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Modulation of genetic associations with serum urate levels by body-mass-index in humans.

TitleModulation of genetic associations with serum urate levels by body-mass-index in humans.
Publication TypeJournal Article
Year of Publication2015
AuthorsHuffman JE, Albrecht E, Teumer A, et al.
Secondary AuthorsVitart V
JournalPLoS One
Volume10
Issue3
Paginatione0119752
Date Published2015
ISSN1932-6203
KeywordsAntigens, Nuclear, ATP Binding Cassette Transporter, Subfamily G, Member 2, ATP-Binding Cassette Transporters, Body Mass Index, Edar Receptor, Female, Genetic Loci, Genome-Wide Association Study, Genotype, Gout, Humans, Linear Models, Male, Membrane Glycoproteins, Neoplasm Proteins, Nerve Tissue Proteins, Obesity, Overweight, Oxidoreductases Acting on Sulfur Group Donors, Polymorphism, Single Nucleotide, Risk Factors, Uric Acid
Abstract

We tested for interactions between body mass index (BMI) and common genetic variants affecting serum urate levels, genome-wide, in up to 42569 participants. Both stratified genome-wide association (GWAS) analyses, in lean, overweight and obese individuals, and regression-type analyses in a non BMI-stratified overall sample were performed. The former did not uncover any novel locus with a major main effect, but supported modulation of effects for some known and potentially new urate loci. The latter highlighted a SNP at RBFOX3 reaching genome-wide significant level (effect size 0.014, 95% CI 0.008-0.02, Pinter= 2.6 x 10-8). Two top loci in interaction term analyses, RBFOX3 and ERO1LB-EDARADD, also displayed suggestive differences in main effect size between the lean and obese strata. All top ranking loci for urate effect differences between BMI categories were novel and most had small magnitude but opposite direction effects between strata. They include the locus RBMS1-TANK (men, Pdifflean-overweight= 4.7 x 10-8), a region that has been associated with several obesity related traits, and TSPYL5 (men, Pdifflean-overweight= 9.1 x 10-8), regulating adipocytes-produced estradiol. The top-ranking known urate loci was ABCG2, the strongest known gout risk locus, with an effect halved in obese compared to lean men (Pdifflean-obese= 2 x 10-4). Finally, pathway analysis suggested a role for N-glycan biosynthesis as a prominent urate-associated pathway in the lean stratum. These results illustrate a potentially powerful way to monitor changes occurring in obesogenic environment.

DOI10.1371/journal.pone.0119752
Alternate JournalPLoS One
PubMed ID25811787
PubMed Central IDPMC4374966
Grant ListUL1RR025005 / RR / NCRR NIH HHS / United States
G9521010 / / Medical Research Council / United Kingdom
MC_PC_U127527198 / / Medical Research Council / United Kingdom
R01HL59367 / HL / NHLBI NIH HHS / United States
HHSN268201100005C / / PHS HHS / United States
12076 / / Cancer Research UK / United Kingdom
G9521010D / / Medical Research Council / United Kingdom
HHSN268201100009C / / PHS HHS / United States
HHSN268200625226C / / PHS HHS / United States
MR/K026992/1 / / Medical Research Council / United Kingdom
HHSN268201100010C / / PHS HHS / United States
U01HG004402 / HG / NHGRI NIH HHS / United States
HHSN268201100008C / / PHS HHS / United States
HHSN268201100012C / / PHS HHS / United States
095831 / / Wellcome Trust / United Kingdom
R01HL087641 / HL / NHLBI NIH HHS / United States
C348/A12076 / / Cancer Research UK / United Kingdom
MC_PC_U127592696 / / Medical Research Council / United Kingdom
MR/K018647/1 / / Medical Research Council / United Kingdom
MC_PC_U127561128 / / Medical Research Council / United Kingdom
HHSN268201100007C / / PHS HHS / United States
MR/K006584/1 / / Medical Research Council / United Kingdom
N01-AG-12100 / AG / NIA NIH HHS / United States
HHSN268201100011C / / PHS HHS / United States
C348/A6361 / / Cancer Research UK / United Kingdom
G0700704 / / Medical Research Council / United Kingdom
/ / Wellcome Trust / United Kingdom
BB/F019394/1 / / Biotechnology and Biological Sciences Research Council / United Kingdom
HHSN268201100006C / / PHS HHS / United States
G0000657-53203 / / Medical Research Council / United Kingdom
R01HL086694 / HL / NHLBI NIH HHS / United States