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Precision nutrition: LDL cholesterol and heart disease

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Elevated LDL (“bad”) cholesterol is a major risk factor for coronary heart disease and stroke, which is the leading cause of death in the U.S. and across the globe. The interplay of genetics, diet and lifestyle determines a person’s LDL levels. Less than 1% of the population have monogenic or familial hypercholesterolemia (FH), which is due to mutations in one of four known genes, while the vast majority of hypercholesterolemia cases are polygenic in nature, meaning they arise from gene-diet interactions involving multiple common genetic variations. At the heart of hypercholesterolemia, no matter if monogenic or polygenic in nature, is the mismatch between lipid metabolism genes with modern day diet and other lifestyle choices. As we enter the era of precision health, we will increasingly use genetic information to identify health risks and then use preventative strategies to avoid disease. Genetic-targeted precision nutrition will be a key player in early prevention of hypercholesterolemia and heart disease.

Dietary and lifestyle management for high LDL cholesterol

Dietary and other lifestyle modifications are essential as a first-line treatment for people with monogenic or polygenic hypercholesterolemia. A diet with plenty of fruits and vegetables (which are high in fiber and plant sterols) and low in meat and dairy (which are high in fat and cholesterol) will help promote healthy LDL levels. (Mozaffarian, 2005; Jenkins, 2003).

“As we enter the era of precision health, we will increasingly use genetic information to identify health risks and then use preventative strategies to avoid disease. Genetic-targeted precision nutrition will be a key player in early prevention of hypercholesterolemia and heart disease.”

More specifically:

  • Limit caloric intake to maintain a healthy body weight.
  • Keep fat intake within 20-35% of total calories.
  • Restrict saturated fat to less than 7% of total calories.
  • Replace saturated fats with poly and monounsaturated fats (Hooper, 2015).
  • Avoid trans fats.
  • Restrict dietary cholesterol intake to less than 200 mg/day.
  • Eat foods rich in soluble fiber (aim for 10-20 g/day)Include 2 g/day of plant sterols in your diet.
  • Avoid smoking as it strongly increases cardiovascular disease risk.
  • Engage in modest aerobic exercise regularly.

Monogenic vs polygenic hypercholesterolemia: A closer look

MONOGENIC

People with familial hypercholesterolemia (FH) are at greatly increased risk (more than 20-fold) for premature coronary heart disease. Mutations in one of four genes, LDLR, APOB, PCSK9 and LDLRAP1, account for 60-80% of monogenic FH cases. This disease is dominant in nature, as a single (heterozygous) mutant copy of one of these genes gives rise to FH. Homozygous mutant FH carriers have a more severe form of the disease. Mutations in LDLRAP1 are recessive meaning that both copies of the gene (one from each biological parent) need to be mutated to cause FH. Heterozygous FH affects about 1 in 300 to 500 people in the general population where homozygous FH affects about 1 in a million people. Certain populations have a higher frequency of FH, such as French Canadians, South African Afrikaners and others.

Diet and lifestyle factors as well as the presence of other genetic variants can influence disease penetrance, which is the proportion of disease manifested due to a genetic mutation (Sato, 2004; Bertolini, 2004). Strong evidence for lifestyle-influence on the clinical significance of FH comes from a study showing that people with LDLR mutations residing in China show few clinical signs of elevated cholesterol while those with LDLR mutations that migrate to countries with a more “Western” lifestyle show significant clinical signs (Pimstone, 1998). Subsequent studies have shed light on secondary factors that influence risk of coronary heart disease in people with FH. They are similar to those that influence the general population without FH, namely low HDL cholesterol, smoking, type 2 diabetes and hypertension (Jansen, 2004). Collectively, these studies highlight the importance of genetics, diet and other lifestyle choices in mitigating the risks of monogenic elevated blood cholesterol.

