Back to Search
Start Over
Loss-of-function genomic variants with impact on liver-related blood traits highlight potential therapeutic targets for cardiovascular disease
- Publication Year :
- 2019
- Publisher :
- Cold Spring Harbor Laboratory, 2019.
-
Abstract
- SUMMARYCardiovascular diseases (CVD), and in particular cerebrovascular and ischemic heart diseases, are leading causes of death globally.1Lowering circulating lipids is an important treatment strategy to reduce risk.2,3However, some pharmaceutical mechanisms of reducing CVD may increase risk of fatty liver disease or other metabolic disorders.4,5,6To identify potential novel therapeutic targets, which may reduce risk of CVD without increasing risk of metabolic disease, we focused on the simultaneous evaluation of quantitative traits related to liver function and CVD. Using a combination of low-coverage (5×) whole-genome sequencing and targeted genotyping, deep genotype imputation based on the TOPMed reference panel7, and genome-wide association study (GWAS) meta-analysis, we analyzed 12 liver-related blood traits (including liver enzymes, blood lipids, and markers of iron metabolism) in up to 203,476 people from three population-based cohorts of different ancestries. We identified 88 likely causal protein-altering variants that were associated with one or more liver-related blood traits. We identified several loss-of-function (LoF) variants reducing low-density lipoprotein cholesterol (LDL-C) or risk of CVD without increased risk of liver disease or diabetes, including variants in known lipid genes (e.g.APOB,LPL). A novel LoF variant,ZNF529:p.K405X, was associated with decreased levels of LDL-C (P=1.3×10−8) but demonstrated no association with liver enzymes or non-fasting blood glucose levels. Silencing ofZNF529in human hepatocytes resulted in upregulation of LDL receptor (LDLR) and increased LDL-C uptake in the cells, suggesting that inhibition ofZNF529or its gene product could be used for treating hypercholesterolemia and hence reduce the risk of CVD. Taken together, we demonstrate that simultaneous consideration of multiple phenotypes and a focus on rare protein-altering variants may identify promising therapeutic targets.
- Subjects :
- 2. Zero hunger
0303 health sciences
education.field_of_study
business.industry
Population
Fatty liver
Blood lipids
Genome-wide association study
Disease
030204 cardiovascular system & hematology
Bioinformatics
medicine.disease
3. Good health
03 medical and health sciences
Liver disease
0302 clinical medicine
Diabetes mellitus
Medicine
Liver function
business
education
030304 developmental biology
Subjects
Details
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....a9ab439754e92e14817883bdadc485f8
- Full Text :
- https://doi.org/10.1101/597377