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

TitreGenome-wide Association Studies Identify Genetic Loci Associated With Albuminuria in Diabetes.
Publication TypeJournal Article
Year of Publication2016
AuthorsTeumer, A, Tin, A, Sorice, R, Gorski, M, Yeo, NCher, Chu, AY, Li, M, Li, Y, Mijatovic, V, Ko, Y-A, Taliun, D, Luciani, A, Chen, M-H, Yang, Q, Foster, MC, Olden, M, Hiraki, LT, Tayo, BO, Fuchsberger, C, Dieffenbach, AKarina, Shuldiner, AR, Smith, AV, Zappa, AM, Lupo, A, Kollerits, B, Ponte, B, Stengel, B, Krämer, BK, Paulweber, B, Mitchell, BD, Hayward, C, Helmer, C, Meisinger, C, Gieger, C, Shaffer, CM, Muller, C, Langenberg, C, Ackermann, D, Siscovick, D, Boerwinkle, E, Kronenberg, F, Ehret, GB, Homuth, G, Waeber, G, Navis, G, Gambaro, G, Malerba, G, Eiriksdottir, G, Li, G, H Wichmann, E, Grallert, H, Wallaschofski, H, Volzke, H, Brenner, H, Kramer, H, I Leach, M, Rudan, I, Hillege, HL, Beckmann, JS, Lambert, JCharles, Luan, J'an, Zhao, JHua, Chalmers, J, Coresh, J, Denny, JC, Butterbach, K, Launer, LJ, Ferrucci, L, Kedenko, L, Haun, M, Metzger, M, Woodward, M, Hoffman, MJ, Nauck, M, Waldenberger, M, Pruijm, M, Bochud, M, Rheinberger, M, Verweij, N, Wareham, NJ, Endlich, N, Soranzo, N, Polasek, O, van der Harst, P, Pramstaller, PPaul, Vollenweider, P, Wild, PS, Gansevoort, RT, Rettig, R, Biffar, R, Carroll, RJ, Katz, R, Loos, RJF, Hwang, S-J, Coassin, S, Bergmann, S, Rosas, SE, Stracke, S, Harris, TB, Corre, T, Zeller, T, Illig, T, Aspelund, T, Tanaka, T, Lendeckel, U, Völker, U, Gudnason, V, Chouraki, V, Koenig, W, Kutalik, Z, O'Connell, JR, Parsa, A, Heid, IM, Paterson, AD, de Boer, IH, Devuyst, O, Lazar, J, Endlich, K, Susztak, K, Tremblay, J, Hamet, P, Jacob, HJ, Böger, CA, Fox, CS, Pattaro, C, Köttgen, A
Corporate AuthorsDCCT/EDIC
JournalDiabetes
Volume65
Issue3
Pagination803-17
Date Published2016 Mar
DOI10.2337/db15-1313
ISSN1939-327X
ISBN Number1939-327X (Electronic)
Mots-clésAdult, Aged, Albuminuria, Animals, Cathepsin C, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 2, Diabetic Nephropathies, Female, Gene Knockout Techniques, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Kidney, Kidney Tubules, Male, Middle Aged, Polymorphism, Single Nucleotide, rab GTP-Binding Proteins, Rats, Receptors, Cell Surface, Sulfotransferases
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.

Notes

Publication Status: aheadofprint

Alternate URL

http://www.ncbi.nlm.nih.gov/pubmed/26631737?dopt=Abstract

WOS ID (UT)

