Genome-wide association studies identify genetic loci associated with Albuminuria in diabetes

Alexander Teumer, Adrienne Tin, Rossella Sorice, Mathias Gorski, Nan Cher Yeo, Audrey Y. Chu, Man Li, Yong Li, Vladan Mijatovic, Yi An Ko, Daniel Taliun, Alessandro Luciani, Ming Huei Chen, Qiong Yang, Meredith C. Foster, Matthias Olden, Linda T. Hiraki, Bamidele O. Tayo, Christian Fuchsberger, Aida Karina Dieffenbach & 106 others Alan R. Shuldiner, Albert V. Smith, Allison M. Zappa, Antonio Lupo, Barbara Kollerits, Belen Ponte, Bénédicte Stengel, Bernhard K. Krämer, Bernhard Paulweber, Braxton D. Mitchell, Caroline Hayward, Catherine Helmer, Christa Meisinger, Christian Gieger, Christian M. Shaffer, Christian Müller, Claudia Langenberg, Daniel Ackermann, David Siscovick, Caroline S. Fox, Eric Boerwinkle, Florian Kronenberg, Georg B. Ehret, Georg Homuth, Gerard Waeber, Gerjan Navis, Giovanni Gambaro, Giovanni Malerba, Gudny Eiriksdottir, Guo Li, H. Erich Wichmann, Harald Grallert, Henri Wallaschofski, Henry Völzke, Herrmann Brenner, Holly Kramer, I. Mateo Leach, Igor Rudan, Hans L. Hillege, Jacques S. Beckmann, Jean Charles Lambert, Jian'an Luan, Jing Hua Zhao, John Chalmers, Josef Coresh, Joshua C. Denny, Katja Butterbach, Lenore J. Launer, Luigi Ferrucci, Lyudmyla Kedenko, Margot Haun, Marie Metzger, Mark Woodward, Matthew J. Hoffman, Matthias Nauck, Melanie Waldenberger, Menno Pruijm, Murielle Bochud, Myriam Rheinberger, Niek Verweij, Nicholas J. Wareham, Nicole Endlich, Nicole Soranzo, Ozren Polasek, Pim Van Der Harst, Peter Paul Pramstaller, Peter Vollenweider, Philipp S. Wild, Ron T. Gansevoort, Rainer Rettig, Reiner Biffar, Robert J. Carroll, Ronit Katz, Ruth J F Loos, Shih Jen Hwang, Stefan Coassin, Sven Bergmann, Sylvia E. Rosas, Sylvia Stracke, Tamara B. Harris, Tanguy Corre, Tanja Zeller, Thomas Illig, Thor Aspelund, Toshiko Tanaka, Uwe Lendeckel, Uwe Völker, Vilmundur Gudnason, Vincent Chouraki, Wolfgang Koenig, Zoltan Kutalik, Jeffrey R. O'Connell, Afshin Parsa, Iris M. Heid, Andrew D. Paterson, Ian H. De Boer, Olivier Devuyst, Jozef Lazar, Karlhans Endlich, Katalin Susztak, Johanne Tremblay, Pavel Hamet, Howard J. Jacob, Carsten A. Böger, Cristian Pattaro, Anna Köttgen

Research output: Contribution to journalArticle

Abstract

Elevated concentrations of albumin in the urine, albuminuria, are a hallmark of diabetic kidney disease and are associated with an increased risk for end-stage renal disease and cardiovascular events. To gain insight into the pathophysiological mechanisms underlying albuminuria, we conducted meta-analyses of genome-wide association studies and independent replication in up to 5,825 individuals of European ancestry with diabetes and up to 46,061 without diabetes, followed by functional studies. Known associations of variants in CUBN, encoding cubilin, with the urinary albumin-to-creatinine ratio (UACR) were confirmed in the overall sample (P = 2.4 × 10210). Gene-by-diabetes interactions were detected and confirmed for variants in HS6ST1 and near RAB38/CTSC. Single nucleotide polymorphisms at these loci demonstrated a genetic effect on UACR in individuals with but not without diabetes. The change in the average UACR per minor allele was 21% for HS6ST1 (P = 6.3 × 10-7) and 13% for RAB38/CTSC (P = 5.8 × 1027). Experiments using streptozotocin-induced diabetic Rab38 knockout and control rats showed higher urinary albumin concentrations and reduced amounts of megalin and cubilin at the proximal tubule cell surface in Rab38 knockout versus control rats. Relative expression of RAB38 was higher in tubuli of patients with diabetic kidney disease compared with control subjects. The loci identified here confirm known pathways and highlight novel pathways influencing albuminuria.