A family history of elevated cholesterol and/or coronary heart disease during mid-life is common criteria for diagnosing FH. With genetic sequencing technology, it is currently cost-effective to screen genes involved in cholesterol metabolism to identify known or novel mutations that cause FH. One of the major benefits of genetic sequencing for suspected FH is that identifying a specific mutation may help to precisely tailor dietary and medical treatments for prevention of the disorder, perhaps even before lab tests can detect elevated LDL cholesterol or clinical signs of coronary heart disease. Early adoption of a cholesterol-lowering diet and other lifestyle modifications as well as medical therapy can delay or eliminate disease risk and enhance quality of life and longevity.

Highlighting the benefit of genetic sequencing and the promise of precision health, there is one mutation within the PCSK9 gene (known as D374Y) known to manifest a particularly severe phenotype. In one analysis, people with FH with this mutation had higher LDL cholesterol and coronary heart disease on average 10 years earlier than people with mutations in their LDLR gene. In addition, people with the D374Y mutation do not respond to cholesterol-lowering statin medications as well as people with LDLR mutations (Naoumova, 2004). The authors of this study nonetheless report that adherence to a “very strict low-cholesterol, low-fat diet” in addition to medical management did seem to get LDL cholesterol within acceptable ranges. These patients may also benefit from eating more plant sterols, which effectively compete with the absorption of cholesterol in our gut and therefore lower LDL cholesterol levels (Calpe-Berdiel, 2009).

Foods that are good sources of plant sterols/stanols include:

  • Wheat germ and wheat bran
  • Plant-sourced oils (corn, sesame, canola and olive)
  • Peanuts and almonds
  • Brussels sprouts

POLYGENIC

Nearly a third of all adults in the U.S. have elevated LDL cholesterol. Genetics plays a role in non-familial cases of elevated LDL cholesterol. Whereas monogenic hypercholesterolemia is caused by a single mutation and accounts for less than 1% of hypercholesterolemia cases, 90% of hypercholesterolemia arises from variations in multiple genes that by themselves would have only minor influence. Several groups have independently demonstrated that people with a high genetic risk score have higher LDL cholesterol and elevated risk of heart disease (Futema, 2014; Talmud, 2013; Kathiresan, 2008). A genetic risk score assigns a weighted score to multiple risk variants. Higher scores indicate a person has more risk variants and an increased risk of developing hypercholesterolemia. In a study done in the United Kingdom of people with significantly elevated LDL cholesterol, 27% were found to have polygenic hypercholesterolemia with a high genetic risk score and no mutations identified in FH genes (LDLR, APOB, PCSK9 or LDLRAP1) (Futema, 2014).The polygenic risk score used in at least a couple of studies includes 12 common polymorphisms that are known to increase risk of elevated LDL cholesterol modestly. The common APOE (rs7412 and rs429358) genotypes are given the highest weight, followed by common polymorphisms in LDLR (rs6511720), CELSR2 (rs629301) and APOB (rs1367117) (Talmud, 2013; Futema, 2014). Carriers of APOE-E4 can benefit from a low-fat and low-cholesterol diet. Just like the APOE-E4 allele, common variants within the LDLR and APOB genes limit clearance of LDL cholesterol from the blood. Common genetic variants within the CELSR2 gene affect the production of the SORT1 gene product that in turn affects VLDL (the precursor of LDL) secretion (Musunuru, 2010). In one major genome-wide association study, a variant near the SORT1 gene had the single largest influence on LDL cholesterol levels (Teslovich, 2010).

See video on the APOE Gene Diet

Our genetics change over time to help us adapt to our environment. This has been of benefit during antiquity, but may be problematic in our current era of globalization and mass migration. The APOE-E4 allele, weighted strongest for high cholesterol (Talmud, 2013), is found in highest frequency amongst Nigerians at 31%. The traditional Nigerian diet consists primarily of starchy root vegetables, grains and fruits and includes little animal meat. This diet is beneficial as it keeps cholesterol levels within normal ranges. However, when people with APOE-E4 alleles consume a more “Westernized” diet with higher cholesterol and sodium and low potassium, disease emerges.

Whether monogenic or polygenic FH, genetic testing may help shine light on the root causes of this disease and help to precisely formulate dietary and medical solutions to stave off coronary heart disease.

