© 1997 American Heart Association, Inc.
Articles |
Polymorphisms of the Genes Encoding Apoproteins A-I, B, C-III, and E and LDL Receptor, and Cholesterol and LDL Metabolism During Increased Cholesterol Intake
Common Alleles of the Apoprotein E Gene Show the Greatest Regulatory Impact
the Department of Medicine, Division of Internal Medicine (H.G., K.K., H.E.M., T.A.M.), and the Institute of Biotechnology (U.-M.K.), University of Helsinki, Finland.
Correspondence to Tatu A. Miettinen, MD, Department of Medicine, Division of Internal Medicine, University of Helsinki, Haartmaninkatu 4, FIN-00290 Helsinki, Finland.
Genetic and dietary factors regulate serum cholesterol level, but detailed investigations into their interactions have not been established. We assessed the effects of apoprotein (apo) E phenotype and polymorphic alleles of the apo A-I, apo B, apo C-III, and LDL receptor genes, separately and together, on regulation of serum LDL cholesterol level. The study group consisted of 29 middle-aged men, and cholesterol absorption, bile acid, and cholesterol synthesis and LDL apo B kinetics were studied in these men during low- and high-cholesterol diets. The six apo B alleles were identified on the basis of Xba I, EcoRI, and Msp I restriction fragment length polymorphism (RFLP), the apo A-I alleles with the Msp I RFLP, and the apo C-III and LDL receptor alleles corresponded to the Sst I and PvuII RPLPs of these genes, respectively. During low cholesterol intake, LDL cholesterol levels were similar in all of the genetic groups except for men with apo E2 phenotype. They had significantly (P<.05) lower levels of LDL apo B and cholesterol than men without the 
2 allele. The low values were caused by a significantly higher removal of LDL apo B (apo E2, 0.453±0.03 versus apo E3, 0.312±0.01 pools per day, P<.05). High cholesterol intake increased LDL cholesterol levels in all genetic categories except in the apo E2 phenotype irrespective of the combinations with other polymorphisms. Carriers of the apo B R+ allele (EcoRI site present) presented with the most prominent LDL cholesterol rise (from 2.71±0.14 to 3.37±0.29 mmol/L). In multiple stepwise regression analysis, apo B EcoRI RFLP and apo E phenotypes were the only variables that explained the variability of high cholesterol intake–induced change in LDL cholesterol levels. In summary, in any genetic combination, individuals with the 2 allele had the lowest LDL cholesterol values and were nonresponders to dietary cholesterol, whereas subjects with the apo B R+ allele had marked LDL elevations, especially in combination with the 4.
Key Words: cholesterol absorption • cholesterol synthesis • LDL kinetics • genetic polymorphism • dietary cholesterol
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