, Heikki

    AU - Tolonen, Nina

    AU - Tryggvason, Karl

    AU - Tuomilehto, Jaakko

    AU - Waden, Johan

    AU - Gill, Geoffrey V.

    AU - Prior, Sarah

    AU - Guiducci, Candace

    AU - Mirel, Daniel B.

    AU - Taylor, Andrew

    AU - Colhoun, Helen M.

    AU - Paterson, Andrew D.

    AU - DCCT-EDIC Res Grp

    PY - 2012/9/20

    Y1 - 2012/9/20

    N2 - 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.

    AB - 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.

    KW - GENE

    KW - RISK

    KW - NATURAL-HISTORY

    KW - GENOME-WIDE ASSOCIATION

    KW - COLLAGEN CHAINS

    KW - GROWTH-FACTOR

    KW - RENAL-FUNCTION

    KW - EXPRESSION

    KW - NEPHROPATHY

    KW - AF4/FMR2 FAMILY

    U2 - 10.1371/journal.pgen.1002921

    DO - 10.1371/journal.pgen.1002921

    M3 - Article

    VL - 8

    JO - PLoS Genetics

    JF - PLoS Genetics

    SN - 1553-7390

    IS - 9

    M1 - e1002921

    ER -

    Sandholm N, Salem RM, McKnight AJ, Brennan EP, Forsblom C, Isakova T et al. New Susceptibility Loci Associated with Kidney Disease in Type 1 Diabetes. PLoS Genetics. 2012 Sep 20;8(9). e1002921. https://doi.org/10.1371/journal.pgen.1002921