AIMS/HYPOTHESIS: An abnormal urinary albumin excretion rate (AER) is often the first clinically detectable manifestation of diabetic nephropathy. Our aim was to estimate the heritability and to detect genetic variation associated with elevated AER in patients with type 1 diabetes. METHODS: The discovery phase genome-wide association study (GWAS) included 1,925 patients with type 1 diabetes and with data on 24 h AER. AER was analysed as a continuous trait and the analysis was stratified by the use of antihypertensive medication. Signals with a p value <10(-4) were followed up in 3,750 additional patients with type 1 diabetes from seven studies. RESULTS: The narrow-sense heritability, captured with our genotyping platform, was estimated to explain 27.3% of the total AER variability, and 37.6% after adjustment for covariates. In the discovery stage, five single nucleotide polymorphisms in the GLRA3 gene were strongly associated with albuminuria (p < 5 × 10(-8)). In the replication group, a nominally significant association (p = 0.035) was observed between albuminuria and rs1564939 in GLRA3, but this was in the opposite direction. Sequencing of the surrounding genetic region in 48 Finnish and 48 UK individuals supported the possibility that population-specific rare variants contribute to the synthetic association observed at the common variants in GLRA3. The strongest replication (p = 0.026) was obtained for rs2410601 between the PSD3 and SH2D4A genes. Pathway analysis highlighted natural killer cell mediated immunity processes. CONCLUSIONS/ INTERPRETATION: This study suggests novel pathways and molecular mechanisms for the pathogenesis of albuminuria in type 1 diabetes.
AIMS/HYPOTHESIS: An abnormal urinary albumin excretion rate (AER) is often the first clinically detectable manifestation of diabetic nephropathy. Our aim was to estimate the heritability and to detect genetic variation associated with elevated AER in patients with type 1 diabetes. METHODS: The discovery phase genome-wide association study (GWAS) included 1,925 patients with type 1 diabetes and with data on 24 h AER. AER was analysed as a continuous trait and the analysis was stratified by the use of antihypertensive medication. Signals with a p value <10(-4) were followed up in 3,750 additional patients with type 1 diabetes from seven studies. RESULTS: The narrow-sense heritability, captured with our genotyping platform, was estimated to explain 27.3% of the total AER variability, and 37.6% after adjustment for covariates. In the discovery stage, five single nucleotide polymorphisms in the GLRA3 gene were strongly associated with albuminuria (p < 5 × 10(-8)). In the replication group, a nominally significant association (p = 0.035) was observed between albuminuria and rs1564939 in GLRA3, but this was in the opposite direction. Sequencing of the surrounding genetic region in 48 Finnish and 48 UK individuals supported the possibility that population-specific rare variants contribute to the synthetic association observed at the common variants in GLRA3. The strongest replication (p = 0.026) was obtained for rs2410601 between the PSD3 and SH2D4A genes. Pathway analysis highlighted natural killer cell mediated immunity processes. CONCLUSIONS/ INTERPRETATION: This study suggests novel pathways and molecular mechanisms for the pathogenesis of albuminuria in type 1 diabetes.
