Ahmed Khattab1,2, Ali Torkamani3,4. 1. Integrative Structural and Computational Biology, Scripps Research, 3344 North Torrey Pines Court, Suite 300, La Jolla, CA, 92037, USA. 2. Scripps Research Translational Institute, La Jolla, CA, 92037, USA. 3. Integrative Structural and Computational Biology, Scripps Research, 3344 North Torrey Pines Court, Suite 300, La Jolla, CA, 92037, USA. atorkama@scripps.edu. 4. Scripps Research Translational Institute, La Jolla, CA, 92037, USA. atorkama@scripps.edu.
Abstract
BACKGROUND: Diabetic kidney disease (DKD) affects about 40% of patients with diabetes. It is incurable and usually leads to end-stage renal disease (ESRD). The pathogenesis of DKD is still not fully understood, and the genetics of DKD have not yet been extensively studied. In this study, we investigate the genetic basis of DKD in type 2 diabetes (T2D) to provide more insights into the pathogenesis of the disease. RESULTS: Using the data provided by the UK Biobank (UKBB), we performed a DKD genome-wide association study (GWAS) in 13,123 individuals with T2D as well as two creatinine estimated glomerular filtration rate (eGFR) GWA studies: one in 26,786 individuals with T2D and the other in 339,080 non-diabetic individuals. We also conducted a DKD GWAS meta-analysis combining our results with those published by the surrogate markers for micro- and macro-vascular hard endpoints for Innovative diabetes Tools (SUMMIT) consortium. We confirm two loci previously reported to be associated with chronic kidney disease (CKD) and eGFR in T2D. The UMOD-PDILT locus is associated with DKD (P = 1.17E-09) as well as creatinine eGFR in both people with T2D (P = 1.31E-15) and people without diabetes (P = 3.95E-73). The PRKAG2 locus is associated with creatinine eGFR in people with (P = 2.78E-10) and without (P = 5.65E-72) T2D. Our meta-analysis reveals a novel association between DKD and variant rs72763500 (chr1:236116561) which is a splicing quantitative trait locus (sQTL) for nidogen-1 (NID1) gene. CONCLUSION: Our data confirm two loci previously reported in association with CKD and creatinine eGFR in T2D. It also suggests that NID1, a major component of the renal tubular basement membrane, could play a role in DKD development in T2D. While our NID1 finding remains to be replicated, it is a step toward a more comprehensive understanding of DKD pathogenesis.
BACKGROUND: Diabetic kidney disease (DKD) affects about 40% of patients with diabetes. It is incurable and usually leads to end-stage renal disease (ESRD). The pathogenesis of DKD is still not fully understood, and the genetics of DKD have not yet been extensively studied. In this study, we investigate the genetic basis of DKD in type 2 diabetes (T2D) to provide more insights into the pathogenesis of the disease. RESULTS: Using the data provided by the UK Biobank (UKBB), we performed a DKD genome-wide association study (GWAS) in 13,123 individuals with T2D as well as two creatinine estimated glomerular filtration rate (eGFR) GWA studies: one in 26,786 individuals with T2D and the other in 339,080 non-diabetic individuals. We also conducted a DKD GWAS meta-analysis combining our results with those published by the surrogate markers for micro- and macro-vascular hard endpoints for Innovative diabetes Tools (SUMMIT) consortium. We confirm two loci previously reported to be associated with chronic kidney disease (CKD) and eGFR in T2D. The UMOD-PDILT locus is associated with DKD (P = 1.17E-09) as well as creatinine eGFR in both people with T2D (P = 1.31E-15) and people without diabetes (P = 3.95E-73). The PRKAG2 locus is associated with creatinine eGFR in people with (P = 2.78E-10) and without (P = 5.65E-72) T2D. Our meta-analysis reveals a novel association between DKD and variant rs72763500 (chr1:236116561) which is a splicing quantitative trait locus (sQTL) for nidogen-1 (NID1) gene. CONCLUSION: Our data confirm two loci previously reported in association with CKD and creatinine eGFR in T2D. It also suggests that NID1, a major component of the renal tubular basement membrane, could play a role in DKD development in T2D. While our NID1 finding remains to be replicated, it is a step toward a more comprehensive understanding of DKD pathogenesis.
Authors: Natalie R van Zuydam; Emma Ahlqvist; Niina Sandholm; Harshal Deshmukh; N William Rayner; Moustafa Abdalla; Claes Ladenvall; Daniel Ziemek; Eric Fauman; Neil R Robertson; Paul M McKeigue; Erkka Valo; Carol Forsblom; Valma Harjutsalo; Annalisa Perna; Erica Rurali; M Loredana Marcovecchio; Robert P Igo; Rany M Salem; Norberto Perico; Maria Lajer; Annemari Käräjämäki; Minako Imamura; Michiaki Kubo; Atsushi Takahashi; Xueling Sim; Jianjun Liu; Rob M van Dam; Guozhi Jiang; Claudia H T Tam; Andrea O Y Luk; Heung Man Lee; Cadmon K P Lim; Cheuk Chun Szeto; Wing Yee So; Juliana C N Chan; Su Fen Ang; Rajkumar Dorajoo; Ling Wang; Tan Si Hua Clara; Amy-Jayne McKnight; Seamus Duffy; Marcus G Pezzolesi; Michel Marre; Beata Gyorgy; Samy Hadjadj; Linda T Hiraki; Tarunveer S Ahluwalia; Peter Almgren; Christina-Alexandra Schulz; Marju Orho-Melander; Allan Linneberg; Cramer Christensen; Daniel R Witte; Niels Grarup; Ivan Brandslund; Olle Melander; Andrew D Paterson; David Tregouet; Alexander P Maxwell; Su Chi Lim; Ronald C W Ma; E Shyong Tai; Shiro Maeda; Valeriya Lyssenko; Tiinamaija Tuomi; Andrzej S Krolewski; Stephen S Rich; Joel N Hirschhorn; Jose C Florez; David Dunger; Oluf Pedersen; Torben Hansen; Peter Rossing; Giuseppe Remuzzi; Mary Julia Brosnan; Colin N A Palmer; Per-Henrik Groop; Helen M Colhoun; Leif C Groop; Mark I McCarthy Journal: Diabetes Date: 2018-04-27 Impact factor: 9.461
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