Original languageEnglish (US)
Pages (from-to)803-817
Number of pages15
JournalDiabetes
Volume65
Issue number3
DOIs
StatePublished - Mar 1 2016

Fingerprint

Albuminuria
Genetic Loci
Genome-Wide Association Study
Albumins
Creatinine
Diabetic Nephropathies
Low Density Lipoprotein Receptor-Related Protein-2
Streptozocin
Chronic Kidney Failure
Single Nucleotide Polymorphism
Meta-Analysis
Alleles
Urine
Genes

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Teumer, A., Tin, A., Sorice, R., Gorski, M., Yeo, N. C., Chu, A. Y., ... Köttgen, A. (2016). Genome-wide association studies identify genetic loci associated with Albuminuria in diabetes. Diabetes, 65(3), 803-817. https://doi.org/10.2337/db15-1313

Genome-wide association studies identify genetic loci associated with Albuminuria in diabetes. / Teumer, Alexander; Tin, Adrienne; Sorice, Rossella; Gorski, Mathias; Yeo, Nan Cher; Chu, Audrey Y.; Li, Man; Li, Yong; Mijatovic, Vladan; Ko, Yi An; Taliun, Daniel; Luciani, Alessandro; Chen, Ming Huei; Yang, Qiong; Foster, Meredith C.; Olden, Matthias; Hiraki, Linda T.; Tayo, Bamidele O.; Fuchsberger, Christian; Dieffenbach, Aida Karina; Shuldiner, Alan R.; Smith, Albert V.; Zappa, Allison M.; Lupo, Antonio; Kollerits, Barbara; Ponte, Belen; Stengel, Bénédicte; Krämer, Bernhard K.; Paulweber, Bernhard; Mitchell, Braxton D.; Hayward, Caroline; Helmer, Catherine; Meisinger, Christa; Gieger, Christian; Shaffer, Christian M.; Müller, Christian; Langenberg, Claudia; Ackermann, Daniel; Siscovick, David; Fox, Caroline S.; Boerwinkle, Eric; Kronenberg, Florian; Ehret, Georg B.; Homuth, Georg; Waeber, Gerard; Navis, Gerjan; Gambaro, Giovanni; Malerba, Giovanni; Eiriksdottir, Gudny; Li, Guo; Wichmann, H. Erich; Grallert, Harald; Wallaschofski, Henri; Völzke, Henry; Brenner, Herrmann; Kramer, Holly; Leach, I. Mateo; Rudan, Igor; Hillege, Hans L.; Beckmann, Jacques S.; Lambert, Jean Charles; Luan, Jian'an; Zhao, Jing Hua; Chalmers, John; Coresh, Josef; Denny, Joshua C.; Butterbach, Katja; Launer, Lenore J.; Ferrucci, Luigi; Kedenko, Lyudmyla; Haun, Margot; Metzger, Marie; Woodward, Mark; Hoffman, Matthew J.; Nauck, Matthias; Waldenberger, Melanie; Pruijm, Menno; Bochud, Murielle; Rheinberger, Myriam; Verweij, Niek; Wareham, Nicholas J.; Endlich, Nicole; Soranzo, Nicole; Polasek, Ozren; Van Der Harst, Pim; Pramstaller, Peter Paul; Vollenweider, Peter; Wild, Philipp S.; Gansevoort, Ron T.; Rettig, Rainer; Biffar, Reiner; Carroll, Robert J.; Katz, Ronit; Loos, Ruth J F; Hwang, Shih Jen; Coassin, Stefan; Bergmann, Sven; Rosas, Sylvia E.; Stracke, Sylvia; Harris, Tamara B.; Corre, Tanguy; Zeller, Tanja; Illig, Thomas; Aspelund, Thor; Tanaka, Toshiko; Lendeckel, Uwe; Völker, Uwe; Gudnason, Vilmundur; Chouraki, Vincent; Koenig, Wolfgang; Kutalik, Zoltan; O'Connell, Jeffrey R.; Parsa, Afshin; Heid, Iris M.; Paterson, Andrew D.; De Boer, Ian H.; Devuyst, Olivier; Lazar, Jozef; Endlich, Karlhans; Susztak, Katalin; Tremblay, Johanne; Hamet, Pavel; Jacob, Howard J.; Böger, Carsten A.; Pattaro, Cristian; Köttgen, Anna.

