Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels
Identifikátory výsledku
Kód výsledku v IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00064190%3A_____%2F19%3AN0000025" target="_blank" >RIV/00064190:_____/19:N0000025 - isvavai.cz</a>
Nalezeny alternativní kódy
RIV/00216208:11110/19:10400902
Výsledek na webu
<a href="http://dx.doi.org/10.1038/s41588-019-0504-x" target="_blank" >http://dx.doi.org/10.1038/s41588-019-0504-x</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1038/s41588-019-0504-x" target="_blank" >10.1038/s41588-019-0504-x</a>
Alternativní jazyky
Jazyk výsledku
angličtina
Název v původním jazyce
Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels
Popis výsledku v původním jazyce
Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.
Název v anglickém jazyce
Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels
Popis výsledku anglicky
Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.
Klasifikace
Druh
J<sub>imp</sub> - Článek v periodiku v databázi Web of Science
CEP obor
—
OECD FORD obor
30201 - Cardiac and Cardiovascular systems
Návaznosti výsledku
Projekt
—
Návaznosti
N - Vyzkumna aktivita podporovana z neverejnych zdroju
Ostatní
Rok uplatnění
2019
Kód důvěrnosti údajů
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Údaje specifické pro druh výsledku
Název periodika
NATURE GENETICS
ISSN
1061-4036
e-ISSN
1546-1718
Svazek periodika
51
Číslo periodika v rámci svazku
10
Stát vydavatele periodika
US - Spojené státy americké
Počet stran výsledku
16
Strana od-do
1459-1474
Kód UT WoS článku
000489016400010
EID výsledku v databázi Scopus
2-s2.0-85074209366