New susceptibility Loci associated with kidney disease in type 1 diabetes

Niina Sandholm; Rany M. Salem; A.J. McKnight; Eoin P. Brennan; Carol Forsblom; Tamara Isakova; Gareth J. McKay; Winfred W. Williams; Denise M. Sadlier; V.P. Mäkinen; E.J. Swan; Cameron D. Palmer; A.P. Boright; Emma Ahlqvist; H.A. Deshmukh; B.J. Keller; H. Huang; Aila J. Ahola; Emma Fagerholm; D. Gordin; Valma Harjutsalo; B. He; O. Heikkila; Kustaa Hietala; J. Kyto; Päivi Lahermo; Markku Lehto; Raija Lithovius; Anne May Österholm; Maija Parkkonen; Janne Pitkäniemi; Milla Rosengård-Bärlund; Markku Saraheimo; C. Sarti; J. Soderlund; A. Soro-Paavonen; Anna Syreeni; L.M. Thorn; H. Tikkanen; Nina Tolonen; K. Tryggvason; Jaakko Tuomilehto; J. Waden; G.V. Gill; S. Prior; C. Guiducci; D.B. Mirel; A. Taylor; S.M. Hosseini; H.H. Parving; P. Rossing; L. Tarnow; C. Ladenvall; F. Alhenc-Gelas; P. Lefebvre; V. Rigalleau; R. Roussel; D.A. Tregouet; A. Maestroni; S. Maestroni; H. Falhammar; T. Gu; A. Mollsten; D. Cimponeriu; M. Ioana; M. Mota; E. Mota; C. Serafinceanu; M. Stavarachi; R.L. Hanson; R.G. Nelson; M. Kretzler; H.M. Colhoun; N.M. Panduru; H.F. Gu; K. Brismar; G. Zerbini; S. Hadjadj; M. Marre; L. Groop; M. Lajer; S.B. Bull; D. Waggott; A.D. Paterson; D.A. Savage; S.C. Bain; F. Martin; J.N. Hirschhorn; C. Godson; J.C. Florez; P.H. Groop; A.P. Maxwell

doi:10.1371/journal.pgen.1002921

New susceptibility Loci associated with kidney disease in type 1 diabetes

Niina Sandholm, Rany M. Salem, A.J. McKnight, Eoin P. Brennan, Carol Forsblom, Tamara Isakova, Gareth J. McKay, Winfred W. Williams, Denise M. Sadlier, V.P. Mäkinen, E.J. Swan, Cameron D. Palmer, A.P. Boright, Emma Ahlqvist, H.A. Deshmukh, B.J. Keller, H. Huang, Aila J. Ahola, Emma Fagerholm, D. GordinValma Harjutsalo, B. He, O. Heikkila, Kustaa Hietala, J. Kyto, Päivi Lahermo, Markku Lehto, Raija Lithovius, Anne May Österholm, Maija Parkkonen, Janne Pitkäniemi, Milla Rosengård-Bärlund, Markku Saraheimo, C. Sarti, J. Soderlund, A. Soro-Paavonen, Anna Syreeni, L.M. Thorn, H. Tikkanen, Nina Tolonen, K. Tryggvason, Jaakko Tuomilehto, J. Waden, G.V. Gill, S. Prior, C. Guiducci, D.B. Mirel, A. Taylor, S.M. Hosseini, H.H. Parving, P. Rossing, L. Tarnow, C. Ladenvall, F. Alhenc-Gelas, P. Lefebvre, V. Rigalleau, R. Roussel, D.A. Tregouet, A. Maestroni, S. Maestroni, H. Falhammar, T. Gu, A. Mollsten, D. Cimponeriu, M. Ioana, M. Mota, E. Mota, C. Serafinceanu, M. Stavarachi, R.L. Hanson, R.G. Nelson, M. Kretzler, H.M. Colhoun, N.M. Panduru, H.F. Gu, K. Brismar, G. Zerbini, S. Hadjadj, M. Marre, L. Groop, M. Lajer, S.B. Bull, D. Waggott, A.D. Paterson, D.A. Savage, S.C. Bain, F. Martin, J.N. Hirschhorn, C. Godson, J.C. Florez, P.H. Groop, A.P. Maxwell

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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 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.

Original language	English
Article number	e1002921
Pages (from-to)	1-13
Journal	PLoS Genetics
Volume	8
Issue number	9
DOIs	https://doi.org/10.1371/journal.pgen.1002921
Publication status	Published - 2012
MoE publication type	A1 Journal article-refereed

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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. D., Boright, A. P., Ahlqvist, E., Deshmukh, H. A., Keller, B. J., Huang, H., Ahola, A. J., Fagerholm, E., ... Maxwell, A. P. (2012). New susceptibility Loci associated with kidney disease in type 1 diabetes. PLoS Genetics, 8(9), 1-13. [e1002921]. https://doi.org/10.1371/journal.pgen.1002921