In: Diabetes, Vol. 65, No. 3, 01.03.2016, p. 803-817.

Research output: Contribution to journalArticle

Teumer, A, Tin, A, Sorice, R, Gorski, M, Yeo, NC, Chu, AY, Li, M, Li, Y, Mijatovic, V, Ko, YA, Taliun, D, Luciani, A, Chen, MH, Yang, Q, Foster, MC, Olden, M, Hiraki, LT, Tayo, BO, Fuchsberger, C, Dieffenbach, AK, Shuldiner, AR, Smith, AV, Zappa, AM, Lupo, A, Kollerits, B, Ponte, B, Stengel, B, Krämer, BK, Paulweber, B, Mitchell, BD, Hayward, C, Helmer, C, Meisinger, C, Gieger, C, Shaffer, CM, Müller, C, Langenberg, C, Ackermann, D, Siscovick, D, Fox, CS, Boerwinkle, E, Kronenberg, F, Ehret, GB, Homuth, G, Waeber, G, Navis, G, Gambaro, G, Malerba, G, Eiriksdottir, G, Li, G, Wichmann, HE, Grallert, H, Wallaschofski, H, Völzke, H, Brenner, H, Kramer, H, Leach, IM, Rudan, I, Hillege, HL, Beckmann, JS, Lambert, JC, Luan, J, Zhao, JH, Chalmers, J, Coresh, J, Denny, JC, Butterbach, K, Launer, LJ, Ferrucci, L, Kedenko, L, Haun, M, Metzger, M, Woodward, M, Hoffman, MJ, Nauck, M, Waldenberger, M, Pruijm, M, Bochud, M, Rheinberger, M, Verweij, N, Wareham, NJ, Endlich, N, Soranzo, N, Polasek, O, Van Der Harst, P, Pramstaller, PP, Vollenweider, P, Wild, PS, Gansevoort, RT, Rettig, R, Biffar, R, Carroll, RJ, Katz, R, Loos, RJF, Hwang, SJ, Coassin, S, Bergmann, S, Rosas, SE, Stracke, S, Harris, TB, Corre, T, Zeller, T, Illig, T, Aspelund, T, Tanaka, T, Lendeckel, U, Völker, U, Gudnason, V, Chouraki, V, Koenig, W, Kutalik, Z, O'Connell, JR, Parsa, A, Heid, IM, Paterson, AD, De Boer, IH, Devuyst, O, Lazar, J, Endlich, K, Susztak, K, Tremblay, J, Hamet, P, Jacob, HJ, Böger, CA, Pattaro, C & Köttgen, A 2016, 'Genome-wide association studies identify genetic loci associated with Albuminuria in diabetes', Diabetes, vol. 65, no. 3, pp. 803-817. https://doi.org/10.2337/db15-1313
Teumer, Alexander ; Tin, Adrienne ; Sorice, Rossella ; Gorski, Mathias ; Yeo, Nan Cher ; Chu, Audrey Y. ; Li, Man ; Li, Yong ; Mijatovic, Vladan ; Ko, Yi An ; Taliun, Daniel ; Luciani, Alessandro ; Chen, Ming Huei ; Yang, Qiong ; Foster, Meredith C. ; Olden, Matthias ; Hiraki, Linda T. ; Tayo, Bamidele O. ; Fuchsberger, Christian ; Dieffenbach, Aida Karina ; Shuldiner, Alan R. ; Smith, Albert V. ; Zappa, Allison M. ; Lupo, Antonio ; Kollerits, Barbara ; Ponte, Belen ; Stengel, Bénédicte ; Krämer, Bernhard K. ; Paulweber, Bernhard ; Mitchell, Braxton D. ; Hayward, Caroline ; Helmer, Catherine ; Meisinger, Christa ; Gieger, Christian ; Shaffer, Christian M. ; Müller, Christian ; Langenberg, Claudia ; Ackermann, Daniel ; Siscovick, David ; Fox, Caroline S. ; Boerwinkle, Eric ; Kronenberg, Florian ; Ehret, Georg B. ; Homuth, Georg ; Waeber, Gerard ; Navis, Gerjan ; Gambaro, Giovanni ; Malerba, Giovanni ; Eiriksdottir, Gudny ; Li, Guo ; Wichmann, H. Erich ; Grallert, Harald ; Wallaschofski, Henri ; Völzke, Henry ; Brenner, Herrmann ; Kramer, Holly ; Leach, I. Mateo ; Rudan, Igor ; Hillege, Hans L. ; Beckmann, Jacques S. ; Lambert, Jean Charles ; Luan, Jian'an ; Zhao, Jing Hua ; Chalmers, John ; Coresh, Josef ; Denny, Joshua C. ; Butterbach, Katja ; Launer, Lenore J. ; Ferrucci, Luigi ; Kedenko, Lyudmyla ; Haun, Margot ; Metzger, Marie ; Woodward, Mark ; Hoffman, Matthew J. ; Nauck, Matthias ; Waldenberger, Melanie ; Pruijm, Menno ; Bochud, Murielle ; Rheinberger, Myriam ; Verweij, Niek ; Wareham, Nicholas J. ; Endlich, Nicole ; Soranzo, Nicole ; Polasek, Ozren ; Van Der Harst, Pim ; Pramstaller, Peter Paul ; Vollenweider, Peter ; Wild, Philipp S. ; Gansevoort, Ron T. ; Rettig, Rainer ; Biffar, Reiner ; Carroll, Robert J. ; Katz, Ronit ; Loos, Ruth J F ; Hwang, Shih Jen ; Coassin, Stefan ; Bergmann, Sven ; Rosas, Sylvia E. ; Stracke, Sylvia ; Harris, Tamara B. ; Corre, Tanguy ; Zeller, Tanja ; Illig, Thomas ; Aspelund, Thor ; Tanaka, Toshiko ; Lendeckel, Uwe ; Völker, Uwe ; Gudnason, Vilmundur ; Chouraki, Vincent ; Koenig, Wolfgang ; Kutalik, Zoltan ; O'Connell, Jeffrey R. ; Parsa, Afshin ; Heid, Iris M. ; Paterson, Andrew D. ; De Boer, Ian H. ; Devuyst, Olivier ; Lazar, Jozef ; Endlich, Karlhans ; Susztak, Katalin ; Tremblay, Johanne ; Hamet, Pavel ; Jacob, Howard J. ; Böger, Carsten A. ; Pattaro, Cristian ; Köttgen, Anna. / Genome-wide association studies identify genetic loci associated with Albuminuria in diabetes. In: Diabetes. 2016 ; Vol. 65, No. 3. pp. 803-817.
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abstract = "Elevated concentrations of albumin in the urine, albuminuria, are a hallmark of diabetic kidney disease and are associated with an increased risk for end-stage renal disease and cardiovascular events. To gain insight into the pathophysiological mechanisms underlying albuminuria, we conducted meta-analyses of genome-wide association studies and independent replication in up to 5,825 individuals of European ancestry with diabetes and up to 46,061 without diabetes, followed by functional studies. Known associations of variants in CUBN, encoding cubilin, with the urinary albumin-to-creatinine ratio (UACR) were confirmed in the overall sample (P = 2.4 × 10210). Gene-by-diabetes interactions were detected and confirmed for variants in HS6ST1 and near RAB38/CTSC. Single nucleotide polymorphisms at these loci demonstrated a genetic effect on UACR in individuals with but not without diabetes. The change in the average UACR per minor allele was 21{\%} for HS6ST1 (P = 6.3 × 10-7) and 13{\%} for RAB38/CTSC (P = 5.8 × 1027). Experiments using streptozotocin-induced diabetic Rab38 knockout and control rats showed higher urinary albumin concentrations and reduced amounts of megalin and cubilin at the proximal tubule cell surface in Rab38 knockout versus control rats. Relative expression of RAB38 was higher in tubuli of patients with diabetic kidney disease compared with control subjects. The loci identified here confirm known pathways and highlight novel pathways influencing albuminuria.",
