A1 Refereed original research article in a scientific journal
The Genetic Landscape of Renal Complications in Type 1 Diabetes
Authors: Sandholm N, Van Zuydam N, Ahlqvist E, Juliusdottir T, Deshmukh HA, Rayner NW, Di Camillo B, Forsblom C, Fadista J, Ziemek D, Salem RM, Hiraki LT, Pezzolesi M, Tregouet D, Dahlstrom E, Valo E, Oskolkov N, Ladenvall C, Marcovecchio ML, Cooper J, Sambo F, Malovini A, Manfrini M, McKnight AJ, Lajer M, Harjutsalo V, Gordin D, Parkkonen M; The FinnDiane Study Group, Tuomilehto J, Lyssenko V, McKeigue PM, Rich SS, Brosnan MJ, Fauman E, Bellazzi R, Rossing P, Hadjadj S, Krolewski A, Paterson AD, Florez JC, Hirschhorn JN, Maxwell AP, Dunger D, Cobelli C, Colhoun HM, Groop L, McCarthy MI, Groop PH; on behalf of The SUMMIT Consortium
Publisher: AMER SOC NEPHROLOGY
Publication year: 2017
Journal: Journal of the American Society of Nephrology
Journal name in source: JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
Journal acronym: J AM SOC NEPHROL
Volume: 28
Issue: 2
First page : 557
Last page: 574
Number of pages: 18
ISSN: 1046-6673
DOI: https://doi.org/10.1681/ASN.2016020231
Diabetes is the leading cause of ESRD. Despite evidence for a substantial heritability of diabetic kidney disease, efforts to identify genetic susceptibility variants have had limited success. We extended previous efforts in three dimensions, examining a more comprehensive set of genetic variants in larger numbers of subjects with type 1 diabetes characterized for a wider range of cross-sectional diabetic kidney disease phenotypes. In 2843 subjects, we estimated that the heritability of diabetic kidney disease was 35% (P=6.4x10(-3)). Genome-wide association analysis and replication in 12,540 individuals identified no single variants reaching stringent levels of significance and, despite excellent power, provided little independent confirmation of previously published associated variants. Whole-exome sequencing in 997 subjects failed to identify any large-effect coding alleles of lower frequency influencing the risk of diabetic kidney disease. However, sets of alleles increasing body mass index (P=2.2x10(-5)) and the risk of type 2 diabetes (P=6.1x10(-4)) associated with the risk of diabetic kidney disease. We also found genome-wide genetic correlation between diabetic kidney disease and failure at smoking cessation (P=1.1x10(-4)). Pathway analysis implicated ascorbate and aldarate metabolism (P=9.0x10(-6)), and pentose and glucuronate interconversions (P=3.0x10(-6)) in pathogenesis of diabetic kidney disease. These data provide further evidence for the role of genetic factors influencing diabetic kidney disease in those with type 1 diabetes and highlight some key pathways that may be responsible. Altogether these results reveal important biology behind the major cause of kidney disease.
