Heart disease is the number one cause of death in the US and most countries around the world. We often have a picture in our heads of someone at risk for a heart attack… For example, an overweight, older man who looks unhealthy, probably with a stressful job. It is often tempting to think that people who exercise, are thin, and look healthy are at low risk for heart disease. But beneath all the healthiness can lurk a genetically driven risk factor for a heart attack: elevated lipoprotein(a).
Look at the numbers: Being obese increases the relative risk of heart disease by 28%.[ref] But someone with genetically elevated Lp(a) can have a 300% increase in the risk of a heart attack.
This article digs into research on lipoprotein (a) and the genetic variants that can cause it to be elevated. I’ll explain how to check your genetic data (e.g., 23 and Me or AncestryDNA) to see if you carry the variants and then the next steps to take with getting blood tests done. Members will see their genotype report below, plus additional solutions in the Lifehacks section. Join today.
What is lipoprotein a?
Lipoprotein(a) or LP(a) — said “L- P- little a” — is a blood particle that carries LDL cholesterol and proteins. Elevated levels of Lp(a) are a strong risk factor for having a heart attack due to atherosclerosis.[ref]
We all know that fats and water don’t mix. It remains true in the body regarding moving around fats in the bloodstream. The term lipoprotein is a general term for a glob of fatty acid plus protein that is packaged so it can easily be transported throughout the body. Lipoproteins include low-density and high-density cholesterol.
Lipoprotein (a) includes an LDL particle bound to an apolipoprotein (a) – known as apo(a) – and apoB100. The apo(a) part is what increases atherosclerosis. It also promotes clotting by interfering with the way that the body dissolves clots.[ref] So, you have a double-whammy of increasing atherosclerosis via increased inflammation plus oxidized LDL. The LDL tends to oxidize once inside a vessel wall adding more inflammation responses because their structure has changed. It all adds to a mechanism that increases the risk of blood clots.[ref]
The Lp(a) molecule can vary a lot in size, and you can inherit two different sizes of Lp(a) – one from mom and one from dad.[ref]
Lp(a), Bob Harper, and the risk of a sudden heart attack:
The Biggest Loser host and fitness trainer, Bob Harper, has been open about his recovery from a very serious heart attack in 2017. He was the epitome of healthiness – fitness trainer, nutritional guru, athlete, and only in his early fifties. But he also had genetically elevated levels of Lp(a). Here is a Today Show interview where he explains some of his recovery and what he is doing to prevent a second heart attack.
A recent study in India showed that high Lp(a) levels – defined as >50mg/dl) increased the risk of coronary artery disease in younger people by 2 to 3-fold.[ref]
Is lipoprotein heritable?
“Family history” is always mentioned by the doctor as an important indicator of your risk of heart disease, especially if a family member had a heart attack at a young age. Lp(a) is often the reason that this question is asked.
A significant way that researchers have found family history playing a role is through the inheritance of a genetic variant that increases lipoprotein(a).
Lp(a) levels are estimated to be 90% hereditary. (That’s really high when it comes to hereditary estimates!)[ref]
Is Lp(a) a big deal – or just another scare tactic?
There are questions and controversy on the role cholesterol plays in heart disease, which may lead some people to dismiss Lp(a) as just the latest number to talk about. I think it would be a big mistake to dismiss the research on Lp(a).
There is abundant research that high Lp(a) increases the risk for:[ref][ref][ref][ref]
- sudden heart attack
- narrowing of the arteries
- aortic stenosis.
Additionally, low Lp(a) levels are linked with a lower risk of heart failure, stroke, vascular disease, and aortic stenosis.[ref]
The kicker: Genetic studies show that variants linked to high Lp(a) correlate to a shorter lifespan. When averaging together information from more than 100,000 people, the presence of an Lp(a) genetic variant caused an average decrease in lifespan of 1.5 years.[ref]
How high is high?
When you get your Lp(a) test results, how do you know if it is just slightly high or seriously scary?