Authors: Alkes L Price; Nick J Patterson; Robert M Plenge; Michael E Weinblatt; Nancy A Shadick; David Reich Journal: Nat Genet Date: 2006-07-23 Impact factor: 38.330
Authors: Ming Yin; Zhi Zhong; Henry D Connor; Hartwig Bunzendahl; William F Finn; Ivan Rusyn; Xiangli Li; James A Raleigh; Ronald P Mason; Ronald G Thurman Journal: Am J Physiol Renal Physiol Date: 2002-03
Authors: E Ritz; G C Viberti; L M Ruilope; A J Rabelink; J L Izzo; S Katayama; S Ito; A Mimran; J Menne; L C Rump; A Januszewicz; H Haller Journal: Diabetologia Date: 2009-10-30 Impact factor: 10.122
Authors: Anna Möllsten; Ingrid Kockum; Maria Svensson; Susanne Rudberg; Anna Ugarph-Morawski; Kerstin Brismar; Jan W Eriksson; Gisela Dahlquist Journal: J Diabetes Complications Date: 2008-04-16 Impact factor: 2.852
Authors: Scott G Frodsham; Zhe Yu; Ann M Lyons; Adhish Agarwal; Melissa H Pezzolesi; Li Dong; Titte R Srinivas; Jian Ying; Tom Greene; Kalani L Raphael; Ken R Smith; Marcus G Pezzolesi Journal: Diabetes Date: 2018-11-13 Impact factor: 9.461
Authors: Bixiao Zhao; Qiongshi Lu; Yuwei Cheng; Justin M Belcher; Edward D Siew; David E Leaf; Simon C Body; Amanda A Fox; Sushrut S Waikar; Charles D Collard; Heather Thiessen-Philbrook; T Alp Ikizler; Lorraine B Ware; Charles L Edelstein; Amit X Garg; Murim Choi; Jennifer A Schaub; Hongyu Zhao; Richard P Lifton; Chirag R Parikh Journal: Am J Respir Crit Care Med Date: 2017-02-15 Impact factor: 21.405
Authors: Niina Sandholm; Natalie Van Zuydam; Emma Ahlqvist; Thorhildur Juliusdottir; Harshal A Deshmukh; N William Rayner; Barbara Di Camillo; Carol Forsblom; Joao Fadista; Daniel Ziemek; Rany M Salem; Linda T Hiraki; Marcus Pezzolesi; David Trégouët; Emma Dahlström; Erkka Valo; Nikolay Oskolkov; Claes Ladenvall; M Loredana Marcovecchio; Jason Cooper; Francesco Sambo; Alberto Malovini; Marco Manfrini; Amy Jayne McKnight; Maria Lajer; Valma Harjutsalo; Daniel Gordin; Maija Parkkonen; Jaakko Tuomilehto; Valeriya Lyssenko; Paul M McKeigue; Stephen S Rich; Mary Julia Brosnan; Eric Fauman; Riccardo Bellazzi; Peter Rossing; Samy Hadjadj; Andrzej Krolewski; Andrew D Paterson; Jose C Florez; Joel N Hirschhorn; Alexander P Maxwell; David Dunger; Claudio Cobelli; Helen M Colhoun; Leif Groop; Mark I McCarthy; Per-Henrik Groop Journal: J Am Soc Nephrol Date: 2016-09-19 Impact factor: 10.121
Authors: Rany M Salem; Jennifer N Todd; Niina Sandholm; Joanne B Cole; Wei-Min Chen; Darrell Andrews; Marcus G Pezzolesi; Paul M McKeigue; Linda T Hiraki; Chengxiang Qiu; Viji Nair; Chen Di Liao; Jing Jing Cao; Erkka Valo; Suna Onengut-Gumuscu; Adam M Smiles; Stuart J McGurnaghan; Jani K Haukka; Valma Harjutsalo; Eoin P Brennan; Natalie van Zuydam; Emma Ahlqvist; Ross Doyle; Tarunveer S Ahluwalia; Maria Lajer; Maria F Hughes; Jihwan Park; Jan Skupien; Athina Spiliopoulou; Andrew Liu; Rajasree Menon; Carine M Boustany-Kari; Hyun M Kang; Robert G Nelson; Ronald Klein; Barbara E Klein; Kristine E Lee; Xiaoyu Gao; Michael Mauer; Silvia Maestroni; Maria Luiza Caramori; Ian H de Boer; Rachel G Miller; Jingchuan Guo; Andrew P Boright; David Tregouet; Beata Gyorgy; Janet K Snell-Bergeon; David M Maahs; Shelley B Bull; Angelo J Canty; Colin N A Palmer; Lars Stechemesser; Bernhard Paulweber; Raimund Weitgasser; Jelizaveta Sokolovska; Vita Rovīte; Valdis Pīrāgs; Edita Prakapiene; Lina Radzeviciene; Rasa Verkauskiene; Nicolae Mircea Panduru; Leif C Groop; Mark I McCarthy; Harvest F Gu; Anna Möllsten; Henrik Falhammar; Kerstin Brismar; Finian Martin; Peter Rossing; Tina Costacou; Gianpaolo Zerbini; Michel Marre; Samy Hadjadj; Amy J McKnight; Carol Forsblom; Gareth McKay; Catherine Godson; A Peter Maxwell; Matthias Kretzler; Katalin Susztak; Helen M Colhoun; Andrzej Krolewski; Andrew D Paterson; Per-Henrik Groop; Stephen S Rich; Joel N Hirschhorn; Jose C Florez Journal: J Am Soc Nephrol Date: 2019-09-19 Impact factor: 14.978