@article{dde281024e854dc3a71596fce12b048c,

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 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.",

author = "Niina Sandholm and Salem, {Rany M.} and A.J. McKnight and Brennan, {Eoin P.} and Carol Forsblom and Tamara Isakova and McKay, {Gareth J.} and Williams, {Winfred W.} and Sadlier, {Denise M.} and V.P. M{\"a}kinen and E.J. Swan and Palmer, {Cameron D.} and A.P. Boright and Emma Ahlqvist and H.A. Deshmukh and B.J. Keller and H. Huang and Ahola, {Aila J.} and Emma Fagerholm and D. Gordin and Valma Harjutsalo and B. He and O. Heikkila and Kustaa Hietala and J. Kyto and P{\"a}ivi Lahermo and Markku Lehto and Raija Lithovius and {\"O}sterholm, {Anne May} and Maija Parkkonen and Janne Pitk{\"a}niemi and Milla Roseng{\aa}rd-B{\"a}rlund and Markku Saraheimo and C. Sarti and J. Soderlund and A. Soro-Paavonen and Anna Syreeni and L.M. Thorn and H. Tikkanen and Nina Tolonen and K. Tryggvason and Jaakko Tuomilehto and J. Waden and G.V. Gill and S. Prior and C. Guiducci and D.B. Mirel and A. Taylor and S.M. Hosseini and H.H. Parving and P. Rossing and L. Tarnow and C. Ladenvall and F. Alhenc-Gelas and P. Lefebvre and V. Rigalleau and R. Roussel and D.A. Tregouet and A. Maestroni and S. Maestroni and H. Falhammar and T. Gu and A. Mollsten and D. Cimponeriu and M. Ioana and M. Mota and E. Mota and C. Serafinceanu and M. Stavarachi and R.L. Hanson and R.G. Nelson and M. Kretzler and H.M. Colhoun and N.M. Panduru and H.F. Gu and K. Brismar and G. Zerbini and S. Hadjadj and M. Marre and L. Groop and M. Lajer and S.B. Bull and D. Waggott and A.D. Paterson and D.A. Savage and S.C. Bain and F. Martin and J.N. Hirschhorn and C. Godson and J.C. Florez and P.H. Groop and A.P. Maxwell",

year = "2012",

doi = "10.1371/journal.pgen.1002921",

language = "English",

volume = "8",

pages = "1--13",

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, Mäkinen, VP, Swan, EJ, Palmer, CD, 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, Österholm, AM, Parkkonen, M, Pitkäniemi, J, Rosengård-Bärlund, 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, Hosseini, SM, 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, Mollsten, 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 2012, 'New susceptibility Loci associated with kidney disease in type 1 diabetes', PLoS Genetics, vol. 8, no. 9, e1002921, pp. 1-13. https://doi.org/10.1371/journal.pgen.1002921

TY - JOUR

T1 - New susceptibility Loci associated with kidney disease in type 1 diabetes

AU - Sandholm, Niina

AU - Salem, Rany M.

AU - McKnight, A.J.

AU - Brennan, Eoin P.

AU - Forsblom, Carol

AU - Isakova, Tamara

AU - McKay, Gareth J.

AU - Williams, Winfred W.

AU - Sadlier, Denise M.

AU - Mäkinen, V.P.

AU - Swan, E.J.

AU - Palmer, Cameron D.

AU - Boright, A.P.

AU - Ahlqvist, Emma

AU - Deshmukh, H.A.

AU - Keller, B.J.

AU - Huang, H.

AU - Ahola, Aila J.

AU - Fagerholm, Emma

AU - Gordin, D.

AU - Harjutsalo, Valma

AU - He, B.

AU - Heikkila, O.

AU - Hietala, Kustaa

AU - Kyto, J.

AU - Lahermo, Päivi

AU - Lehto, Markku

AU - Lithovius, Raija

AU - Österholm, Anne May

AU - Parkkonen, Maija

AU - Pitkäniemi, Janne

AU - Rosengård-Bärlund, Milla

AU - Saraheimo, Markku

AU - Sarti, C.

AU - Soderlund, J.

AU - Soro-Paavonen, A.

AU - Syreeni, Anna

AU - Thorn, L.M.

AU - Tikkanen, H.

AU - Tolonen, Nina

AU - Tryggvason, K.

AU - Tuomilehto, Jaakko

AU - Waden, J.

AU - Gill, G.V.

AU - Prior, S.

AU - Guiducci, C.

AU - Mirel, D.B.

AU - Taylor, A.

AU - Hosseini, S.M.

AU - Parving, H.H.

AU - Rossing, P.

AU - Tarnow, L.

AU - Ladenvall, C.

AU - Alhenc-Gelas, F.

AU - Lefebvre, P.

AU - Rigalleau, V.

AU - Roussel, R.

AU - Tregouet, D.A.

AU - Maestroni, A.

AU - Maestroni, S.

AU - Falhammar, H.

AU - Gu, T.

AU - Mollsten, A.

AU - Cimponeriu, D.

AU - Ioana, M.

AU - Mota, M.

AU - Mota, E.

AU - Serafinceanu, C.

AU - Stavarachi, M.

AU - Hanson, R.L.

AU - Nelson, R.G.

AU - Kretzler, M.

AU - Colhoun, H.M.

AU - Panduru, N.M.

AU - Gu, H.F.

AU - Brismar, K.

AU - Zerbini, G.

AU - Hadjadj, S.

AU - Marre, M.

AU - Groop, L.

AU - Lajer, M.

AU - Bull, S.B.

AU - Waggott, D.

AU - Paterson, A.D.

AU - Savage, D.A.

AU - Bain, S.C.

AU - Martin, F.

AU - Hirschhorn, J.N.

AU - Godson, C.

AU - Florez, J.C.

AU - Groop, P.H.

AU - Maxwell, A.P.

PY - 2012

Y1 - 2012

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 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.

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 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.

U2 - 10.1371/journal.pgen.1002921

DO - 10.1371/journal.pgen.1002921

M3 - Article

VL - 8

SP - 1

EP - 13

JO - PLoS Genetics

JF - PLoS Genetics

SN - 1553-7390

IS - 9

M1 - e1002921

ER -

New susceptibility Loci associated with kidney disease in type 1 diabetes

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