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

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 D.; Dunger, David B.; Paterson, Andrew D.; Zerbini, Gianpaolo; Groop, Leif; Tarnow, Lise; Maxwell, Alexander P.; Tryggvason, Karl; Groop, Per Henrik

doi:10.1007/s00125-014-3202-3

Cited by 52 publications

(56 citation statements)

References 41 publications

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“…There have been a few albuminuria GWASs in the past decade [10–12, 31], all exploring the common genetic variants (MAF>5%), but in the current study we examined low-frequency and rare variants, particularly from the coding region (exome) of the genome.…”

Section: Discussionmentioning

confidence: 99%

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A novel rare CUBN variant and three additional genes identified in Europeans with and without diabetes: results from an exome-wide association study of albuminuria

et al. 2018

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Aims/hypothesisIdentifying rare coding variants associated with albuminuria may open new avenues for preventing chronic kidney disease and end-stage renal disease, which are highly prevalent in individuals with diabetes. Efforts to identify genetic susceptibility variants for albuminuria have so far been limited, with the majority of studies focusing on common variants.MethodsWe performed an exome-wide association study to identify coding variants in a two-stage (discovery and replication) approach. Data from 33,985 individuals of European ancestry (15,872 with and 18,113 without diabetes) and 2605 Greenlanders were included.ResultsWe identified a rare (minor allele frequency [MAF]: 0.8%) missense (A1690V) variant in CUBN (rs141640975, β = 0.27, p = 1.3 × 10−11) associated with albuminuria as a continuous measure in the combined European meta-analysis. The presence of each rare allele of the variant was associated with a 6.4% increase in albuminuria. The rare CUBN variant had an effect that was three times stronger in individuals with type 2 diabetes compared with those without (pinteraction = 7.0 × 10−4, β with diabetes = 0.69, β without diabetes = 0.20) in the discovery meta-analysis. Gene-aggregate tests based on rare and common variants identified three additional genes associated with albuminuria (HES1, CDC73 and GRM5) after multiple testing correction (pBonferroni < 2.7 × 10−6).Conclusions/interpretationThe current study identifies a rare coding variant in the CUBN locus and other potential genes associated with albuminuria in individuals with and without diabetes. These genes have been implicated in renal and cardiovascular dysfunction. The findings provide new insights into the genetic architecture of albuminuria and highlight target genes and pathways for the prevention of diabetes-related kidney disease.Electronic supplementary materialThe online version of this article (10.1007/s00125-018-4783-z) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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Section: Discussionmentioning

confidence: 99%

“…None of the studies overlapped with the previous albuminuria GWASs except two replication cohorts within the IMI-SUMMIT Consortia (Finnish Diabetic Nephropathy Study [FinnDiane] and Scania Diabetes Register) that participated in the type 1 diabetes albuminuria GWAS [12]. …”

Section: Methodsmentioning

confidence: 99%

A novel rare CUBN variant and three additional genes identified in Europeans with and without diabetes: results from an exome-wide association study of albuminuria

et al. 2018

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“…As in other series in our center, some patients developed clinical DN relatively late in the post-transplantation period (5 to 13 years) expressed by micro-and macro-albuminuria [8] and decline of graft function. Graft biopsy results revealed a histologic diagnosis of diabetic glomerulosclerosis.…”

Section: Discussionmentioning

confidence: 84%

Renal Transplantation in Type 1 Diabetes Mellitus: An Unusual Case Report

Guerra

Melo

Gonçalves

et al. 2015

Transplantation Proceedings

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“…In 2014, Sandholm performed a GWAS including 1,925 patients with T1D to analyze the 24-hour AER as a continuous trait [88]. The analysis was stratified by the use of antihypertensive medication.…”

Section: Genome Wide Association Studiesmentioning

confidence: 99%

Novel Genetic Actors of Diabetes-Associated Microvascular Complications: Retinopathy, Kidney Disease and Neuropathy

Davoudi¹,

Sobrin²

2016

Rev Diabet Stud

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■ AbstractBoth type 1 and type 2 diabetes mellitus can lead to the common microvascular complications of diabetic retinopathy, kidney disease, and neuropathy. Diabetic patients do not universally develop these complications. Long duration of diabetes and poor glycemic control explain a lot of the variability in the development of microvascular complications, but not all. Genetic factors account for some of the remaining variability because of the heritability and familial clustering of these complications. There have been a large number of investigations, including linkage studies, candidate gene studies, and genome-wide association studies, all of which have sought to identify the specific variants that increase susceptibility. For retinopathy, several genomewide association studies have been performed in small or midsize samples, but no reproducible loci across the studies have been identified. For diabetic kidney disease, genomewide association studies in larger samples have been performed, and loci for this complication are beginning to emerge. However, validation of the existing discoveries, and further novel discoveries in larger samples is ongoing. The amount of genetic research into diabetic neuropathy has been very limited, and much is dedicated to the understanding of genetic risk factors only. Collaborations that pool samples and aim to detect phenotype classifications more precisely are promising avenues for a better explanation of the genetics of diabetic microvascular complications.

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

Abstract: This study suggests novel pathways and molecular mechanisms for the pathogenesis of albuminuria in type 1 diabetes.

Cited by 52 publications

References 41 publications

A novel rare CUBN variant and three additional genes identified in Europeans with and without diabetes: results from an exome-wide association study of albuminuria

A novel rare CUBN variant and three additional genes identified in Europeans with and without diabetes: results from an exome-wide association study of albuminuria

Renal Transplantation in Type 1 Diabetes Mellitus: An Unusual Case Report

Novel Genetic Actors of Diabetes-Associated Microvascular Complications: Retinopathy, Kidney Disease and Neuropathy

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