The Cost Benefit Analysis of Polymorphisms within Lipoprotein Metabolism

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Apolipoprotein E is central to blood lipoprotein homeostasis and lipid transport within tissues. The gene (APO-E) encoding this protein is polymorphic. Although the APO-E4 allele is a well-established risk factor for both vascular disease and Alzheimer's disease in

Mthfr C677t Gene Polymorphism
Figure 2.8. Schematic showing the MTHFR locus, which is encoded by a variant C677T-MTHFR gene. The implication of the genetic selection of the MTHFR genotype, folate metabolism, and reproductive efficiency is dealt with in an important paper by Reyes-Engel et al. (37).
Old Boat Plans
Figure 2.9. Highly simplified schematic of folate-dependent processes. Includes locus of involvement for other vitamins.

post-reproductive years, it may, however, in certain cultures/feeding modes, offer a distinct survival advantage. The common APO-E3 allele is found in all human populations, but it is particularly prevalent in long-established agricultural economies, such as persist around the Mediterranean Sea. This contrasts with the prevalence of the APO-E4 allele, which is highest in cultures that still have an economy based on foraging, or where food supply is unpredictable and scarce. Such populations include Pygmies, African Khoi San, Malaysian and Australian Aborigines, Papuans, Lapps, and Native Americans (59). Based on this distribution, it has been suggested that the ancestral APO-E4 allele may be a "thrifty" allele with functional properties that influence lipoprotein metabolism, including cholesterol levels in a beneficial manner in the appropriate ancestral environment. However, out of their ancestral context (i.e., within a contemporary environment where Western diets and longevity prevail) chronic degenerative diseases more readily manifest themselves (59). Although feeding mode may well have influenced metabolome selection in these populations, the APO-E polymorphism may also influence reproductive efficiency/fertility via the effect it has on cholesterol and hence steroidogenesis (60).

APO-E4 is not the only thrifty allele to influence cholesterol levels. Ancestral diets rich in fiber, vegetable protein, plant sterols, etc., were clearly low in trans-fatty acids and the other substrates of cholesterol biosynthesis (Figure 2.10). It has been suggested that, as a result, a range of cholesterol raising polymorphisms exist that have been conserved by evolution (61). These include the B2B2 genotype of the cholesteryl ester transfer protein-TaqlB, which favors cholesterol transfer to the liver for bile acid synthesis (62), and the T54 GA/AA genotypes of the intestinal fatty acid binding protein gene which favors fatty acid absorption for cholesterol synthesis (63). Clearly, a partial return to our ancestral diet of vegetables, fruit, and nuts would be an effective measure to reduce aberrant blood lipid profiles. Figure 2.10 shows how plant sterols like ^-sitosterol are structurally similar to cholesterol and hence may competitively reduce cholesterol absorption.

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