31 March 2017
Incredible advances in human genome sequencing over the last fifteen years have decreased the cost of finding out the story of our genes to a level that is affordable for the general population, as well as scientists. This has opened the door to personalized medicine and nutrigenetics, which use information about genetics to guide medical therapy or nutritional advice. While this area of research is still in an early phase, and focused on macronutrients, evidence is growing that suggests our genes can affect micronutrient requirements as well.
The relationship between folate and neural tube defects is well known. Women who are planning a pregnancy are advised to consume adequate folic acid to avoid neural tube defects (Viswanathan, 2017). Half the cases of neural tube defects are estimated to be caused by low folic acid levels, however this is only part of the tale. Blood folate levels are related to not only diet but also genetics. In particular, differences in the MTHFR (methylenetetrahydrofolate reductase) enzyme, caused by slight genetic variations, lead to clear changes in blood levels of folate (Tsang, 2015).
The MTHFR enzyme is responsible for converting dietary folate into the active form that is used in the body. The 677TT variant of the gene results in an enzyme that is more likely to break down in response to heat than the normal 677CC variant, and is less stable in general, thus circulating folate concentrations are lower (Molloy, 1997). While supplementation with folic acid is able to improve folate status regardless of genes, the effect in people with the 677TT variant is much smaller than for those with the other genetic variants (Cabo, 2015). Yan and co-workers (2012) report that women with the TT variant had double the risk of having a pregnancy affected by a neural tube defect, compared to the CC variant. It seems likely that women with the 677TT variant should pay close attention to their folate intake and status. In future, we may see changes in folic acid recommendations based on MTHFR variant if genetic testing becomes more commonplace.
Beta-carotene – found in orange, yellow and dark green fruits and vegetables – is a major source of vitamin A in people’s diets. For people who do not eat animal-based products, it is the only way they get enough vitamin A from their foods. Beta-carotene is considered a pro-vitamin because it must first be converted to vitamin A before it can be used by the body. The first step in this conversion process happens in the intestines. An enzyme produced by cells in the intestinal lining, β,β-carotene-15,15′-monooxygenase, cuts beta-carotene in two. The result is two molecules of retinal, a form of vitamin A. This enzyme is also able to convert the other pro-vitamin A carotenoids, beta-cryptoxantin and apocarotenal, to vitamin A as well.
Variations in the gene that produces the beta-carotene conversion enzyme, BCMO1, affect vitamin A status and levels of carotenoids in the body. If the enzyme does not work well, carotenoid levels in the body tend to increase while vitamin A levels remain low. For example, some families are prone to an orange color forming in their skin despite a normal diet, and may show signs of vitamin A deficiency (Sharvill, 1970). A small change in the gene responsible for BCMO1 produces an enzyme with only 10 percent of the activity of the normal gene (Lindqvist, 2007), which means that beta-carotene is absorbed but not converted to vitamin A, leading to excessive levels in the skin and the potential for vitamin A deficiency. Other studies have found more subtle, yet still significant, effects of small genetic variations on beta-carotene conversion to vitamin A. For example, several genetic variations in the DNA close to the BCMO1 gene mean that it works about half as well as it should, and this also results in a much lower vitamin A level (Lietz, 2012). Likewise, another small change within the BCMO1 gene sequence results in an enzyme that has a lower activity than normal, and circulating beta-carotene concentrations were considerably higher (Hendrickson, 2012). People with a poorly functioning version of the BCMO1 gene have a higher risk of vitamin A deficiency and must ensure their diets include a source of vitamin A other than fruits and vegetables.
The importance of a balanced diet can be seen with the B-vitamins – four all contribute together to DNA synthesis and the metabolism of amino acids. Riboflavin in particular is considered to be an “active co-factor” in the conversion of dietary folate to its active form, and helps vitamin B6 to remove the undesirable amino acid homocysteine from the body (McMahon, 2016). For people with the 677TT variant of the MTHFR enzyme, as discussed above in the folate example, riboflavin may be particularly important. These people have lower circulating levels of folate and elevated levels of homocysteine in the blood. They also have a greater risk of cardiovascular disease, partly due to their higher blood pressure (Wilson, 2012). It seems that the poorly functioning 677TT variant of the MTHFR enzyme can be stabilized by an adequate riboflavin status. Improvements in blood pressure are thought to come from the resulting increase in active folate in the body, which helps blood vessels to widen (McMahon, 2016).
Preliminary clinical trials have looked at the effect of riboflavin supplementation in people with the 677TT variant of the MTHFR enzyme. In the first trial, patients with premature cardiovascular disease were screened for the MTHFR 677C→T variant and then randomized to 1.6 mg riboflavin daily or a placebo for two months. The dose used is close to the recommended intake for adults. The same supplementation strategy was performed in the same patient group four years later, however treatment groups were reversed. After two months of riboflavin supplementation at both time points, blood pressure decreased significantly, but only in adults with the 677TT genetic variant (Wilson, 2012). The same research group conducted a second study in patients with the 677TT genotype only. After four months of taking 4.6 mg per day of riboflavin, the subjects had a significant reduction in their systolic blood pressure (Wilson, 2013). These two studies have tested a nutritionally obtainable dose of riboflavin to produce a small reduction in blood pressure. Research is ongoing to determine whether a higher dose can further reduce blood pressure in the RIBOGENE study.
As genetic testing becomes more commonplace, the ease of conducting nutrigenetic research will increase. Other micronutrients that are being investigated include:
Breakthroughs in the understanding of how our genes and diet interact to affect our health and nutrient requirements are slowly changing the field of nutrition. While it is too soon to be able to prescribe a particular diet based on genetic testing, in the future we may see personalized nutrition plans emerge to complement general diet and lifestyle advice that will maximize the effect that nutrition has on our health.
26 July 2012
A recent Australian study has delivered the first human data showing that early postnatal fish oil supplementation increases n-3 polyunsaturated fatty acid (PUFA) levels in infants and is associated with lowered allergenic responses to allergens such as dust mites.
20 October 2012
Supplementation with omega-3 fatty acids may alleviate symptoms of depression in elderly patients, says a new Italian study.
29 January 2014
A new study from Denmark suggests that multivitamin use during the period from before conception to early pregnancy may be linked to a slightly higher risk of early fetal loss. Experts criticize the study for not proving a cause and effect relationship.
