Cholesterol

High Cholesterol

Variance on the PEMT gene and suboptimal levels of betaine are associated with risk of metabolic stress (indicated by alterations in lipoproteins, triglycerides, glucose and liver function markers), examples being lower HDL-C, higher LDL-C and TC/ HDL-C.

Choline is important for lipid transport, and insufficiency is associated with NAFLD. Low betaine and low activity BHMT are associated with depleted choline. This is well accepted, although the exact mechanisms aren't fully understood. 

Folate cycle SNPs, and particularly the MTHFR C677T SNP ('red' AA) genotype could impact the supply of methyl folate, and subsequently the methyl transfer to the Methionine cycle via MTR. This can be proactively supported with methyl-folate (or food folates which are predominantly methyl-form) and the other B vitamin cofactors – particularly B2, B3 and B6 (these are important as they support the recycling of the folate and regeneration of methyl-folate).

The methyl group is transferred from methyl-folate to B12 (by the MTR gene) to enter the  Methionine cycle. The B12 part of the picture may compromised (genetically) by FUT2, TCN2 and/ or MTRR (also check the MUT gene on the Transsulphuration pathway). It may be useful to check B12 levels (if B12 is low, then the methyl group has nowhere to be transferred on to – B12 – and then off it again to homocysteine). So if the folate (and B2, B3, B6) part of the process, is supported without ensuring B12 is sufficient then the B12 would be the sticking point. The B vitamin dependent part of the Methionine cycle is known as the 'long route' for removing/ recycling homocysteine by methylating it to methionine.

If homocysteine is still high, this would likely be a factor in inflammation, and  would also indicate that either the 'long route' or the 'slow route' or both are not working optimally.

The 'short route' for removing/ recycling homocysteine requires a methyl group supplied by betaine (or TMG tri methylglycine) which can be impacted by SNPs on PEMT (heterozygous/yellow) or BHMT (yellow and red). 

Summary

Folate cycle SNPs (genetic inefficiencies) can significantly impact the Methionine cycle due to limiting the supply of Methyl groups, which impact the 'long route' for converting homocysteine to methionine.

If the 'long route' is compromised, this can put more pressure/ demand on the 'short route' with effects on homocysteine, but also on lipid and cholesterol metabolism.

Also ensure adequate Zinc as this is essential for both the long and short routes.

Familial hypercholesterolemia

Familial hypercholesterolemia (FH) is a genetic disorder characterised by high cholesterol levels, specifically very high levels of low-density lipoprotein (LDL, 'bad cholesterol'), in the blood and early cardiovascular disease.

The most common mutations diminish the number of functional LDL receptors in the liver. Since the underlying body biochemistry is slightly different in individuals with FH, their high cholesterol levels are less responsive to the kinds of cholesterol control methods which are usually more effective in people without FH (such as dietary modification and statin tablets). Nevertheless, treatment (including higher statin doses) may be effective.

Apolipoprotein E (APOE) is a protein that is best known for its role in lipid metabolism by helping to remove cholesterol from the blood stream. It can exist in three main forms known as E2, E3 and E4. Variances on the APOE gene determine which forms of the APOE protein are present. The different forms of APOE work in different ways (2).

The E4 (epsilon 4) form of the APOE gene has been associated with disorders of lipid metabolism (increased plasma cholesterol and triglyceride levels), susceptibility to cardiovascular disease (heart attacks or strokes due to atherosclerosis), insulin resistance and Alzheimer's disease.

Lifecode Gx® Reports

Our Methylation Report and APOE Report are useful in the context of high cholesterol – (sub-optimal/ low Methylation can contribute to this (so the Methylation test can help to improve this), and the APOE can inform how we process it (transport cholesterol).

There are a number of reasons why your cholesterol could be high. Familial Hypercholesterolemia is due to inheritance of certain genetic SNPs. Unfortunately this isn't a test that we do as it requires testing requires deep analysis of a few specific genes and SNPs including rare variants which occur in less than 1% of the population.

Apart from FHC, high cholesterol could be due to more common genetic SNPs interacting with environmental aspects such as stress and nutrition – including foods that might be considered generally healthy but that your body doesn't process as well, and/ or increased need for nutrients such as vitamins to support the processing of these nutrients. We recommend that everyone starts with the Nutrient Core Report to assess their essential nutrient needs, and then you could consider adding other reports.