Genome-wide association study of urinary albumin excretion rate in patients with type 1 diabetes

• Published in: Diabetologia Vol. 57; no. 6; pp. 1143 - 1153
• Main Authors: Sandholm, Niina, Forsblom, Carol, Mäkinen, Ville-Petteri, McKnight, Amy Jayne, Österholm, Anne-May, He, Bing, Harjutsalo, Valma, Lithovius, Raija, Gordin, Daniel, Parkkonen, Maija, Saraheimo, Markku, Thorn, Lena M., Tolonen, Nina, Wadén, Johan, Tuomilehto, Jaakko, Lajer, Maria, Ahlqvist, Emma, Möllsten, Anna, Marcovecchio, M. Loredana, Cooper, Jason, Dunger, David, Paterson, Andrew D., Zerbini, Gianpaolo, Groop, Leif, Tarnow, Lise, Maxwell, Alexander P., Tryggvason, Karl, Groop, Per-Henrik
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.06.2014; Springer; Springer Nature B.V
• Subjects: Adult; Albumin excretion rate; Albuminuria; Albuminuria - genetics; Antihypertensives; Associated diseases and complications; Biological and medical sciences; Biology; Breath tests; Clinical Medicine; Creatinine; Diabetes; Diabetes Mellitus, Type 1 - urine; Diabetes. Impaired glucose tolerance; Diabetic nephropathy; Endocrine pancreas. Apud cells (diseases); Endocrinology and Diabetes; Endocrinopathies; Endokrinologi och diabetes; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Genetics; Genome-Wide Association Study - methods; Genomes; Genotype; GLRA3; GWAS; Heritability; Hospitals; Human Physiology; Humans; Internal Medicine; Kidneys; Klinisk medicin; Male; Medical and Health Sciences; Medical sciences; Medicin och hälsovetenskap; Medicine; Medicine & Public Health; Metabolic Diseases; Metabolism; Middle Aged; Nephrology; Nephrology. Urinary tract diseases; Pediatrics; Polymorphism, Single Nucleotide - genetics; Science; Type 1 diabetes; Urinary system involvement in other diseases. Miscellaneous; Los Angeles California; Sweden; United Kingdom > UK; United States > US; Ireland; Finland; Denmark; Aarhus Denmark; GWAS; Albumin excretion rate; Type 1 diabetes; Diabetic nephropathy; Genetics; Heritability; Albuminuria; Endocrinopathy; Kidney disease; Human; Immunopathology; Excretion; Urinary system disease; Albumin; Autoimmune disease; Concomitant disease; GLRA3; Genome
• ISSN: 0012-186X; 1432-0428; 1432-0428
• DOI: 10.1007/s00125-014-3202-3

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.