of six candidate genes on early aging in a population

Yongjing Xia1, René Gueguen2, Monique Vincent-Viry1, Gérard Siest1, and Sophie Visvikis1 1Laboratoire du Centre de Médecine Préventive and Unité INSERM 525, 2Département Statistique du Centre de Médecine Préventive, Vandoeuvre-lès-Nancy, France

INTRODUCTION

ABSTRACT. Background and aims: The objective of this study was to examine the association between an ag- ing indicator previously defined from a nationwide pop- ulation study, and lipids and apolipoproteins, angiotensin converting enzyme, paraoxonase activities, and six can- didate genes related to the aging process. Methods: Two hundred and fifty-six healthy Caucasian men (69.8±4.0 years) were included in the study. Total cholesterol, triglycerides, HDL-cholesterol, lipoprotein(a), apolipoprotein A1, B and E concentrations, and the activities of paraoxonase, arylesterase, and angiotensin- converting enzymes were determined by standardized lab- oratory methods. A multiplex assay was used to genotype the studied polymorphisms: apolipoprotein E, lipoprotein lipase, paraoxonase, methylenetetrahydrofolate reduc- tase, cystathionine β-synthase and angiotensin-convert- ing enzymes. Results: Paraoxonase polymorphism at codon 192 (Gln/Arg) was the only one significantly as- sociated with the aging indicator, Gln homozygotes be- ing more advanced in aging compared with Arg allele car- riers. It was also observed that the aging indicator was positively correlated with serum concentrations of total cholesterol, triglycerides and apolipoprotein B, and neg- atively with the activities of basal and stimulated paraox- onase and arylesterase. Multiple regression analysis showed that triglycerides and basal paraoxonase activi- ty explain 13.6% of the variance of the aging indicator. Conclusions: Triglyceride concentration and paraox- onase gene and activities may contribute to the aging pro- cess. Taking into account the smallness of the sample size, and the poor level of significance due to the im- plication of paraoxonase polymorphism at codon 192, these results need to be verified in further studies on a

Cardiovascular disease (CVD) is age-related and a leading cause of death worldwide. Elderly individuals who have avoided CVD should possess a protective and biological background in both genetic profiles and plasma constituents against CVD. Consequently, many studies have investigated genetic polymorphisms and serum vari- ables associated with CVD in a general healthy elderly population to search for the biological factors contribut- ing to successful aging (1, 2). Therefore, we chose to ex- amine the associations between lipids, apolipoproteins, ACE and PON activities, six common bi-allele polymor- phisms, and the aging indicator (AI), representing the dif- ference of biological age (BA) from chronological age (CA). The studied candidate genes are apolipoprotein (apo) E, lipoprotein lipase (LPL), paraoxonase (PON), methylenetetrahydrofolate reductase genes (MTHFR), cystathionine β-synthase (CBS) and angiotensin-convert- ing enzymes (ACE). The polymorphisms of these genes are: apoE at codons 112/158 (ε2, ε3, ε4 alleles), ACE (Alu insertion/deletion alleles, I/D), MTHFR (Ala222Val or 677C/T), PON (Gln192Arg), LPL (Ser447Ter) and CBS (Ile278Thr).

ApoE is one of the major proteins of several lipoprotein particles and plays a central role in lipoprotein metabolism. Human apoE gene is located on chromosome 19 and has three common alleles, designated as ε2, ε3, ε4, encoding three major apoE isoforms, E2, E3 and E4. The difference in these three isoforms lies in the substitution of amino acid at codons 112 and 158 (3). In comparison with the most common isoform E3, E2 is associated with higher con- centrations of apoE and triglycerides (TG) and lower total cholesterol (TC), whereas E4 is related to lower concen- trations of apoE and TG, and higher TC in plasma in Eu- ropean populations (3). Many studies have confirmed that the ε4 allele is a genetic risk factor for both CVD (4)

Key words: Aging, candidate genes, genetic polymorphism, paraoxonase. Correspondence: G. Siest, Ph.D., Centre de Médecine Préventive, 2 Rue du Doyen Jacques Parisot, 54500 Vandoeuvre-lès-Nancy, E-mail: Gérard.Siest@cmp.u-nancy.fr Received October 30, 2001; accepted in revised form October 2, 2002.