Genetic studies indicate potential of ANGPTL4 inhibition for lowering triglycerides and preventing coronary disease

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15 April 2016

Two recent genetic studies indicate that loss-of-function or inactivating variants in ANGPTL4 are associated with favourable lipid profiles, notably lowering of triglycerides, as well as protection from coronary heart disease.

Dewey FE, Gusarova V, O’Dushlaine C et al. Inactivating variants in ANGPTL4 and risk of coronary artery disease. N Engl J Med 2016;374:1123-33. Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators. Coding variation in ANGPTL4, LPL, and SVEP1 and the risk of coronary disease. N Engl J Med 2016;374:1134-44.

STUDY SUMMARY
Inactivating variants in ANGPTL4 and risk of coronary artery disease

Objective:

To investigate associations between variants in ANGPTL4 (including E40K, which is known to be associated with reduced plasma triglyceride levels, and novel rare, inactivating mutations) and lipid levels and coronary artery disease risk.

Study design:

Exome sequencing study, based on the DiscovEHR human genetics study.

Study population:

42,930 subjects of mainly European ancestry in the DiscovEHR human genetics study (median age 58 years, 59% female, 25% with coronary artery disease, and 38% on lipid-lowering therapy). Subjects included outpatients from primary care and specialty clinics and the cardiac catheterization laboratory, as well as patients who were referred for bariatric or abdominal vascular surgery.

Key outcomes:

Association of ANGPTL4 variants with lipid levels and coronary artery disease

Methods:

Mixed linear models (with age, sex, and log10-transformed body-mass index as fixed-effects covariates) were used to test for the association between genotype and lipid levels (low-density lipoprotein cholesterol [LDL-C], log10 high-density lipoprotein cholesterol [HDL-C) and log10 triglycerides). The model was additive for 0, 1, and 2 alleles for ANGPTL4 variants. Levels of total cholesterol and LDL-C were adjusted for the use of lipid modifying therapy. The same model (but without log10-transformed body-mass index) was used to test for the association between coronary artery disease (as defined by ICD-9–based diagnosis codes) and the ANGPTL4 variants in 10,552 participants with coronary artery disease and 29,223 controls without coronary artery disease. Odds ratios for coronary artery disease were estimated using logistic regression. An alpha level of 0.05 was indicative of statistical significance.

Main results:

Exome sequencing identified 1,661 heterozygotes and 17 homozygotes for the E40K variant. Additionally, 75 subjects had 13 other monoallelic inactivating mutations in ANGPTL4.

Compared with non-carriers, carriers of the E40K variant had

13% lower triglycerides levels (p=2.0×10−23); median (range) 115 (85–157) mg/dl in heterozygotes and 81 (61–122) mg/dl in homozygotes, versus 132 (95–182) mg/dl in non-carriers
7% higher HDL-C concentration (p=1.6×10−17): 52 (43–63) mg/dl in heterozygotes and 67 (54–72) mg/dl in homozygotes versus 48 (40–59) mg/dl in controls
19% lower risk of coronary artery disease (odds ratio, 0.81; 95% confidence interval [CI] 0.70 to 0.92; p = 0.002) per allele.
There was no difference in LDL-C and total cholesterol levels between carriers and non-carriers.

Carriers of other inactivating mutations also had lower triglyceride levels (by 13%, p=0.02) and higher HDL-C levels (by 9%, p=0.009), and were less likely to have coronary artery disease than non-carriers (by 44%, odds ratio, 0.56; 95% CI,0.32 to 1.00; p = 0.05)

Authors’ conclusion:

Carriers of E40K and other inactivating mutations in ANGPTL4 had lower levels of triglycerides and a lower risk of coronary artery disease than did non-carriers.

STUDY SUMMARY
Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators:

Objective:

To investigate the association of variants in ANGPTL4, LPL, and SVEP1 and the risk of coronary disease

Study design:

large-scale exome wide DNA genotyping study

Study population:

72,868 patients with coronary artery disease and 120,770 controls who did not have coronary artery disease. With the exception of 5755 subjects in the Bangladesh Risk of Acute Vascular Events (BRAVE) study and the 22,072 subjects in the Pakistan Risk of Myocardial Infarction Study (PROMIS), all other subjects were of European ancestry.