- One study shows a 3x risk of aortic valve stenosis for those with Lp(a) levels greater than 90 mg/dl.[ref]
- Another source says normal Lp(a) levels are less than 30 mg/dl (or 75 nmol/L).[ref]
- Some researchers consider normal to be less than 50 mg/dl.[ref][ref]
It is important enough to talk to a doctor about and keep up with the research as it comes out.
Not all studies agree… as usual
A 2012 study in people with diabetes found that higher Lp(a) levels did not correlate with an increased risk of heart disease. Note that there was no additional risk above the high risk from having diabetes.[ref]
A study on women found that Lp(a) levels were only important in cardiovascular disease if the women also had high cholesterol (>220 mg/dl).[ref]
One problem with the epidemiological studies on Lp(a) is that most of them only last for 5 to 10 years, which may not be enough time to really determine causality.
Lipoprotein (a) Genotype Report
Not a member? Join here. Membership lets you see your data right in each article and also gives you access to the member’s only information in the Lifehacks sections.
The LPA gene controls the formation of the lipoprotein(a) molecule. Variants in the gene cause the body to create more Lp(a).
These first two genetic variants cover about 40% of the variation in Lp(a) levels — other, less common variants also raise Lp(a) levels.
Check your genetic data for rs3798220 (23andMe v4, v5, AncestryDNA):
- C/C: risk of elevated Lp(a), increased risk for heart disease – 3.7x risk of aortic stenosis[ref][ref][ref]
- C/T: risk of elevated Lp(a), increased risk for heart disease, increased risk of aortic stenosis
- T/T: typical
Members: Your genotype for rs3798220 is —.
Check your genetic data for rs10455872 (23andMe v4, v5; AncestryDNA):
- G/G: likely elevated Lp(a), increased risk for heart disease – 2x risk of aortic stenosis[ref][ref][ref]
- A/G: likely elevated Lp(a), increased risk for heart disease
- A/A: typical
Members: Your genotype for rs10455872 is —.
Studies also showed that carrying one risk allele for both of the above — compound heterozygous — also doubled the risk of aortic stenosis.[ref]
Genetic variants that increase LDL cholesterol levels are also linked with higher Lp(a) levels. It makes sense that there could be more Lp(a) if your cholesterol levels are really high.
If you have full genome testing, check for these other LPA gene variants as well:
- rs9457951 – this may be a better marker for African-Americans[ref]
- rs6415085 – T allele linked to higher Lp(a)[ref]
Variants that lower Lp(a):
Check your genetic data for rs6919346 (23andMe v5; AncestryDNA):
Members: Your genotype for rs6919346 is —
Check your genetic data for rs41272114 (23andMe v4, v5):
Members: Your genotype for rs41272114 is —.
So what do you do if you carry the risk alleles for high Lp(a)? Knowledge is power here!
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Arsenault, Benoit J., et al. “Association of Long-Term Exposure to Elevated Lipoprotein(a) Levels With Parental Life Span, Chronic Disease–Free Survival, and Mortality Risk.” JAMA Network Open, vol. 3, no. 2, Feb. 2020, p. e200129. PubMed Central, https://doi.org/10.1001/jamanetworkopen.2020.0129.
Attia, Peter. “The Straight Dope on Cholesterol – Part I.” Peter Attia, 25 Apr. 2012, https://peterattiamd.com/the-straight-dope-on-cholesterol-part-i/.
Chang, Xinxia, et al. “Lipid Profiling of the Therapeutic Effects of Berberine in Patients with Nonalcoholic Fatty Liver Disease.” Journal of Translational Medicine, vol. 14, Sept. 2016, p. 266. PubMed Central, https://doi.org/10.1186/s12967-016-0982-x.
Chapman, M. John, et al. “Niacin and Fibrates in Atherogenic Dyslipidemia: Pharmacotherapy to Reduce Cardiovascular Risk.” Pharmacology & Therapeutics, vol. 126, no. 3, June 2010, pp. 314–45. PubMed, https://doi.org/10.1016/j.pharmthera.2010.01.008.