author = "Alexander Teumer and Adrienne Tin and Rossella Sorice and Mathias Gorski and Yeo, {Nan Cher} and Chu, {Audrey Y.} and Man Li and Yong Li and Vladan Mijatovic and Ko, {Yi An} and Daniel Taliun and Alessandro Luciani and Chen, {Ming Huei} and Qiong Yang and Foster, {Meredith C.} and Matthias Olden and Hiraki, {Linda T.} and Tayo, {Bamidele O.} and Christian Fuchsberger and Dieffenbach, {Aida Karina} and Shuldiner, {Alan R.} and Smith, {Albert V.} and Zappa, {Allison M.} and Antonio Lupo and Barbara Kollerits and Belen Ponte and B{\'e}n{\'e}dicte Stengel and Kr{\"a}mer, {Bernhard K.} and Bernhard Paulweber and Mitchell, {Braxton D.} and Caroline Hayward and Catherine Helmer and Christa Meisinger and Christian Gieger and Shaffer, {Christian M.} and Christian M{\"u}ller and Claudia Langenberg and Daniel Ackermann and David Siscovick and Fox, {Caroline S.} and Eric Boerwinkle and Florian Kronenberg and Ehret, {Georg B.} and Georg Homuth and Gerard Waeber and Gerjan Navis and Giovanni Gambaro and Giovanni Malerba and Gudny Eiriksdottir and Guo Li and Wichmann, {H. Erich} and Harald Grallert and Henri Wallaschofski and Henry V{\"o}lzke and Herrmann Brenner and Holly Kramer and Leach, {I. Mateo} and Igor Rudan and Hillege, {Hans L.} and Beckmann, {Jacques S.} and Lambert, {Jean Charles} and Jian'an Luan and Zhao, {Jing Hua} and John Chalmers and Josef Coresh and Denny, {Joshua C.} and Katja Butterbach and Launer, {Lenore J.} and Luigi Ferrucci and Lyudmyla Kedenko and Margot Haun and Marie Metzger and Mark Woodward and Hoffman, {Matthew J.} and Matthias Nauck and Melanie Waldenberger and Menno Pruijm and Murielle Bochud and Myriam Rheinberger and Niek Verweij and Wareham, {Nicholas J.} and Nicole Endlich and Nicole Soranzo and Ozren Polasek and {Van Der Harst}, Pim and Pramstaller, {Peter Paul} and Peter Vollenweider and Wild, {Philipp S.} and Gansevoort, {Ron T.} and Rainer Rettig and Reiner Biffar and Carroll, {Robert J.} and Ronit Katz and Loos, {Ruth J F} and Hwang, {Shih Jen} and Stefan Coassin and Sven Bergmann and Rosas, {Sylvia E.} and Sylvia Stracke and Harris, {Tamara B.} and Tanguy Corre and Tanja Zeller and Thomas Illig and Thor Aspelund and Toshiko Tanaka and Uwe Lendeckel and Uwe V{\"o}lker and Vilmundur Gudnason and Vincent Chouraki and Wolfgang Koenig and Zoltan Kutalik and O'Connell, {Jeffrey R.} and Afshin Parsa and Heid, {Iris M.} and Paterson, {Andrew D.} and {De Boer}, {Ian H.} and Olivier Devuyst and Jozef Lazar and Karlhans Endlich and Katalin Susztak and Johanne Tremblay and Pavel Hamet and Jacob, {Howard J.} and B{\"o}ger, {Carsten A.} and Cristian Pattaro and Anna K{\"o}ttgen",
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T1 - Genome-wide association studies identify genetic loci associated with Albuminuria in diabetes

