Genome-wide Association Studies Identify Genetic Loci Associated with Albuminuria in Diabetes

Elevated concentrations of albumin in the urine, albuminuria, are a hallmark of diabetic kidney disease and associate with increased risk for end-stage renal disease and cardiovascular events. To gain insight into the pathophysiological mechanisms underlying albuminuria, we conducted meta-analyses of genome-wide association studies and independent replication in up to 5,825 individuals of European ancestry with diabetes mellitus and up to 46,061 without diabetes, followed by functional studies. Known associations of variants in CUBN, encoding cubilin, with the urinary albumin-to-creatinine ratio (UACR) were confirmed in the overall sample (p=2.4*10(-10)). Gene-by-diabetes interactions were detected and confirmed for variants in HS6ST1 and near RAB38/CTSC. SNPs at these loci demonstrated a genetic effect on UACR in individuals with but not without diabetes. The change in average UACR per minor allele was 21% for HS6ST1 and 13% for RAB38/CTSC (p=6.3*10(-7) and 5.8*10(-7), respectively). Experiments using streptozotocin-treated diabetic Rab38 knockout and control rats showed higher urinary albumin concentrations and reduced amounts of megalin and cubilin at the proximal tubule cell surface in Rab38 knockout vs. control rats. Relative expression of RAB38 was higher in tubuli of patients with diabetic kidney disease compared to controls. The loci identified here confirm known and highlight novel pathways influencing albuminuria.

False -positives and false-negatives in tests for trend

False-positive and false-negative values were calculated for five different designs of the trend test and it was demonstrated that a design suggested by Portier and Hoel in 1984 for a different problem produced the lowest false-positive and false-negative rates when applied to historical spontaneous tumor rate data for Fischer Rats. ^

Caii Crispi Sallustii Opera /

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C. Cornelii Taciti Opera /

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C. Cornelii Taciti Opera /

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C. Cornelii Taciti Opera /

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Richardi Porsoni Notae in Aristophanem,

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Publications of the Buffalo Historical Society.

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Ausgewählte lateinische Gedichte.

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Ricardi Prosoni Notae in Aristophanem, quibus Plutum comoediam /

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Heide und moor,

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The anatomy of melancholy : what it is, with all the kinds, causes, symptomes, prognostics, and several cures of it : in three partitions. With yheir several sections, members, and subsections, philosophically, medicinally, historically opened and cut up. /

Added engraved t.-p.

The anatomy of melancholy, what it is, with all the kinds, causes, symptoms, prognostics, and several cures of it. In three partitions: with their several sections, members, and subsections, philosophically, medicinally, historically opened and cut up.

Mode of access: Internet.