[R01] Hispanic Latino Lipid Consortium
Ente: National Heart Lung and Blood Institute
Scadenza: 2027-03-31
Importo max: 634.509 EUR
Paese: US
Descrizione
Cardiometabolic diseases (CMD), including obesity, dyslipidemia, type 2 diabetes, and hypertension, are the leading cause of disease burden in the world. In the first funding period of our project, The Hispanic/Latino Lipid Consortium (HLLC), our efforts centered on discovering genetic factors impacting serum lipid levels, obesity, and T2D in self-identified Hispanic/Latinos (HL), a population with high rates of genetic admixture and markedly elevated rates of CMD and CMD risk factors relative to other US populations. Importantly, our study is nested within populations reflecting a variety of genetic ancestries prevalent in the US that experience a disproportionate burden of disease driven by distinct environmental exposures, thereby enhancing our ability to identify novel biological mechanisms and targets with broad relevance and translational potential across populations. This highly impactful research, which has resulted in 39 published papers to date, leveraged extant genetic data as well as new genetic data generated for the project in >63k participants of admixed genetic ancestry to identify multiple new CMD loci. We also characterized the regulatory mechanisms influencing lipid levels using a new resource of whole blood (WB) gene expression profiles in 880 participants. Yet, the mechanism of action of most GWAS signals and the molecular pathways disrupted in metabolic tissues are just emerging. As such, in the second funding period of the HLLC, we propose to build on our remarkable success and experience generating, analyzing, and integrating transcriptomic data. Here, we aim to investigate the role of multi-tissue gene expression (WB and subcutaneous adipose tissue [SAT]) and changes in WB expression over time with the goal of identifying key modifiable molecular signatures associated with CMDs in an even larger sample of individuals with a high burden of disease. Specifically, we propose to: first, identify multi-tissue transcriptomic patterns associated with CMD and related traits (obesity,T2D, dyslipidemia, hypertension measures) in recently acquired WB RNA sequencing data from 14k participants as well as in 300 SAT tissue specimens from participants recruited for the present application; second, identify longitudinal changes in WB transcriptomic data associated with changes in CMD-related risk factors in participants (1500 RNA measures from 750 participants with an average of 5 years between the two RNA sequencing measures for each person); and third, conduct integrative analyses of genetic and transcriptomic data from populations to establish causality via Mendelian Randomization and characterize existing genomic findings with functional evidence. Our aims are entirely independent, exceptionally well powered, and designed to answer critical questions about the causal pathways underlying observed transcriptomic differences in CMD. This work will result in creation of a publicly available resource of eQTL information for metabolic tiss
Istituzione: VANDERBILT UNIVERSITY MEDICAL CENTER
PI: Jennifer Below, JOSEPH MCCORMICK, Kari E. North
Progetto: 5R01HL142302-08
Settori: National Heart Lung and Blood Institute
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