It has been known since the 1920s that there are naturally occurring variations in human biochemistry and metabolism caused specific diseases. The basis for these in-born errors of metabolism was subsequently found to be due to genetic variants. The genetic variants that result in serious illness are fortunately very rare but are numerous and have provided insight into human nutrient metabolism. Patients with such metabolic disorders are supported by www.climb.org.uk
What has become apparent over the last two decades is that there are many minor genetic variants in nutrient metabolism that help to explain a number of previously unexplained phenomena:
Additionally some of the genetic variants sometimes protect against certain diseases e.g. malaria and because of this are more prevalent in certain populations.
Examples of Genetically Determined Variations in Nutrient Metabolism
The enzyme – MTFHR, 5,10-methylenetetrahydrofolate reductase [NADPH] is encoded by a gene located on the short (p) arm of chromosome 1. The enzyme uses folate for the conversion of the amino acid homocysteine to the amino acid methionine, which is needed for the production of proteins and other important compounds. Homocysteine can accumulate as a result of variants in MTHFR. Genetic variants in MTFHR or due to folate deficiency lead to an increased risk of neural tube defect pregnancy and a slight increase in the risk of vascular disease and possibly high blood pressure in pregnancy.
A common variant of this gene is the replacement of the DNA nucleotide cytosine in position 667 with thymine (C667T), which is present in homozygous form in about 10% and in heterozygous form in about 38% of Europeans. The dietary intake of folate, as well as other factors, appears to influence the health risk associated with this genetic variant.
Absorbed vitamin B12 is transported in the blood by a carrier protein transcobalamin 2, TCN2, which aids its delivery to tissues. A complete deficiency of transcobalamin is an extremely rare cause of vitamin B12 deficiency.
However, genetically determined variations in transcobalamin are very common and can influence the ease with which vitamin B12 is delivered to the tissues and thus the susceptibility of the individual to deficiency. The 776CàG variant is widely distributed and is found in 60% of Chinese and approximately 40% of many other populations. The TCN2 GG phenotype was twice as common as expected in those with severe malaria and may offer some protection from this disease. However such individuals may have an increased risk of miscarriage.
There are known genetic variants in vitamin D receptor, VDR, which were originally thought to influence the risk of osteoporosis. This is now not thought to be the case but it now appears they might influence adult height in white populations and some variants have been linked with the risk of developing progressive form of multiple sclerosis. Other genetically determined variations in the vitamin D-binding protein found in the blood and the calcium channel/transporter gene, TRPV6, found in the duodenum may also influence calcium balance.
Scientific Advisory Committee on Nutrition. Update on Vitamin D. London, TSO. 2007
Vitamin A, retinol, is transported from liver stores to peripheral tissues by a carrier protein, retinol binding protein 4, RBP4. Very rarely there may be an absence of this carrier protein resulting in vitamin A deficiency despite an adequate intake of the vitamin.
Some recent studies have shown that genetic variants result in this protein being produced in excess by abdominal fat cells in those with truncal obesity resulting in high levels of RBP4. This is associated with an increased risk of type II diabetes as well as polycystic ovaries in women and diabetic nephropathy.
Its presence may also explain, in part, the elevated plasma levels of retinol seen in overweight, heavy consumers of alcohol who paradoxically may also have low liver stores of retinol. High plasma levels of retinol have been associated with an increased risk of osteoporosis in some but not all studies.
A high prevalence of underactivity of riboflavin-dependent enzymes in red blood cells has been repeatedly observed in some populations. The enzymes glutathione reductase and pyridoxal phosphate oxidase require riboflavin – vitamin B2 and despite good dietary intake of this nutrient appear to be frequently underactive in the red blood cells of adults in Northern Italy, Thailand and Africa. The usual generalised features of riboflavin deficiency do not always appear.
These biochemical variants may be more common (20% to 100%) in countries where malaria has been endemic as riboflavin deficiency in the red blood cells may inhibit the multiplication of the malaria parasite. These variations in the activity of vitamin B2-dependent enzymes erythrocyte glutathione reductase and pyridoxal phosphate oxidase may also limit the production of the active form of vitamin B6.
The clinical impact is uncertain but some Africans are prone to vitamin B6 deficiency neuropathy as a result of treatment with the anti-TB drug isoniazid. Such genetic variants, which affect approximately 6% of British adults, might also explain some of the variability in response to different vitamin B supplements.
Acrodermatitis enteropathica, AE, is a very rare autosomal recessive disorder of zinc metabolism characterised by skin changes, poor immunity, diarrhoea and failure to thrive in infants. The picture of severe zinc deficiency despite a normal dietary intake typically appears when the infant stops breast feeding.
Acrodermatitis enteropathica is now known to be due to defect in zinc absorption as a result of a loss of zinc transport proteins that are coded for on chromosome 8.
Haemochromatosis is a disease of iron excess and is one of the commonest genetic disorders in everyday medical practice as it can effect 1 in 160 of European adults. It can be due to several genetic variations in iron the commonest of which involves xxxx
As a result there is an increase in the amount of dietary iron which is absorbed. Over several decades this leads to iron accumulation as the body has no ready way of excreting the excess. As a result liver disease, fatigue, arthritis, type II diabetes and other health problems develop.
Having the genes for haemochromatosis would make it much less likely for affected children or menstruating women to become iron deficient a problem in up to 50% of such individuals in developing countries.
The disease haemochromatosis seems to be more prevalent (3%) in those presenting with liver disease as well as type II diabetics and should always be checked for in such individuals
Variations in the enzyme phosphatidylethanolamine N-methyltransferase (G744C) predisposed adults, when placed on a low choline diet for up to 42 days to the clinical effects of deficiency resulting in mild elevations in the muscle enzyme CPK and the liver enzyme ALT. Variations in another gene responsible for the enzyme CHDH choline dehydrogenase appeared to have a protective effect.
The clinical significance of these findings has yet to become clear but may influence predisposition to liver and muscle disease and possibly the side-effects of some drugs.
It would appear that men are more susceptible to deficiency than women though their risk rises after the menopause due to the loss of the beneficial effect of oestrogen upon choline-metabolising enzymes.