EDITORIAL
Gene
mutations can produce polymorphisms that alter minimal daily micronutrient
requirements
____________________________________________________
Victor Herbert, MD,JD
Dr.
Herbert is Director of the Nutrition Research Center and
Chief, Mount Sinai Hematology and
Nutrition Research Laboratory at Veterans Affairs Medical Center, Bronx, NY
Medical subject headings: folic acid; genes; mutation; oxidoreductases; polymorphism (genetics); requirements, nutritional; vitamin B 12
Clin
invest Med 2001;24(1):54-5.
©
2001 Canadian Medical
Association
____________________________________
Each
gene codes for a specific protein. If a gene mutation alters a protein that is
part of the biochemical machinery for absorption, transport, delivery or
utilization of an essential micronutrient, the amount of that nutrient we must
ingest to sustain health may be raised or lowered. All enzymes are proteins. A
classic illustration of this interplay of genetics and nutrition, which some
call ìgenetic nutrition,î is reviewed in this issue of Clinical and
Investigative Medicine by David Rosenblatt (page 56). He discusses
bow gene mutations producing alterations (polymorphisms, alleles) in the
folate-utilizing enzyme methylenetetrahydrofolate reductase (MTHFR) reduce its
specific activity, requiring an increase in dietary folic acid intake to
overcome the problem.
As Rosenblatt notes, a single
substitution in the gene for MTHFR, of a valine for an alanine (the 677C→T mutation) or an alanine for a
glutamate (the 1298A→C mutation), produces an MTHFR
polymorph with slowed ability (lower specific activity) to convert
methylene-THF to methyl-THF, which is the dominant circulating form of folic
acid (see Rosenblattís Fig. 1). Methyl-THE supplies the methyl group, which
in the presence of vitamin B12 converts potentially vasculotoxic2
homocysteine to methionine. Methionine (and its product, S-adenosylmethionine)
are the major 1-carbon donors in human intermediary metabolism.3 As
with many sluggish ìtraffic copî enzymes, the slowed conversion of
methylene-THF (substrate) to methyl‚THF (product) may be improved by
increasing the supply of substrate, in this case folic acid. Net result: for
normal metabolism, persons with these abnormal alleles have a minimal daily
requirement (MDR) of folic acid greater than those without them.
Note that the phrase, as used by Kaplan
and associates in this issue (page 5) is ìincreasing the minimal daily
requirementî (MDR), not increasing the recommended dietary allowance (RDA).
As noted by Kaplan and associates, RDAs are set at a level far above the MDR
but below the level of toxicity, to assure adequate reserve stores. The MDR
for folic acid as pteroylglutaniic acid (PGA) is only 25 µg.
A daily oral intake of 250 to 400 µg of PGA corrects for sluggish MTHFR.3 Almost every nutrient
is toxic in megadoses. Oral megadoses of PGA, since it is oxidized,
shelf-stable and metabolically inactive folate, rather than reduced, highly
photolabile and thermolabile metabolically active folate, may produce such
high absorption of unreduced folate as to act as an anti-fol.3
ìMore is betterî is an appealing
sales pitch to sell supplements but in fact may do more harm than good.4í5
A classic example is the genetic polymorphism that produces
hemochromatosis. 6-8 This polymorphism so sharply enhances the
intestinal absorption of dietary iron above the ìnormalî approximately
10% that the MDR to sustain normal iron metabolism falls close to zero, since
nearly all the iron the body needs to make hemoglobin and iron-containing
enzymes can be pulled from the excessive body iron stores.
The autosomal recessive gene of bemochromatosis produces a deformed
intestinal ìmucosal blockî protein, less able than the normal such protein
to inhibit iron absorption. About 8% of North Americans (including about 20%
of Irish Americans and about 30% of African Americans) have one such gene
(i.e., are heterozygous) and absorb daily approximately 50% more
dietary iron than the majority of people. Approximately 0.5% (including
about 1% of Irish Americans and African Americans) are homozygous and absorb
daily about 300% more dietary iron. Normally, we absorb about 3% of the iron
in plant foods and about 15% of that in animal foods, because heme iron
is absorbed by a different and more efficient biochemical machinery than is
non-beme iron. Thus, those having a hemochromatosis gene are better off being
vegetarians (who regularly donate blood, since phlebotomy is the treatment of
choice for hemochromatosis: once to 4 times a year in heterozygotes; up to
once a day to start treatment in homozygotes).
An example of a gene mutation altering a protein involved in the transport and delivery of a micronutrient is genetic deficiency of the circulating vitamin B12-delivery protein transcobalamin II, a rare autosomal recessive condition producing severe global vitamin B12 deficiency disease in infancy, which, if not recognized in infancy and treated from then on with adequate amounts of B12, is lethal.9í10
References
1. Simopoulos A, Herbert V, Jacobson B: Genetic nutrition:
designing a diet based on your family medical history. New York: Macmillan
Publishing and Maxwell Macmillan International; 1994.
2. Herbert V. Folic acid. In: Shils ME. Olson JA, Shike M,
Ross AC, editors. Modem nutrition in health and
disease. 9th ed. Baltimore: Williams & Wilkins; 1999.
3. Markle HV. Unmetabolized folic acid and masking of
cobalamin deficiency. Am J Clin Nutr 1997;66:1480-l.
4. Herbert V. The antioxidant supplement myth. Am J Clin
Nutr 1994;60: 157-8.
5. Herbert
V. Destroying immune homeostasis in normal adults with antioxidant
supplements. Am J Clin Nutr 1997;65:1901-3.
6. Herbert V, Shaw 5, Jayatilleke E. Vitamin C-driven free
radical generation from iron [published errata appear in J Nutr 1996;126:1746
and J Nutr 1996; 126:1902]. J Nutr 1996;126(Suppl
4):1213S-1220S.
7. Herbert V. Clinical, biochemical, and molecular as‚pects
of hemochromatosis. Program for the 2001 annual meeting of the Society for
Inherited Metabolic Disorders, Mar. 4-7, 2001, Wyndham Miami Beach Resort,
Miami Beach, FL; 2000.
8. Burton JC, Edwards CQ. Hemochromatosis. Cam‚bridge
(UK): Cambridge University Press, 2000.
9. Bibi H, Gelman-Kohaz Z, Baumgartner ER, Rosenblatt DS.
Transcobalamin II deficiency with
methylmalonic aciduria in three sisters. J Inherit Metab Dis,
1999;22:765-72.
10. Nexo
E, Christensen AL, Petersen TE, Fedosov SN. Measurement of transcobalamin by
ELISA. Clin Chem 2000;46(l0):643-9.
