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

Sergey V. Anisimov, Maria V. Volkova, Lilia V. Lenskaya, Vladimir K. Khavinson, Dina V. Solovieva, and Eugene I. Schwartz

Department of Cardiology, I.P. Pavlov St. Petersburg State Medical University, Russia.
Laboratory of Human Molecular Genetics, St. Petersburg Institute of Nuclear Physics RAS, Gatchina, Russia.
City Geriatric Center, St. Petersburg, Russia.
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 restriction 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 < 0.005). No statistically significant difference in allele 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 indicates 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.

Human apolipoprotein C-III (apoC-III) is a major component of very low-density lipoproteins and plasma chylomicrons and a minor component of high-density lipoproteins (HDLs). It plays an important role in modulating the hydrolysis of triglycerides and cholesterol through inhibition of lipoprotein lipase (14); 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 positions -935, -641, -630, -625, -482 and -455 (6,7). The promoter 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 allows 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 increases the sequence identity of the -454 to -462 element to the corresponding area in the PEPCK gene. A functional insulin-response element (IRE) in the human apoC-III promoter (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 partially inhibits the ability of the variant apoC-III promoter to respond to insulin in vitro (12). The location of this polymorphism in the IRE and its ability to influence the expression of apoC-III suggest a link between two major components of syndrome X: abnormal glucose metabolism and hypertriglyceridemia (13,14). Elevated plasma levels of insulin are highly associated with increased blood pressure through activation of the sympathoadrenal system, and a strong correlation between these two indices occurs in states of insulin resistance (15-17). Thus, hypertension, as a constituent part of syndrome X, could result from an altered response of the apoC-III promoter to insulin.

Among the polymorphisms in the apoC-III promoter region, 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 children (7), the increased incidence of the C allele was, however, 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 Indians (19). Moreover, among two recentThe text has been processed below:

Divided into several age-differentiated subgroups: group 1 (43 subjects, 70-79 years old; mean age, 74.4 years), group 2 (52 subjects, 80-89 years old; mean age, 84.4 years), and group 3 (42 subjects, 90-106 years old; mean age, 94.5 years). Information about AH and IHD was obtained based on long-standing clinical observations. The control group included 110 schoolchildren aged 6 to 17 years old (group 4; mean age, 11.0 years) from three secondary schools in St. Petersburg. The ethnic composition in both the elderly and control groups was controlled via the analysis of last names and was found to be identical, with a major preponderance of Russian names and a minor presence.

RESULTS AND DISCUSSION

We analyzed DNA samples from the following groups of St. Petersburg citizens: group 1 (43 subjects, 70-79 years old), group 2 (52 subjects, 80-89 years old), group 3 (42 subjects, 90-106 years old), and group 4 (110 subjects, 6-17 years old). The frequencies of T and C alleles in the control group (group 4) were 0.550 and 0.450, respectively. This distribution is comparable with 0.700/0.300 in a healthy adult white American population (18), and 0.690/0.310 (21) or 0.655/0.345 (20) in healthy Dutch populations (p<0.05).

AT cAGCCAGIGATGCCCGGTCT TCTGTGCCTITACTCCAAACATCCCCCAGCCCAA.. ~449B c#@ ... CCAAACATCCCC... Genomic DNACc*Gi) k .. .CCAAAGATCCCC... 1 PCR Product-480 -327455Mbol |iy .. -CCAAALGATCCCC...23 131Digested-455 PCR Products. ...CCAAAGACCCCC...ag S_154< 154 bp+131 bp