AU - Teumer, Alexander

AU - Tin, Adrienne

AU - Sorice, Rossella

AU - Gorski, Mathias

AU - Yeo, Nan Cher

AU - Chu, Audrey Y.

AU - Li, Man

AU - Li, Yong

AU - Mijatovic, Vladan

AU - Ko, Yi An

AU - Taliun, Daniel

AU - Luciani, Alessandro

AU - Chen, Ming Huei

AU - Yang, Qiong

AU - Foster, Meredith C.

AU - Olden, Matthias

AU - Hiraki, Linda T.

AU - Tayo, Bamidele O.

AU - Fuchsberger, Christian

AU - Dieffenbach, Aida Karina

AU - Shuldiner, Alan R.

AU - Smith, Albert V.

AU - Zappa, Allison M.

AU - Lupo, Antonio

AU - Kollerits, Barbara

AU - Ponte, Belen

AU - Stengel, Bénédicte

AU - Krämer, Bernhard K.

AU - Paulweber, Bernhard

AU - Mitchell, Braxton D.

AU - Hayward, Caroline

AU - Helmer, Catherine

AU - Meisinger, Christa

AU - Gieger, Christian

AU - Shaffer, Christian M.

AU - Müller, Christian

AU - Langenberg, Claudia

AU - Ackermann, Daniel

AU - Siscovick, David

AU - Fox, Caroline S.

AU - Boerwinkle, Eric

AU - Kronenberg, Florian

AU - Ehret, Georg B.

AU - Homuth, Georg

AU - Waeber, Gerard

AU - Navis, Gerjan

AU - Gambaro, Giovanni

AU - Malerba, Giovanni

AU - Eiriksdottir, Gudny

AU - Li, Guo

AU - Wichmann, H. Erich

AU - Grallert, Harald

AU - Wallaschofski, Henri

AU - Völzke, Henry

AU - Brenner, Herrmann

AU - Kramer, Holly

AU - Leach, I. Mateo

AU - Rudan, Igor

AU - Hillege, Hans L.

AU - Beckmann, Jacques S.

AU - Lambert, Jean Charles

AU - Luan, Jian'an

AU - Zhao, Jing Hua

AU - Chalmers, John

AU - Coresh, Josef

AU - Denny, Joshua C.

AU - Butterbach, Katja

AU - Launer, Lenore J.

AU - Ferrucci, Luigi

AU - Kedenko, Lyudmyla

AU - Haun, Margot

AU - Metzger, Marie

AU - Woodward, Mark

AU - Hoffman, Matthew J.

AU - Nauck, Matthias

AU - Waldenberger, Melanie

AU - Pruijm, Menno

AU - Bochud, Murielle

AU - Rheinberger, Myriam

AU - Verweij, Niek

AU - Wareham, Nicholas J.

AU - Endlich, Nicole

AU - Soranzo, Nicole

AU - Polasek, Ozren

AU - Van Der Harst, Pim

AU - Pramstaller, Peter Paul

AU - Vollenweider, Peter

AU - Wild, Philipp S.

AU - Gansevoort, Ron T.

AU - Rettig, Rainer

AU - Biffar, Reiner

AU - Carroll, Robert J.

