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Identifying the Lipidomic Effects of a Rare Loss-of-Function Deletion in ANGPTL3
Nicholas B Blackburn1,2,3, Peter J Meikle4, Juan M Peralta1,2,3
1South Texas Diabetes and Obesity Institute (N.B.B., J.M.P., S.K., A.C.L., M.C.M., H.H.H.G., J.L.V., S.W.-B., R.D., J.B., J.E.C.), School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX.
Insights
Genetic variation in angiopoietin-like 3 (ANGPTL3) significantly impacts its protein levels and is linked to atherosclerotic cardiovascular disease risk factors. Loss-of-function variants in ANGPTL3 are associated with lower levels and altered plasma lipidome, highlighting its therapeutic potential.
Area of Science:
- Genetics and genomics
- Cardiovascular disease research
- Metabolic disorders
Background:
- Atherosclerotic cardiovascular disease (ASCVD) poses a significant global health and economic burden.
- Inhibition of angiopoietin-like 3 (ANGPTL3) shows cardioprotective effects and is a promising therapeutic target for ASCVD.
- Understanding the genetic basis of ANGPTL3 variation is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the genetic underpinnings of variation in ANGPTL3 protein levels within a Mexican American cohort.
- To explore the correlation between ANGPTL3 levels, its genetic variants, and the plasma lipidome.
- To further elucidate ANGPTL3's role as a therapeutic target for atherosclerotic cardiovascular disease.
Main Methods:
- Assayed ANGPTL3 protein levels in approximately 1000 Mexican Americans from extended pedigrees.
- Utilized existing plasma lipidome profiles and genomic data for comprehensive analysis.
- Conducted variance components analysis and genome-wide linkage scans to identify genetic influences on ANGPTL3 levels.
Main Results:
- ANGPTL3 protein levels exhibited significant heritability (h²=0.33, P=1.31×10⁻¹⁶).
- A significant linkage signal was identified on chromosome 1, corresponding to the ANGPTL3 gene locus.
- A novel loss-of-function variant (rs398122988) in ANGPTL3 was strongly associated with lower ANGPTL3 levels and linked to phosphatidylinositol variations.
Conclusions:
- Variation in ANGPTL3 protein levels is substantially heritable and genetically controlled.
- Both ANGPTL3 levels and its loss-of-function variants demonstrate significant associations with the plasma lipidome.
- These findings reinforce ANGPTL3's potential as a key therapeutic target for atherosclerotic cardiovascular disease.
Background:
The identification and understanding of therapeutic targets for atherosclerotic cardiovascular disease is of fundamental importance given its global health and economic burden. Inhibition of ANGPTL3 (angiopoietin-like 3) has demonstrated a cardioprotective effect, showing promise for atherosclerotic cardiovascular disease treatment, and is currently the focus of ongoing clinical trials. Here, we assessed the genetic basis of variation in ANGPTL3 levels in the San Antonio Family Heart Study.
Methods:
We assayed ANGPTL3 protein levels in ≈1000 Mexican Americans from extended pedigrees. By drawing upon existing plasma lipidome profiles and genomic data we conducted analyses to understand the genetic basis to variation in ANGPTL3 protein levels, and accordingly the correlation with the plasma lipidome.
Results:
In a variance components framework, we identified that variation in ANGPTL3 was significantly heritable (h2=0.33, P=1.31×10-16). To explore the genetic basis of this heritability, we conducted a genome-wide linkage scan and identified significant linkage (logarithm of odds =6.18) to a locus on chromosome 1 at 90 centimorgans, corresponding to the ANGPTL3 gene location. In the genomes of 23 individuals from a single pedigree, we identified a loss-of-function variant, rs398122988 (N121Kfs*2), in ANGPTL3, that was significantly associated with lower ANGPTL3 levels (β=-1.69 SD units, P=3.367×10-13), and accounted for the linkage signal at this locus. Given the known role of ANGPTL3 as an inhibitor of endothelial and lipoprotein lipase, we explored the association of ANGPTL3 protein levels and rs398122988 with the plasma lipidome and related phenotypes, identifying novel associations with phosphatidylinositols.
Conclusions:
Variation in ANGPTL3 protein levels is heritable and under significant genetic control. Both ANGPTL3 levels and loss-of-function variants in ANGPTL3 have significant associations with the plasma lipidome. These findings further our understanding of ANGPTL3 as a therapeutic target for atherosclerotic cardiovascular disease.