Chasman, Daniel I., et al. “Polymorphism in the Apolipoprotein(a) Gene, Plasma Lipoprotein(a), Cardiovascular Disease, and Low-Dose Aspirin Therapy.” Atherosclerosis, vol. 203, no. 2, Apr. 2009, pp. 371–76. PubMed, https://doi.org/10.1016/j.atherosclerosis.2008.07.019.
Chen, Hao Yu, et al. “Association of LPA Variants With Aortic Stenosis: A Large-Scale Study Using Diagnostic and Procedural Codes From Electronic Health Records.” JAMA Cardiology, vol. 3, no. 1, Jan. 2018, pp. 18–23. PubMed, https://doi.org/10.1001/jamacardio.2017.4266.
Chmielewski, K. “[Clinical and bacteriological observations on the use of immediate prostheses made of quickly polymerizing methyl polymetacrylane].” Czasopismo stomatologiczne, vol. 19, no. 5, May 1966, pp. 549–53.
Clarke, Robert, et al. “Genetic Variants Associated with Lp(a) Lipoprotein Level and Coronary Disease.” New England Journal of Medicine, vol. 361, no. 26, Dec. 2009, pp. 2518–28. Taylor and Francis+NEJM, https://doi.org/10.1056/NEJMoa0902604.
Emdin, Connor A., et al. “Phenotypic Characterization of Genetically Lowered Human Lipoprotein(a) Levels.” Journal of the American College of Cardiology, vol. 68, no. 25, Dec. 2016, pp. 2761–72. ScienceDirect, https://doi.org/10.1016/j.jacc.2016.10.033.
Enas, Enas A., et al. “Lipoprotein(a): An Independent, Genetic, and Causal Factor for Cardiovascular Disease and Acute Myocardial Infarction.” Indian Heart Journal, vol. 71, no. 2, Mar. 2019, pp. 99–112. ScienceDirect, https://doi.org/10.1016/j.ihj.2019.03.004.
Erhart, Gertraud, et al. “Genetic Factors Explain a Major Fraction of the 50% Lower Lipoprotein(a) Concentrations in Finns.” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 38, no. 5, May 2018, pp. 1230–41. ahajournals.org (Atypon), https://doi.org/10.1161/ATVBAHA.118.310865.
Franchini, Massimo, et al. “Lipoprotein Apheresis for the Treatment of Elevated Circulating Levels of Lipoprotein(a): A Critical Literature Review.” Blood Transfusion, vol. 14, no. 5, Sept. 2016, pp. 413–18. PubMed Central, https://doi.org/10.2450/2015.0163-15.
Hanssen, Ruth, and Ioanna Gouni-Berthold. “Lipoprotein(a) Management: Pharmacological and Apheretic Treatment.” Current Medicinal Chemistry, vol. 24, no. 10, 2017, pp. 957–68. PubMed, https://doi.org/10.2174/0929867324666170112110928.
Joshi, Parag H., et al. “Do We Know When and How to Lower Lipoprotein(a)?” Current Treatment Options in Cardiovascular Medicine, vol. 12, no. 4, Aug. 2010, pp. 396–407. PubMed, https://doi.org/10.1007/s11936-010-0077-6.
Kamstrup, Pia R., et al. “Elevated Lipoprotein(a) and Risk of Aortic Valve Stenosis in the General Population.” Journal of the American College of Cardiology, vol. 63, no. 5, Feb. 2014, pp. 470–77. PubMed, https://doi.org/10.1016/j.jacc.2013.09.038.
Kronenberg, F., and G. Utermann. “Lipoprotein(a): Resurrected by Genetics.” Journal of Internal Medicine, vol. 273, no. 1, Jan. 2013, pp. 6–30. DOI.org (Crossref), https://doi.org/10.1111/j.1365-2796.2012.02592.x.
Kronenberg, Florian. “Prediction of Cardiovascular Risk by Lp(a) Concentrations or Genetic Variants within the LPA Gene Region.” Clinical Research in Cardiology Supplements, vol. 14, no. 1, Apr. 2019, pp. 5–12. Springer Link, https://doi.org/10.1007/s11789-019-00093-5.
