Age-Associated Accumulation of the Apolipoprotein C-III Gene T-455C Polymorphism C Allele in a Russian Population

Sergey V. Anisimov,1 Maria V. Volkova,1,2 Lilia V. Lenskaya,3 Vladimir K. Khavinson,4 Dina V. Solovieva,4 and Eugene I. Schwartz1,2

1 Department of Cardiology, I.P. Pavlov St. Petersburg State Medical University, Russia. 2 Laboratory of Human Molecular Genetics, St. Petersburg Institute of Nuclear Physics RAS, Gatchina, Russia. 3 City Geriatric Center, St. Petersburg, Russia.

4 St. Petersburg Institute of Bioregulation and Gerontology,

Apolipoprotein C-III (apoC-III) is the major component of triglyceride-rich lipoproteins. One of six identified polymorphisms in the apoC-III 59-untranslated region (T-455C) is located within a functional insulin-response element. In a group of 137 elderly individuals (70–106 years old), the allele distribution was analyzed using re- striction fragment length polymorphisms. Statistical analysis of allele frequencies was performed on subgroups selected by age and in elderly patients with arterial hypertension or ischemic heart disease. A greater frequency of the apoC-III 2455C allele was demonstrated with aging (p , .005). No statistically significant difference in al- lele distributions was detected between healthy subjects and groups of elderly patients of the same age with either ischemic heart disease or arterial hypertension. The increased incidence of the C allele with advanced age indi- cates that this variant promoter is associated with longevity. The greater incidence of this allele is detectable only in adults older than 80 years of age.

H UMAN apolipoprotein C-III (apoC-III) is a major component of very low-density lipoproteins and plasma chylomicrons and a minor component of high den- sity lipoproteins (HDLs). It plays an important role in mod- ulating the hydrolysis of triglycerides and cholesterol through inhibition of lipoprotein lipase (1–4); therefore, the plasma levels of triglycerides correlate directly with the quantity of apoC-III (4,5). Six polymorphisms have been identified in the promoter region of the apoC-III gene at po- sitions -935, -641, -630, -625, -482 and -455 (6,7). The pro- moter region containing these polymorphic sites is essential for maximal expression of apoC-III in cultured cells (8). The most proximal polymorphism, T-455C, is located within a 10-base-pair (bp) region whose sequence is similar to that of the rat phosphoenolpyruvate carboxykinase (PEPCK) insulin/phorbol ester response element (9). This region al- lows insulin to influence the metabolism of apoC-III through the regulation of the gene’s transcriptional activity (10). Interestingly, the apoC-III variant (-455C) allele in- creases the sequence identity of the -454 to -462 element to the corresponding area in the PEPCK gene. A functional in- sulin-response element (IRE) in the human apoC-III pro- moter (C3IRE) has been mapped to the -490 to -449 region (11,12). This 42 nucleotide region contains two sequence variants at -455 and -482 positions, which strongly affect apoC-III gene expression following insulin treatment (12). It has been shown that a single bp change of T-455C par- tially inhibits the ability of the variant apoC-III promoter to respond to insulin in vitro (12). The location of this poly- morphism in the IRE and its ability to influence the expres- sion of apoC-III suggest a link between two major compo-

nents of syndrome X: abnormal glucose metabolism and hypertriglyceridemia (13,14). Elevated plasma levels of in- sulin are highly associated with increased blood pressure through activation of sympathoadrenal system, and a strong correlation between these two indices occurs in states of in- sulin resistance (15–17). Thus, hypertension, as a constitu- ent part of syndrome X, could result from an altered re- sponse of the apoC-III promoter to insulin.

Among the polymorphisms in the apoC-III promoter re- gion, the T-455C polymorphism has been studied in several populations (Table 1). Although no statistically significant differences were detected in the distribution of T/C alleles in a group of white Americans (18) and among Italian chil- dren (7), the increased incidence of the C allele was, how- ever, associated with elevated triglycerides and depressed HDL cholesterol, as well as higher total cholesterol to HDL ratio and apolipoprotein B (apoB) to apolipoprotein A-I (apoA-I) ratio in a group of young Sandy Lake Canadian In- dians (19). Moreover, among two recent studies, both per- formed on Dutch populations, one failed to associate the IRE polymorphisms with any changes in plasma lipid traits (20), although another confirmed previous findings, demon- strating an association of the -455C allele with family dys- betalipoprotinaemia and hypertriglyceridemia (21).

The picture is intensely complicated by the linkage dise- quilibrium of the studied T-455C polymorphism with other polymorphisms of the apoA-I/C-III/A-IV complex. The 9 apoC-III 3 -untranslated region SstI polymorphism, which is generally believed to play an important role in the devel- opment of endogenous hypertriglyceridemia (6,7,12,18), excluding some ethnic and age groups (22–24), is not oblig-

Table 1. -455 ApoC-III Polymorphism T/C Allele Distribution in Different Populations

Sample Size Age Range Mean Age T-Allele C-Allele Population (n) (y) (y) Frequency Frequency Reference St. Petersburg, Russia 110 6–17 11.0 0.550 0.450 Present study Sandy Lake Indians, Canada 188 9–17 13.7 0.556 0.444 Hegele and colleagues (19) Rome, Italy 503 11–13 — 0.596 0.404 Shoulders and colleagues (7) Utrecht, The Netherlands 236 47–49 48.0 0.655 0.345 Groenendijk and colleagues (20) Leiden, The Netherlands 102 35 35.0 0.690 0.310 Hoffer and colleagues (21) White population, United States 45 44–65 53.8 0.700 0.300 Surguchev and colleagues (18)

of other Slavic (mainly Ukrainian) and Jewish names, which represents a typical ethnic constitution in St. Petersburg.