Concluding thoughts

Elevated total and LDL cholesterol levels are a clear risk factor for heart disease. Understanding the causes can help develop solutions to minimize risk. Genetic sequencing may help to uncover mutations in monogenic hypercholesterolemia as well as polygenic risk scores. In either case, following a healthful diet and sensible lifestyle choices aimed at reducing risk factors have clear benefit. The HealthWatch 360 app developed by GB HealthWatch provides personalized diet and nutrition recommendations for the prevention of hypercholesterolemia; genetic testing services will soon be offered in conjunction.

We invite you to share your thoughts in the comments section below.

References

Bertolini S, Pisciotta L, Di Scala L, Langheim S et al. Genetic polymorphisms affecting the phenotypic expression of familial hypercholesterolemia. Atherosclerosis. 2004 May;174(1):57-65. PMID: 15135251
Calpe-Berdiel L, Escolà-Gil JC and Blanco-Vaca F. New insights into the molecular actions of plant sterols and stanols in cholesterol metabolism. Atherosclerosis. 2009 Mar;203(1):18-31. PMID: 18692849
Futema M, Plagnol V, Li K, Whittall RA et al. Whole exome sequencing of familial hypercholesterolaemia patients negative for LDLR/APOB/PCSK9 mutations. J Med Genet. 2014 Aug;51(8):537-44. PMID: 24987033
Hooper L, Martin N, Abdelhamid A and Davey Smith G. Reduction in saturated fat intake for cardiovascular disease. Cochrane Database Syst Rev. 2015 Jun 10;6:CD011737. PMID: 26068959
Jansen AC, van Aalst-Cohen ES, Tanck MW, Trip MD et al. . The contribution of classical risk factors to cardiovascular disease in familial hypercholesterolaemia: data in 2400 patients. J Intern Med. 2004 Dec;256(6):482-90. PMID: 15554949
Jenkins DJ, Kendall CW, Marchie A, Faulkner DA et al. Effects of a dietary portfolio of cholesterol-lowering foods vs lovastatin on serum lipids and C-reactive protein. JAMA. 2003 Jul 23;290(4):502-10. PMID: 12876093
Kathiresan S, Melander O, Anevski D, Guiducci C et al. Polymorphisms associated with cholesterol and risk of cardiovascular events. . N Engl J Med. 2008 Mar 20;358(12):1240-9. PMID: 18354102
Mozaffarian D, Ascherio A, Hu FB, Stampfer MJ et al. Interplay between different polyunsaturated fatty acids and risk of coronary heart disease in men. Circulation. 2005 Jan 18;111(2):157-64. PMID: 15630029
Musunuru K, Strong A, Frank-Kamenetsky M, Lee NE et al. From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus. Nature. 2010 Aug 5;466(7307):714-9. PMID: 20686566
Naoumova RP, Tosi I, Patel D, Neuwirth C et al. Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response. Arterioscler Thromb Vasc Biol. 2005 Dec;25(12):2654-60. PMID: 16224054
Pimstone SN, Sun XM, du Souich C, Frohlich JJ et al. Phenotypic variation in heterozygous familial hypercholesterolemia: a comparison of Chinese patients with the same or similar mutations in the LDL receptor gene in China or Canada. Arterioscler Thromb Vasc Biol. 1998 Feb;18(2):309-15. PMID: 9484998
Sato K, Emi M, Ezura Y, Fujita Y et al. Soluble epoxide hydrolase variant (Glu287Arg) modifies plasma total cholesterol and triglyceride phenotype in familial hypercholesterolemia: intrafamilial association study in an eight-generation hyperlipidemic kindred. J Hum Genet. 2004;49(1):29-34. PMID: 14673705
Talmud PJ, Shah S, Whittall R, Futema M et al. Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study. Lancet. 2013 Apr 13;381(9874):1293-301. PMID: 23433573
Teslovich TM, Musunuru K, Smith AV, Edmondson AC et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature. 2010 Aug 5;466(7307):707-13. PMID: 20686565







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