Laschkolnig, Anja, et al. “Lipoprotein (a) Concentrations, Apolipoprotein (a) Phenotypes, and Peripheral Arterial Disease in Three Independent Cohorts.” Cardiovascular Research, vol. 103, no. 1, July 2014, pp. 28–36. PubMed, https://doi.org/10.1093/cvr/cvu107.
Li, Yonghong, et al. “Genetic Variants in the Apolipoprotein(a) Gene and Coronary Heart Disease.” Circulation: Cardiovascular Genetics, vol. 4, no. 5, Oct. 2011, pp. 565–73. DOI.org (Crossref), https://doi.org/10.1161/CIRCGENETICS.111.959601.
Najjar, Rami S., et al. “Consumption of a Defined, Plant‐based Diet Reduces Lipoprotein(a), Inflammation, and Other Atherogenic Lipoproteins and Particles within 4 Weeks.” Clinical Cardiology, vol. 41, no. 8, Aug. 2018, pp. 1062–68. PubMed Central, https://doi.org/10.1002/clc.23027.
PhD, Chris Masterjohn. “026: The 5 Best Ways to Lower Cholesterol Naturally.” Harnessing the Power of Nutrients, 9 May 2017, https://chrismasterjohnphd.substack.com/p/026-the-5-best-ways-to-lower-cholesterol.
Qi, Qibin, et al. “Genetic Variants, Plasma Lipoprotein(a) Levels, and Risk of Cardiovascular Morbidity and Mortality among Two Prospective Cohorts of Type 2 Diabetes.” European Heart Journal, vol. 33, no. 3, Feb. 2012, pp. 325–34. PubMed, https://doi.org/10.1093/eurheartj/ehr350.
Risch, S. C., et al. “Multiendocrine Assessment in the Dexamethasone Suppression Test.” Psychopharmacology Bulletin, vol. 22, no. 3, Jan. 1986, pp. 913–16.
Rodríguez, M., et al. “Reduction of Atherosclerotic Nanoplaque Formation and Size by Ginkgo Biloba (EGb 761) in Cardiovascular High-Risk Patients.” Atherosclerosis, vol. 192, no. 2, June 2007, pp. 438–44. PubMed, https://doi.org/10.1016/j.atherosclerosis.2007.02.021.
Ronald, James, et al. “Genetic Variation in LPAL2 , LPA , and PLG Predicts Plasma Lipoprotein(a) Level and Carotid Artery Disease Risk.” Stroke, vol. 42, no. 1, Jan. 2011, pp. 2–9. DOI.org (Crossref), https://doi.org/10.1161/STROKEAHA.110.591230.
Song, Zi-Kai, et al. “LPA Gene Polymorphisms and Gene Expression Associated with Coronary Artery Disease.” BioMed Research International, vol. 2017, 2017, p. 4138376. PubMed, https://doi.org/10.1155/2017/4138376.
Viney, Nicholas J., et al. “Antisense Oligonucleotides Targeting Apolipoprotein(a) in People with Raised Lipoprotein(a): Two Randomised, Double-Blind, Placebo-Controlled, Dose-Ranging Trials.” Lancet (London, England), vol. 388, no. 10057, Nov. 2016, pp. 2239–53. PubMed, https://doi.org/10.1016/S0140-6736(16)31009-1.
Vogt, Anja. “Lipoprotein(a)-Apheresis in the Light of New Drug Developments.” Atherosclerosis. Supplements, vol. 30, Nov. 2017, pp. 38–43. PubMed, https://doi.org/10.1016/j.atherosclerosissup.2017.05.025.
Wang, Hui, et al. “Berberine Modulates LPA Function to Inhibit the Proliferation and Inflammation of FLS-RA via P38/ERK MAPK Pathway Mediated by LPA1.” Evidence-Based Complementary and Alternative Medicine, vol. 2019, Nov. 2019, p. e2580207. www.hindawi.com, https://doi.org/10.1155/2019/2580207.
“Why Would My Doctor Order a Lipoprotein(a) Blood Test?” Cleveland Clinic, 11 Dec. 2019, https://health.clevelandclinic.org/why-would-my-doctor-order-a-lipoproteina-blood-test/.
Article originally published July 2018. Updated Apr. 2021