Genetic analysis of Paraoxonase (PON1) locus reveals an increased frequency of Arg192 allele in centenarians

Abstract

Human Paraoxonase (PON1) is a High-Density Lipoprotein (HDL)-associated esterase that hydrolyses lipo-peroxides. PON1 has recently attracted attention as a protective factor against oxidative modification of LDL and may therefore play an important role in the prevention of the atherosclerotic process. Two polymorphisms have been extensively studied: a Leucine (L allele) to Methionine (M allele) substitution at codon 55, and a Glutamine (A allele) to Arginine (B allele) substitution at codon 192. We have examined these two aminoacidic changes in 579 people aged 20 to 65 years old, and 308 centenarians. We found that the percentage of carriers of the B allele at codon 192 (B+ individuals) is higher in centenarians than in controls (0.539 vs 0.447), moreover we found that among the B+ individuals, the phenomenon was due to an increase of people carrying M alleles at codon 55 locus. In conclusion, we propose that genetic variability at PON1 locus affects survival at extreme advanced age.

Paraoxonase 1 polymorphisms and survival

“…9 Few studies, however, have investigated the impact of PON1 polymorphisms on survival. Heijmans et al 10 found no significant effect of the Q192R and M55L polymorphisms on mortality risk in 666 subjects age 85 þ years in a 10-year follow-up study, whereas Bonafé et al 11 reported an increase in the frequency of 55M/192R carriers in 308 centenarians as compared to 579 younger individuals. In this study, we examined the association between the À107C/T, M55L and Q192R polymorphisms in a sample of Danish subjects aged 47 -93 years drawn among participants of three populations-based studies.…”

Genetic Association Analysis of Human Longevity in Cohort Studies of Elderly Subjects: An Example of the PON1 Gene in the Danish 1905 Birth Cohort

“…Recent association studies are increasingly emphasizing the important roles that genes may play in affecting human survival at advanced ages (Bonafe et al 2002;Christiansen et al 2004;Bellizzi et al 2005;Hurme et al 2005). Further studies using efficient analytical tools are needed.…”

“…Recently, PON1 gene polymorphisms have been found to affect human survival (Bonafe et al 2002;Christiansen et al 2004). In the study by Christiansen et al (2004), three SNPs in the PON1 gene (two in the coding region, amino acids M55L and Q192R, and one in the promoter region, C-107T) were genotyped.…”

Zinc–gene interaction related to inflammatory/immune response in ageing

“…Genetic analysis of human ageing is mainly approached by searching the genetic basis of susceptibility to major geriatric disorders or the allelic contributions to exceptionally long life span. It is just thanks to these last studies in centenarians populations that several candidate longevity genes or pathways including PON1 [19,130], IGF1/insulin pathway [84,120], elements of lipid metabolism [12], stress response [34] and inflammatory response have been identified [53].…”

“…Genetic analysis of human ageing is mainly approached by searching the genetic basis of susceptibility to major geriatric disorders or the allelic contributions to exceptionally long life span. It is just thanks to these last studies in centenarians populations that several candidate longevity genes or pathways including PON1 [19,130], IGF1/insulin pathway [84,120], elements of lipid metabolism [12], stress response [34] and inflammatory response have been identified [53].Genes related to inflammation and stress response, in particular the pro-inflammatory cytokines IL-1, IL-6, TNFalpha, the anti-inflammatory cytokine IL-10, the HSP70 chaperones and the regulators of trace elements homeostasis, metallothioneins (MT), seem particularly relevant taking into account that the same genes are involved in the susceptibility to major geriatric disease/disorders such as …”