Dataset Information

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

ABSTRACT: Elevated concentrations of albumin in the urine, albuminuria, are a hallmark of diabetic kidney disease and are associated with an 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 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. Single nucleotide polymorphisms at these loci demonstrated a genetic effect on UACR in individuals with but not without diabetes. The change in the average UACR per minor allele was 21% for HS6ST1 (P = 6.3 × 10(-7)) and 13% for RAB38/CTSC (P = 5.8 × 10(-7)). Experiments using streptozotocin-induced 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 versus control rats. Relative expression of RAB38 was higher in tubuli of patients with diabetic kidney disease compared with control subjects. The loci identified here confirm known pathways and highlight novel pathways influencing albuminuria.

SUBMITTER: Teumer A

PROVIDER: S-EPMC4764151 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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

Teumer Alexander A Tin Adrienne A Sorice Rossella R Gorski Mathias M Yeo Nan Cher NC Chu Audrey Y AY Li Man M Li Yong Y Mijatovic Vladan V Ko Yi-An YA Taliun Daniel D Luciani Alessandro A Chen Ming-Huei MH Yang Qiong Q Foster Meredith C MC Olden Matthias M Hiraki Linda T LT Tayo Bamidele O BO Fuchsberger Christian C Dieffenbach Aida Karina AK Shuldiner Alan R AR Smith Albert V AV Zappa Allison M AM Lupo Antonio A Kollerits Barbara B Ponte Belen B Stengel Bénédicte B Krämer Bernhard K BK Paulweber Bernhard B Mitchell Braxton D BD Hayward Caroline C Helmer Catherine C Meisinger Christa C Gieger Christian C Shaffer Christian M CM Müller Christian C Langenberg Claudia C Ackermann Daniel D Siscovick David D Boerwinkle Eric E Kronenberg Florian F Ehret Georg B GB Homuth Georg G Waeber Gerard G Navis Gerjan G Gambaro Giovanni G Malerba Giovanni G Eiriksdottir Gudny G Li Guo G Wichmann H Erich HE Grallert Harald H Wallaschofski Henri H Völzke Henry H Brenner Herrmann H Kramer Holly H Mateo Leach I I Rudan Igor I Hillege Hans L HL Beckmann Jacques S JS Lambert Jean Charles JC Luan Jian'an J Zhao Jing Hua JH Chalmers John J Coresh Josef J Denny Joshua C JC Butterbach Katja K Launer Lenore J LJ Ferrucci Luigi L Kedenko Lyudmyla L Haun Margot M Metzger Marie M Woodward Mark M Hoffman Matthew J MJ Nauck Matthias M Waldenberger Melanie M Pruijm Menno M Bochud Murielle M Rheinberger Myriam M Verweij Niek N Wareham Nicholas J NJ Endlich Nicole N Soranzo Nicole N Polasek Ozren O van der Harst Pim P Pramstaller Peter Paul PP Vollenweider Peter P Wild Philipp S PS Gansevoort Ron T RT Rettig Rainer R Biffar Reiner R Carroll Robert J RJ Katz Ronit R Loos Ruth J F RJ Hwang Shih-Jen SJ Coassin Stefan S Bergmann Sven S Rosas Sylvia E SE Stracke Sylvia S Harris Tamara B TB Corre Tanguy T Zeller Tanja T Illig Thomas T Aspelund Thor T Tanaka Toshiko T Lendeckel Uwe U Völker Uwe U Gudnason Vilmundur V Chouraki Vincent V Koenig Wolfgang W Kutalik Zoltan Z O'Connell Jeffrey R JR Parsa Afshin A Heid Iris M IM Paterson Andrew D AD de Boer Ian H IH Devuyst Olivier O Lazar Jozef J Endlich Karlhans K Susztak Katalin K Tremblay Johanne J Hamet Pavel P Jacob Howard J HJ Böger Carsten A CA Fox Caroline S CS Pattaro Cristian C Köttgen Anna A

Diabetes 20151202 3

Elevated concentrations of albumin in the urine, albuminuria, are a hallmark of diabetic kidney disease and are associated with an 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 and up to 46,061 without diabetes, followed by functional studies. K ...[more]

PMID: 26631737

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Project description:Plants synthesize specialized metabolites to facilitate environmental and ecological interactions. During evolution, plants diversified in their potential to synthesize these metabolites. Quantitative differences in metabolite levels of natural Arabidopsis (Arabidopsis thaliana) accessions can be employed to unravel the genetic basis for metabolic traits using genome-wide association studies (GWAS). Here, we performed metabolic GWAS on seeds of a panel of 315 A. thaliana natural accessions, including the reference genotypes C24 and Col-0, for polar and semi-polar seed metabolites using untargeted ultra-performance liquid chromatography-mass spectrometry. As a complementary approach, we performed quantitative trait locus (QTL) mapping of near-isogenic introgression lines between C24 and Col-0 for specific seed specialized metabolites. Besides common QTL between seeds and leaves, GWAS revealed seed-specific QTL for specialized metabolites, indicating differences in the genetic architecture of seeds and leaves. In seeds, aliphatic methylsulfinylalkyl and methylthioalkyl glucosinolates associated with the ALKENYL HYDROXYALKYL PRODUCING loci (GS-ALK and GS-OHP) on chromosome 4 containing alkenyl hydroxyalkyl producing 2 (AOP2) and 3 (AOP3) or with the GS-ELONG locus on chromosome 5 containing methylthioalkyl malate synthase (MAM1) and MAM3. We detected two unknown sulfur-containing compounds that were also mapped to these loci. In GWAS, some of the annotated flavonoids (kaempferol 3-O-rhamnoside-7-O-rhamnoside, quercetin 3-O-rhamnoside-7-O-rhamnoside) were mapped to transparent testa 7 (AT5G07990), encoding a cytochrome P450 75B1 monooxygenase. Three additional mass signals corresponding to quercetin-containing flavonols were mapped to UGT78D2 (AT5G17050). The association of the loci and associating metabolic features were functionally verified in knockdown mutant lines. By performing GWAS and QTL mapping, we were able to leverage variation of natural populations and parental lines to study seed specialized metabolism. The GWAS data set generated here is a high-quality resource that can be investigated in further studies.

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

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

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