Surprises from genetic analyses of lipid risk factors for atherosclerosis
Open accessAbstract
Observational epidemiological studies have associated plasma lipid concentrations with risk for coronary heart disease (CHD), but these studies cannot distinguish cause from mere correlation. Human genetic studies, when considered with the results of randomized controlled trials of medications, can potentially shed light on whether lipid biomarkers are causal for diseases. Genetic analyses and randomized trials suggest that low-density lipoprotein is causal for CHD, whereas high-density lipoprotein is not. Surprisingly, human genetic evidence suggests that lipoprotein(a) and triglyceride-rich lipoproteins causally contribute to CHD. Gene variants leading to higher levels of plasma apolipoprotein B-containing lipoproteins [low-density lipoprotein, triglyceride-rich lipoproteins, or lipoprotein(a)] consistently increase risk for CHD. For triglyceride-rich lipoproteins, the most compelling evidence revolves around lipoprotein lipase and its endogenous facilitator (APOA5 [apolipoprotein A-V]) and inhibitory proteins (APOC3 [apolipoprotein C-III], ANGPTL4 [angiopoietin like 4]). Combined, these genetic results anticipate that, beyond low-density lipoprotein, pharmacological lowering of triglyceride-rich lipoproteins or lipoprotein(a) will reduce risk for CHD, but this remains to be proven through randomized controlled trials.
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Mendelian randomization is essentially a randomized controlled trial performed by nature because random allocation of alleles to offspring at conception is unaffected by reverse causation and independent of environmental and genetic confounders.
“Mendelian randomization is essentially an RCT that has been performed by nature, because there is a random allocation of alleles to offspring at the time of conception that is unaffected by reverse causation and independent of environmental and genetic confounders”
From The Forgotten Lipids: Triglycerides, Remnant Cholesterol, and Atherosclerotic Cardiovascular Disease Risk (2019) · cites this paper as [110]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredA biomarker is likely not causal for disease if the association between the DNA variant and disease risk seen in observational studies is not apparent.
“The biomarker is likely not causal for the disease if similar association between the DNA variant and disease risk as seen in observational studies is not apparent”
From The Forgotten Lipids: Triglycerides, Remnant Cholesterol, and Atherosclerotic Cardiovascular Disease Risk (2019) · cites this paper as [110]
The Mendelian randomization study design section says that a missing expected association between a DNA variant and disease risk argues against the biomarker being causal. The source makes this inference conditional on the variant influencing the biomarker and the study being adequately powered; the citing sentence omits those conditions. (LLM, conf=0.82)
Experimental — accuracy not yet measuredIf a DNA variant directly influences a biomarker that is causal for disease, the DNA variant should be associated with disease risk without the possibility of reverse causality.
“if a DNA variant is known to have a direct influence on the biomarker level or activity of a protein that influences the biomarker level and that biomarker is causal for disease, then the DNA variant should be associated with the disease risk without the possibility of reverse causality”
From The Forgotten Lipids: Triglycerides, Remnant Cholesterol, and Atherosclerotic Cardiovascular Disease Risk (2019) · cites this paper as [110]
The Mendelian randomization study design section says that a variant directly affecting a causal biomarker should be associated with disease risk, consistent with the variant’s effect on the biomarker. It also describes the design as “fairly impervious” to reverse causation, which supports the point but is less absolute than saying reverse causality is impossible. (LLM, conf=0.84)
Experimental — accuracy not yet measuredGenetic pleiotropy occurs when the gene variant under study affects more than one pathway, so the observed association between the variant and disease risk may not be due to the biomarker of interest.
“This phenomenon occurs when the gene variant under study affects more than one pathway; thus, the observed association between the variant and disease risk may not be due to the biomarker of interest”
From The Forgotten Lipids: Triglycerides, Remnant Cholesterol, and Atherosclerotic Cardiovascular Disease Risk (2019) · cites this paper as [110]
Mendelian randomization studies support the notion that HDL-C may not be causally related to coronary heart disease risk.
“Mendelian randomization studies further support the notion that HDL-C may not be causally related to CHD risk”
From The Forgotten Lipids: Triglycerides, Remnant Cholesterol, and Atherosclerotic Cardiovascular Disease Risk (2019) · cites this paper as [110]
Mendelian randomization analyses are susceptible to genetic pleiotropy.
“a well-known limitation of Mendelian randomization analyses is that they are susceptible to genetic pleiotropy”
From The Forgotten Lipids: Triglycerides, Remnant Cholesterol, and Atherosclerotic Cardiovascular Disease Risk (2019) · cites this paper as [110]
Mendelian randomization studies of variants associated with TGs are commonly affected by pleiotropic effects of single-nucleotide polymorphisms on multiple metabolic pathways affecting plasma lipids, including HDL-C and LDL-C.
“Mendelian randomization studies of variants associated with TGs are commonly affected by the pleiotropic effects of single-nucleotide polymorphisms (SNPs) on multiple metabolic pathways affecting plasma lipids, including HDL-C and LDL-C”
From The Forgotten Lipids: Triglycerides, Remnant Cholesterol, and Atherosclerotic Cardiovascular Disease Risk (2019) · cites this paper as [110]
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References 55 · Cited by 159
- Authors
- Musunuru, K., & Kathiresan, S.
- Affiliations
- Broad Institute (US)
- Venue
- Circulation Research
- Published
- 2016-02-19
- Volume
- 118
- Issue
- 4
- Pages
- 579-585
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- PMC
- PMC4762058
- OpenAlex
- W2286634515
- Cited by
- 159
- References
- 55
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 12 · 2023: 11 · 2022: 17 · 2021: 21 · 2020: 17 · 2019: 20 · 2018: 21 · 2017: 19 · 2016: 9
- FWCI
- 25.46
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL107816, T32HL116275)
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- coronary artery disease, atherosclerosis, plasma lipids, causal inference, low-density lipoprotein, high-density lipoprotein, lipoprotein(a), triglyceride-rich lipoproteins, apolipoprotein B, lipoprotein lipase, APOA5, apolipoprotein C-III, ANGPTL4, lipid-lowering therapy, genetic variants
- MeSH terms
- Animals, Hypolipidemic Agents, Coronary Artery Disease, Genetic Markers, Humans, Cholesterol, HDL, Cholesterol, LDL, Phenotype, Primary Prevention, Prognosis, Risk Factors, Triglycerides, Lipoprotein(a), Risk Assessment, Genetic Predisposition to Disease, 1-Alkyl-2-acetylglycerophosphocholine Esterase, Dyslipidemias, Lipid Metabolism
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