Key result
Rare ANGPTL3 loss-of-function variant linked to ~63% lower circulating ANGPTL3 protein levels.
Why the study?
ANGPTL3 inhibition shows promise for atherosclerotic cardiovascular disease treatment, prompting assessment of the genetic basis of variation in ANGPTL3 levels and its correlation with the plasma lipidome.
Does the rs398122988 loss-of-function variant in ANGPTL3 reduce ANGPTL3 protein levels and alter the plasma lipidome?
Observational (n=1,030)
Does the rs398122988 loss-of-function variant in ANGPTL3 reduce ANGPTL3 protein levels and alter the plasma lipidome?
Standardized Mean Difference: -1.69
Absolute Event Rate: 82.76% vs 221.74%
p-value: p=3.367x10^-13
A loss-of-function variant in ANGPTL3 is associated not only with lower ANGPTL3 and classical lipids but also with decreased phosphatidylinositols, revealing novel lipidomic mechanisms that may contribute to cardioprotection.
Extends ANGPTL3 variant effects to phosphatidylinositols; hypothesis-generating and should not yet change practice.
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 (h 2 =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.
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Blackburn et al. (2021) reported an observational. rs398122988 loss-of-function variant in ANGPTL3 vs. Non-carriers was evaluated on ANGPTL3 protein levels (β=-1.69 SD units, p=3.367x10^-13). The rare loss-of-function variant rs398122988 in ANGPTL3 was associated with significantly lower ANGPTL3 protein levels (β=-1.69 SD units) and novel decreases in phosphatidylinositols.
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