000370961000032

Alternate JournalDiabetes
Citation Key / SERVAL ID6557
Peer reviewRefereed
PubMed ID26631737
PubMed Central IDPMC4764151
Grant List2R01-069321 / / PHS HHS / United States
2R01-LM0-10098 / LM / NLM NIH HHS / United States
DK-063491 / DK / NIDDK NIH HHS / United States
DK0-87635 / DK / NIDDK NIH HHS / United States
HHSN268200625226C / / PHS HHS / United States
HHSN268201100005C / / PHS HHS / United States
HHSN268201100006C / / PHS HHS / United States
HHSN268201100007C / / PHS HHS / United States
HHSN268201100008C / / PHS HHS / United States
HHSN268201100009C / / PHS HHS / United States
HHSN268201100010C / / PHS HHS / United States
HHSN268201100011C / / PHS HHS / United States
HHSN268201100012C / / PHS HHS / United States
HHSN271201200022C / / PHS HHS / United States
K12-RR0-23250 / RR / NCRR NIH HHS / United States
M01-RR-00425 / RR / NCRR NIH HHS / United States
M01-RR-16500 / RR / NCRR NIH HHS / United States
MC_PC_U127561128 / / Medical Research Council / United Kingdom
MC_U106179471 / / Medical Research Council / United Kingdom
MC_UU_12015/1 / / Medical Research Council / United Kingdom
N01-AG-1-2100 / AG / NIA NIH HHS / United States
N01-HC-15103 / HC / NHLBI NIH HHS / United States
N01-HC-25195 / HC / NHLBI NIH HHS / United States
N01-HC-35129 / HC / NHLBI NIH HHS / United States
N01-HC-45133 / HC / NHLBI NIH HHS / United States
N01-HC-55222 / HC / NHLBI NIH HHS / United States
N01-HC-75150 / HC / NHLBI NIH HHS / United States
N01-HC-85079 / HC / NHLBI NIH HHS / United States
N01-HC-85086 / HC / NHLBI NIH HHS / United States
N01-HC-95159 / HC / NHLBI NIH HHS / United States
N01-HC-95160 / HC / NHLBI NIH HHS / United States
N01-HC-95161 / HC / NHLBI NIH HHS / United States
N01-HC-95162 / HC / NHLBI NIH HHS / United States
N01-HC-95163 / HC / NHLBI NIH HHS / United States
N01-HC-95164 / HC / NHLBI NIH HHS / United States
N01-HC-95165 / HC / NHLBI NIH HHS / United States
N01-HC-95166 / HC / NHLBI NIH HHS / United States
N01-HC-95167 / HC / NHLBI NIH HHS / United States
N01-HC-95168 / HC / NHLBI NIH HHS / United States
N01-HC-95169 / HC / NHLBI NIH HHS / United States
N02-HL-6-4278 / HL / NHLBI NIH HHS / United States
P30-DK0-72488 / DK / NIDDK NIH HHS / United States
R01-AG-18728 / AG / NIA NIH HHS / United States
R01-DK0-76077 / DK / NIDDK NIH HHS / United States
R01-HL-071205 / HL / NHLBI NIH HHS / United States
R01-HL-088119 / HL / NHLBI NIH HHS / United States
R01-HL-9367 / HL / NHLBI NIH HHS / United States
R01-HL0-86694 / HL / NHLBI NIH HHS / United States
R01-HL0-87641 / HL / NHLBI NIH HHS / United States
R01-HL0-87652 / HL / NHLBI NIH HHS / United States
RC2-GM092318 / GM / NIGMS NIH HHS / United States
U01 DK094157 / DK / NIDDK NIH HHS / United States
U01 DK094176 / DK / NIDDK NIH HHS / United States
U01-GM-074518-04 / GM / NIGMS NIH HHS / United States
U01-HG0-04402 / HG / NHGRI NIH HHS / United States
U01-HG04603 / HG / NHGRI NIH HHS / United States
U01-HL0-72515-06 / HL / NHLBI NIH HHS / United States
U01-HL0-80295 / HL / NHLBI NIH HHS / United States
U01-HL0-84756 / HL / NHLBI NIH HHS / United States
UL1-RR0-25005 / RR / NCRR NIH HHS / United States
WT091310 / / Wellcome Trust / United Kingdom
WT098051 / / Wellcome Trust / United Kingdom
/ / Cancer Research UK / United Kingdom
/ / Canadian Institutes of Health Research / Canada
/ / Intramural NIH HHS / United States
/ / Medical Research Council / United Kingdom

                         

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