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Aging and genetic variation of plasma apolipoproteins. Relative loss of the apolipoprotein E4 phenotype in centenarians.

Arterioscler Thromb Vasc Biol. 1994;14:1084-1089

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Aging and Genetic Variation of Plasma Apolipoproteins

of Plasma Apolipoproteins Relative Loss of the Apolipoprotein E4

Relative Loss of the Apolipoprotein E4 Phenotype in Centenarians

J. Louhija, H.E. Miettinen, K. Kontula, M.J. Tikkanen, T.A. Miettinen, R.S. Tilvis

Abstract We determined the common polymorphism of apolipoprotein E (E2, E3, and E4), apolipoprotein B Xba I polymorphism, and apolipoprotein C-III Sst I polymorphism in almost all Finnish centenarians alive in 1991 (n=179/185). Plasma lipid and lipoprotein levels in different apolipoprotein genotypes were also measured. In comparison with younger Finnish populations studied previously, the frequency of the apolipoprotein E e2 allele was almost twice as high (7.0% versus 4.1%; P<.05) and that of the e4 allele only approxi- mately one third as high (8.4% versus 22.7%; P<.001) in the centenarians. Plasma cholesterol and high-density lipoprotein cholesterol levels tended to be lowest in the group with the e2 allele (4.33 mmol/L and 1.41 mmol/L, respectively), interme- diate in those with the e3 allele (4.57 mmol/L and 1.48 mmol/L, respectively), and highest in those with the E4 allele (4.82 mmol/L and 1.60 mmol/L, respectively). The frequencies of the apolipoprotein B XI and X2 alleles (Xba I restriction

site absent or present, respectively) among the centenarians and among the young Finns were not significantly different, whereas the apolipoprotein C-III S2 allele (Sst I restriction site present) occurred more often in the centenarians (frequency, 12.9%) than in the youngest reference population (frequency, 8.8%; P<.05). Centenarians with the apolipoprotein B X2X2 genotype and apolipoprotein E4 phenotype had a higher mean plasma cholesterol level than those with the X1X1 genotype and E2 phenotype (5.24 versus 3.43 mmol/L; P<.05). We conclude that genetic variation of apolipoproteins influences blood lipid levels up to very high ages and that the B4 allele may affect life expectancy adversely. (ArterioscUr 1994;14:1084-1089.)

Key Words • centenarians • serum apolipoproteins • serum cholesterol • apolipoprotein gene polymorphisms • longevity

allele is associated with elevated serum total choles- terol, LDL cholesterol, and apoB levels36811 and also with increased risks of coronary artery disease and myocardial infarction.1215 In the Finnish population, in which the incidence of coronary heart disease is high, the frequency of apoE4 is higher and that of apoE2 lower than in most other populations studied.811 The apoB Xba I polymorphism is due to a single nucleotide variation in exon 26 of the apoB gene.16 Although not involving a difference in the apoB primary structure, this polymorphism has been suggested to affect the concentration of serum lipoproteins and also the risk of atherosclerotic vascular disease.2"4 An association be- tween the apoB X2 allele (Xba I restriction site present) and elevated serum LDL cholesterol level has been established in healthy Finnish children17 and adults,18 as well as in Finnish patients with heterozygous familial hypercholesterolemia.19 The apoC-III gene lies in close proximity to the apolipoprotein A-I (apoA-I) gene on chromosome II.20 In many although not all studies, an extra Sst I restriction site (52 allele) in the 3' untrans- lated region of the apoC-III gene has been associated with raised serum triglyceride concentrations and an increased risk of coronary artery disease.34 The 52 allele is present in approximately 60% of Finnish adults with severe primary hypertriglyceridemia but in only 16% of normolipemic control subjects.21

/\ protein metabolism. Apolipoprotein E (apoE) A. \_ is present in chylomicrons and very-low-density lipoprotein and their lipolytic degradation products, ie, chylomicron remnants and intermediate-density lipo- proteins.1-2 It also plays a role in cholesterol absorption and in the receptor-mediated uptake of lipoprotein particles by the liver. Apolipoprotein B (apoB) is essen- tial for the synthesis and secretion of chylomicrons in the intestine and of VLDL in the liver and serves as the ligand allowing the low-density lipoprotein (LDL) re- ceptor to recognize LDL.1'2 Apolipoprotein C-III (ApoC-III) is a major protein constituent of triglycer- ide-rich lipoproteins and may also affect the activities of lipoprotein and hepatic Upases.1-2

Common genetic polymorphisms of apoE, apoB, and apoC-III have been found to influence serum lipid levels in several populations (for reviews, see References 2 through 6). Three major apoE isoforms (E2, E3, and E4), encoded by three separate alleles (E2, E3, and e4), in different combinations determine six different phe- notypes.57 Several studies have indicated that the e4

Received February 23, 1994; revision accepted April 21, 1994. From the Geriatric Unit, Second Department of Medicine (J.L., R.S.T.), Institute of Biotechnology (H.E.M.), Second Department of Medicine (K.K., T.A.M.), and First Department of Medicine (M.J.T.), University of Helsinki (Finland).