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Association of estimated glomerular filtration rate and urinary uromodulin concentrations with rare variants identified by UMOD gene region sequencing.

TitleAssociation of estimated glomerular filtration rate and urinary uromodulin concentrations with rare variants identified by UMOD gene region sequencing.
Publication TypeJournal Article
Year of Publication2012
AuthorsKöttgen A, Yang Q, Shimmin LC, Tin A, Schaeffer C, Coresh JJ, Liu X, Rampoldi L, Hwang S-J, Boerwinkle E, Hixson JE, Kao LWH
Secondary AuthorsFox CS
JournalPLoS One
Volume7
Issue5
Paginatione38311
Date Published2012
ISSN1932-6203
KeywordsAged, Conserved Sequence, Exons, Female, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Glomerular Filtration Rate, Humans, Kidney Diseases, Male, Middle Aged, Regulatory Sequences, Nucleic Acid, Sequence Analysis, DNA, Uromodulin
Abstract

BACKGROUND: Recent genome-wide association studies (GWAS) have identified common variants in the UMOD region associated with kidney function and disease in the general population. To identify novel rare variants as well as common variants that may account for this GWAS signal, the exons and 4 kb upstream region of UMOD were sequenced.

METHODOLOGY/PRINCIPAL FINDINGS: Individuals (n = 485) were selected based on presence of the GWAS risk haplotype and chronic kidney disease (CKD) in the ARIC Study and on the extremes of of the UMOD gene product, uromodulin, in urine (Tamm Horsfall protein, THP) in the Framingham Heart Study (FHS). Targeted sequencing was conducted using capillary based Sanger sequencing (3730 DNA Analyzer). Variants were tested for association with THP concentrations and estimated glomerular filtration rate (eGFR), and identified non-synonymous coding variants were genotyped in up to 22,546 follow-up samples. Twenty-four and 63 variants were identified in the 285 ARIC and 200 FHS participants, respectively. In both studies combined, there were 33 common and 54 rare (MAF

CONCLUSIONS/SIGNIFICANCE: Multiple novel rare variants in the UMOD region were identified, but none were consistently associated with eGFR in two independent study samples. Only V458L had modest association with THP levels in the general population and thus could not account for the observed GWAS signal.

DOI10.1371/journal.pone.0038311
Alternate JournalPLoS One
PubMed ID22693617
PubMed Central IDPMC3365030
Grant ListHHSN268201100012C / HL / NHLBI NIH HHS / United States
N01-HC-25195 / HC / NHLBI NIH HHS / United States
HHSN268201100009I / HL / NHLBI NIH HHS / United States
HHSN268201100010C / HL / NHLBI NIH HHS / United States
HHSN268201100008C / HL / NHLBI NIH HHS / United States
HHSN268201100005G / HL / NHLBI NIH HHS / United States
HHSN268201100008I / HL / NHLBI NIH HHS / United States
HHSN268201100005C / / PHS HHS / United States
TCR08006 / / Telethon / Italy
HHSN268201100009C / / PHS HHS / United States
HSN268201100007C / / PHS HHS / United States
HHSN268201100011I / HL / NHLBI NIH HHS / United States
HHSN268201100011C / HL / NHLBI NIH HHS / United States
HHSN268201100010C / / PHS HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
HHSN268201100006C / HL / NHLBI NIH HHS / United States
/ / Intramural NIH HHS / United States
HHSN268201100008C / / PHS HHS / United States
HHSN268201100012C / / PHS HHS / United States
HHSN268201100005I / HL / NHLBI NIH HHS / United States
1 R01 DK076770-01 / DK / NIDDK NIH HHS / United States
RC2 HG005697 / HG / NHGRI NIH HHS / United States
R01 DK076770 / DK / NIDDK NIH HHS / United States
HHSN268201100009C / HL / NHLBI NIH HHS / United States
HHSN268201100011C / / PHS HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
N01HC25195 / HL / NHLBI NIH HHS / United States
HHSN268201100006C / / PHS HHS / United States