Pulse lineResearch With Heart Logo

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

TitleGenome-wide Association Studies Identify Genetic Loci Associated With Albuminuria in Diabetes.
Publication TypeJournal Article
Year of Publication2016
AuthorsTeumer A, Tin A, Sorice R, et al.
Secondary AuthorsKöttgen A
Corporate AuthorsDCCT/EDIC
JournalDiabetes
Volume65
Issue3
Pagination803-17
Date Published2016 Mar
ISSN1939-327X
KeywordsAdult, 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.

DOI10.2337/db15-1313
Alternate JournalDiabetes
PubMed ID26631737
PubMed Central IDPMC4764151
Grant ListK12 RR023250 / RR / NCRR NIH HHS / United States
N01HC95160 / HL / NHLBI NIH HHS / United States
P30 DK072488 / DK / NIDDK NIH HHS / United States
M01 RR000425 / RR / NCRR NIH HHS / United States
U01-GM-074518-04 / GM / NIGMS NIH HHS / United States
HHSN268201100012C / HL / NHLBI NIH HHS / United States
DK0-87635 / DK / NIDDK NIH HHS / United States
N02-HL-6-4278 / HL / NHLBI NIH HHS / United States
N01-HC-25195 / HC / NHLBI NIH HHS / United States
2R01-LM0-10098 / LM / NLM NIH HHS / United States
U01-HG0-04402 / HG / NHGRI NIH HHS / United States
HHSN268201100009I / HL / NHLBI NIH HHS / United States
U01 DK094176 / DK / NIDDK NIH HHS / United States
N01-HC-95162 / HC / NHLBI NIH HHS / United States
DP3 DK108220 / DK / NIDDK NIH HHS / United States
HHSN268201100010C / HL / NHLBI NIH HHS / United States
UL1 RR025005 / RR / NCRR NIH HHS / United States
U01 HL080295 / HL / NHLBI NIH HHS / United States
N01HC95163 / HL / NHLBI NIH HHS / United States
HHSN268201100008C / HL / NHLBI NIH HHS / United States
HHSN268201100005G / HL / NHLBI NIH HHS / United States
R01-HL-088119 / HL / NHLBI NIH HHS / United States
HHSN268201100008I / HL / NHLBI NIH HHS / United States
U01-HG04603 / HG / NHGRI NIH HHS / United States
F32 HL009367 / HL / NHLBI NIH HHS / United States
HHSN268201100007C / HL / NHLBI NIH HHS / United States
R01 HL069321 / HL / NHLBI NIH HHS / United States
N01-HC-95163 / HC / NHLBI NIH HHS / United States
N01 HC015103 / HC / NHLBI NIH HHS / United States
N01-HC-95168 / HC / NHLBI NIH HHS / United States
N01HC95169 / HL / NHLBI NIH HHS / United States
/ CAPMC / CIHR / Canada
R01-HL0-86694 / HL / NHLBI NIH HHS / United States
HHSN268201100011I / HL / NHLBI NIH HHS / United States
P30 DK079637 / DK / NIDDK NIH HHS / United States
HHSN268201100011C / HL / NHLBI NIH HHS / United States
R01 HL086694 / HL / NHLBI NIH HHS / United States
U01 HG004603 / HG / NHGRI NIH HHS / United States
N01-HC-95159 / HC / NHLBI NIH HHS / United States
R01 DK087635 / DK / NIDDK NIH HHS / United States
R01 HL087652 / HL / NHLBI NIH HHS / United States
N01-HC-95165 / HC / NHLBI NIH HHS / United States
N01HC95164 / HL / NHLBI NIH HHS / United States
N01-AG-1-2100 / AG / NIA NIH HHS / United States
N01HC55222 / HL / NHLBI NIH HHS / United States
HHSN268200625226C / / PHS HHS / United States
U01 HG004402 / HG / NHGRI NIH HHS / United States
N01-HC-85086 / HC / NHLBI NIH HHS / United States
N01HC95162 / HL / NHLBI NIH HHS / United States
N01HC85086 / HL / NHLBI NIH HHS / United States
MC_UU_12015/1 / MRC_ / Medical Research Council / United Kingdom
