POLYMORPHISMS OF THE GENES ENCODING APOPROTEIN-A-I, APOPROTEIN-B, APOPROTEIN-C-III, AND APOPROTEIN-E AND LDL-RECEPTOR, AND CHOLESTEROL AND LDL METABOLISM DURING INCREASED CHOLESTEROL INTAKE - COMMON ALLELES OFTHE APOPROTEIN-E GENE SHOW THE GREATEST REGULATORY IMPACT

Genetic and dietary factors regulate serum cholesterol level, but deta iled investigations into their interactions have not been established. We assessed the effects of apoprotein (apo) E phenotype and polymorph ic alleles of the apo A-I, apo B, apo C-III, and LDL receptor genes, s eparately and together, on regulation of serum LDL cholesterol level. The study group consisted of 29 middle-aged men, and cholesterol absor ption, bile acid, and cholesterol synthesis and LDL apo B kinetics wer e 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 corres ponded to the Sst I and PvuII RPLPs of these genes, respectively. Duri ng 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 m en without the epsilon 2 allele. The low values were caused by a signi ficantly 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 increa sed LDL cholesterol levels in all genetic categories except in the apo E2 phenotype irrespective of the combinations with other polymorphism s. 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 varia bility of high cholesterol intake-induced change in LDL cholesterol le vels. In summary, in any genetic combination, individuals with the eps ilon 2 allele had the lowest LDL cholesterol values and were nonrespon ders to dietary cholesterol, whereas subjects with the apo B R+ allele had marked LDL elevations, especially in combination with the epsilon 4.