AU - Katz, Ronit

AU - Loos, Ruth J F

AU - Hwang, Shih Jen

AU - Coassin, Stefan

AU - Bergmann, Sven

AU - Rosas, Sylvia E.

AU - Stracke, Sylvia

AU - Harris, Tamara B.

AU - Corre, Tanguy

AU - Zeller, Tanja

AU - Illig, Thomas

AU - Aspelund, Thor

AU - Tanaka, Toshiko

AU - Lendeckel, Uwe

AU - Völker, Uwe

AU - Gudnason, Vilmundur

AU - Chouraki, Vincent

AU - Koenig, Wolfgang

AU - Kutalik, Zoltan

AU - O'Connell, Jeffrey R.

AU - Parsa, Afshin

AU - Heid, Iris M.

AU - Paterson, Andrew D.

AU - De Boer, Ian H.

AU - Devuyst, Olivier

AU - Lazar, Jozef

AU - Endlich, Karlhans

AU - Susztak, Katalin

AU - Tremblay, Johanne

AU - Hamet, Pavel

AU - Jacob, Howard J.

AU - Böger, Carsten A.

AU - Pattaro, Cristian

AU - Köttgen, Anna

PY - 2016/3/1

Y1 - 2016/3/1

N2 - Elevated concentrations of albumin in the urine, albuminuria, are a hallmark of diabetic kidney disease and are associated with an increased risk for end-stage renal disease and cardiovascular events. To gain insight into the pathophysiological mechanisms underlying albuminuria, we conducted meta-analyses of genome-wide association studies and independent replication in up to 5,825 individuals of European ancestry with diabetes and up to 46,061 without diabetes, followed by functional studies. Known associations of variants in CUBN, encoding cubilin, with the urinary albumin-to-creatinine ratio (UACR) were confirmed in the overall sample (P = 2.4 × 10210). Gene-by-diabetes interactions were detected and confirmed for variants in HS6ST1 and near RAB38/CTSC. Single nucleotide polymorphisms at these loci demonstrated a genetic effect on UACR in individuals with but not without diabetes. The change in the average UACR per minor allele was 21% for HS6ST1 (P = 6.3 × 10-7) and 13% for RAB38/CTSC (P = 5.8 × 1027). Experiments using streptozotocin-induced diabetic Rab38 knockout and control rats showed higher urinary albumin concentrations and reduced amounts of megalin and cubilin at the proximal tubule cell surface in Rab38 knockout versus control rats. Relative expression of RAB38 was higher in tubuli of patients with diabetic kidney disease compared with control subjects. The loci identified here confirm known pathways and highlight novel pathways influencing albuminuria.

AB - Elevated concentrations of albumin in the urine, albuminuria, are a hallmark of diabetic kidney disease and are associated with an increased risk for end-stage renal disease and cardiovascular events. To gain insight into the pathophysiological mechanisms underlying albuminuria, we conducted meta-analyses of genome-wide association studies and independent replication in up to 5,825 individuals of European ancestry with diabetes and up to 46,061 without diabetes, followed by functional studies. Known associations of variants in CUBN, encoding cubilin, with the urinary albumin-to-creatinine ratio (UACR) were confirmed in the overall sample (P = 2.4 × 10210). Gene-by-diabetes interactions were detected and confirmed for variants in HS6ST1 and near RAB38/CTSC. Single nucleotide polymorphisms at these loci demonstrated a genetic effect on UACR in individuals with but not without diabetes. The change in the average UACR per minor allele was 21% for HS6ST1 (P = 6.3 × 10-7) and 13% for RAB38/CTSC (P = 5.8 × 1027). Experiments using streptozotocin-induced diabetic Rab38 knockout and control rats showed higher urinary albumin concentrations and reduced amounts of megalin and cubilin at the proximal tubule cell surface in Rab38 knockout versus control rats. Relative expression of RAB38 was higher in tubuli of patients with diabetic kidney disease compared with control subjects. The loci identified here confirm known pathways and highlight novel pathways influencing albuminuria.

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