Key outcomes:

Association of low frequency variants with lipid levels and coronary artery disease

Methods:

DNA sequencing was used to study the effects of loss-of-function mutations in selected genes in a discovery cohort of 42,335 patients with coronary artery disease and 78,240 controls from 20 individual studies. A suggestive novel association between a variant and the risk of coronary artery disease was defined by a meta-analysis p value of 1×10−4 or lower. Findings relating to possible associations of these variants with coronary risk were also evaluated in a replication cohort of 30,533 patients and 42,530 controls from 8 individual studies. Significant novel associations had a p-value of <0.05 in the replication cohort, with an overall p- value of <7.7×10−8 in the discovery and replication cohorts combined.

Linear regression was used to test the association between ANGPTL4 loss-of-function alleles and plasma lipid levels in 8085 persons with lipid measurements.

Main results:

Carriers of ANGPTL4 loss of-function alleles had a mean 35% lower triglyceride levels (p=0.003); these loss-of-function alleles were also associated with a 53% lower risk of coronary artery disease (9 carriers of loss-of-function mutations among 6924 patients with myocardial infarction and 19 carriers among 6834 controls.

Authors’ conclusion:

We found that carriers of loss-of-function mutations in ANGPTL4 had triglyceride levels that were lower than those among noncarriers; these mutations were also associated with protection from coronary artery disease.

COMMENT

Growing consensus, supported by epidemiologic, mechanistic and genetic studies, supports a causal role for elevated triglyceride-rich lipoproteins and their remnants (for which plasma triglycerides are a marker) in atherosclerotic cardiovascular disease. Findings from Mendelian randomization studies (a type of ‘natural’ randomized trial), which capture the effect of life-long exposure to elevated (or low) triglycerides, as well as genome-wide association studies, strengthen the evidence-base.^1-3 However, until recently, clinical studies evaluating the impact of treatments targeting elevated triglycerides, i.e. fibrates, have been confounded by the limitations of study design, patient selection criteria, as well as concomitant low HDL-C levels which are commonly associated with elevated triglycerides.

Further understanding of the biology and genetics of triglyceride heritability may offer novel targets.⁴ The two genetic studies in this report provide a strong basis for considering ANGPTL4 (angiopoietin-like protein 4), a secreted protein that increases plasma triglycerides levels by inhibiting lipoprotein lipase (LPL). The studies provide independent evidence that genetic loss of ANGPTL4 function confers not only favourable lipid profiles, but also protection from coronary artery disease. Variants associated with reduced ANGPTL4 function, such as the missense E40K variant and rare loss of function polymorphisms, were associated with reduced triglycerides (by a mean of 35%), as well as reduction in the risk for coronary artery disease (by up to 53%). These findings therefore imply that disordered metabolism of triglyceride-rich lipoproteins, mediated via the LPL pathway, is an important contributor to coronary disease risk. Therapeutic modulation of the LPL pathway, via targeting of ANGPTL4, possibly via monoclonal antibody therapy, may offer therapeutic potential.

References

1. Nordestgaard BG. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease. New insights from epidemiology, genetics, and biology. Circulation Res 2016;118:547-563.

2. Jørgensen AB, Frikke-Schmidt R, West AS et al. Genetically elevated non-fasting triglycerides and calculated remnant cholesterol as causal risk factors for myocardial infarction. Eur Heart J 2013;34:1826–1833.

3. Thomsen M, Varbo A, Tybjærg-Hansen A, Nordestgaard BG. Low nonfasting triglycerides and reduced all-cause mortality: a mendelian randomization study. Clin Chem. 2014;60:737–746

4. Rosenson RS, Davidson MH, Hirsh BJ et al. Genetics and causality of triglyceride-rich lipoproteins in atherosclerotic cardiovascular disease. J Am Coll Cardiol. 2014;64:2525–2540.

Key words

triglycerides; triglyceride-rich lipoproteins; genetic study; coronary disease risk; lipoprotein lipase