R01 HL105756 / HL / NHLBI NIH HHS / United States
N01HC95168 / HL / NHLBI NIH HHS / United States
R01-HL0-87652 / HL / NHLBI NIH HHS / United States
WT091310 / WT_ / Wellcome Trust / United Kingdom
M01-RR-00425 / RR / NCRR NIH HHS / United States
MC_U106179471 / MRC_ / Medical Research Council / United Kingdom
U01 HL084756 / HL / NHLBI NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
HHSN268201100006C / HL / NHLBI NIH HHS / United States
K12-RR0-23250 / RR / NCRR NIH HHS / United States
N01-HC-95169 / HC / NHLBI NIH HHS / United States
HHSN268201100005I / HL / NHLBI NIH HHS / United States
N01-HC-95164 / HC / NHLBI NIH HHS / United States
N01HC95165 / HL / NHLBI NIH HHS / United States
R01-DK0-76077 / DK / NIDDK NIH HHS / United States
RC2-GM092318 / GM / NIGMS NIH HHS / United States
N01-HC-55222 / HC / NHLBI NIH HHS / United States
R01 LM010098 / LM / NLM NIH HHS / United States
R01-HL-071205 / HL / NHLBI NIH HHS / United States
U01-HL0-84756 / HL / NHLBI NIH HHS / United States
N01HC95159 / HL / NHLBI NIH HHS / United States
2R01-069321 / / PHS HHS / United States
N01HC95161 / HL / NHLBI NIH HHS / United States
N01-HC-75150 / HC / NHLBI NIH HHS / United States
P30 DK020541 / DK / NIDDK NIH HHS / United States
HHSN271201200022C / AG / NIA NIH HHS / United States
N01-HC-95160 / HC / NHLBI NIH HHS / United States
MC_PC_U127561128 / MRC_ / Medical Research Council / United Kingdom
U01 HL072515 / HL / NHLBI NIH HHS / United States
M01 RR016500 / RR / NCRR NIH HHS / United States
R01-HL0-87641 / HL / NHLBI NIH HHS / United States
/ ImNIH / Intramural NIH HHS / United States
N01HC75150 / HL / NHLBI NIH HHS / United States
N01HC95167 / HL / NHLBI NIH HHS / United States
U01 DK094157 / DK / NIDDK NIH HHS / United States
U01-HL0-80295 / HL / NHLBI NIH HHS / United States
HHSN268201100009C / HL / NHLBI NIH HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
N01HC25195 / HL / NHLBI NIH HHS / United States
R01 HL071205 / HL / NHLBI NIH HHS / United States
HHSN268201100007I / HL / NHLBI NIH HHS / United States
N01-HC-85079 / HC / NHLBI NIH HHS / United States
N01-HC-95161 / HC / NHLBI NIH HHS / United States
M01-RR-16500 / RR / NCRR NIH HHS / United States
N01HC85079 / HL / NHLBI NIH HHS / United States
N01HC95166 / HL / NHLBI NIH HHS / United States
DK-063491 / DK / NIDDK NIH HHS / United States
R01-AG-18728 / AG / NIA NIH HHS / United States
N01-HC-95166 / HC / NHLBI NIH HHS / United States
R01 HL087641 / HL / NHLBI NIH HHS / United States
P30-DK0-72488 / DK / NIDDK NIH HHS / United States
R01 DK076077 / DK / NIDDK NIH HHS / United States
N01 HC045133 / HC / NHLBI NIH HHS / United States
UL1-RR0-25005 / RR / NCRR NIH HHS / United States
R01 AG018728 / AG / NIA NIH HHS / United States
U01 GM074518 / GM / NIGMS NIH HHS / United States
N01 HC035129 / HC / NHLBI NIH HHS / United States
U01-HL0-72515-06 / HL / NHLBI NIH HHS / United States
/ CRUK_ / Cancer Research UK / United Kingdom
WT098051 / WT_ / Wellcome Trust / United Kingdom
N01-HC-95167 / HC / NHLBI NIH HHS / United States
R01 HL088119 / HL / NHLBI NIH HHS / United States
R01-HL-9367 / HL / NHLBI NIH HHS / United States