Replication studies in longevity: puzzling findings in Danish centenarians at the 3′APOB–VNTR locus

Abstract

In Danes we replicated the 3hAPOB-VNTR gene\longevity association study previously carried out in Italians, by which the Small alleles (less than 35 repeats) had been identified as frailty alleles for longevity. In Danes, neither genotype nor allele frequencies differed between centenarians and 20-64-year-old subjects. However, when Danish and Italian data were compared, a significant difference ( p l 0n0004) was found between the frequencies of Small alleles in youths, which disappeared in centenarians ( p l 0n290). Furthermore, the demographic-genetic approach revealed in Danes a significant gene-sex interaction relevant to Long alleles (more than 37 repeats). The different findings in Denmark and Italy suggest that gene\longevity associations are populationspecific, and heavily affected by the population-specific genetic and environmental history. Association studies in centenarians are one of the tools currently used to ascertain information on the genetic components of human longevity. Historically, association studies have been developed for investigating complex diseases, and only recently have they been applied to human longevity. A must in association studies is replication : the positive association found between a locus and a complex trait in a certain population must be confirmed in another population. However, both the case\control design (De Benedictis, 1996) and the genetic-demographic design (Yashin et al. , 1999Toupance et al. 1998) currently used in gene\ longevity association studies present methodological problems for representing a dynamic process, such as age-related survival selection, within a static framework. Indeed the structure of the centenarian gene pool is the result not only of the genetic history of the population, but also of unstable environmental factors occurring in the last century, which shaped the demographics of the population. Is positive replication expected in such studies ?To investigate this intriguing question we have replicated in Danish centenarians a study carried out in Italian centenarians, where association between longevity and the 3hAPOB-VNTR polymorphism (Boerwinkle et al. 1989)

The Genetics of Human Longevity

“…Moreover, the frequency of the longest variants was found to be significantly higher in centenarians in comparison with young people. Nevertheless, the same study performed using DNA from Danish centenarians did not confirm the data previously obtained for the Italian population, thus suggesting a more complex scenario of population genetics 50 …”

“…Nevertheless, the same study performed using DNA from Danish centenarians did not confirm the data previously obtained for the Italian population, thus suggesting a more complex scenario of population genetics. 50 A study on centenarians and young people from southern Italy showed no difference in allelic and genotypic polymorphisms of APOA4 and APOC3. On the contrary, the frequency of P allele of the APOA1 polymorphism (APOA1-msp1-RFLP, −75 nt from the transcription start site) is significantly increased in male centenarians.…”

Ideal lipid profile and genes for an extended life span

“…PON1 has attracted attention as a protective factor against oxidative modification of LDL particles, and may therefore play an important role in the prevention of the atherosclerotic process. Bonafe et al [45] evaluated centenarians and found that genetic variability at the PON1 locus affects survival at extreme advanced age [45,[90][91][92][93][94]. Also, Marchegiani et al [95] showed that genetic variability at the PON1 locus is related to paraoxonase activity throughout life, and suggested that both parameters affect survival at extreme advanced age.…”

Genetic Determinants of Human Health Span and Life Span: Progress and New Opportunities

“…Particularly striking examples have included PON1 [61–67] IGF-1 [68–71], PAPR-1 [72,73], cytokines, enzymatic antioxidants such as superoxide dismutases [74,75], and elements of lipid metabolism [76,77]. Some significant differences have been noted between younger cohorts and centenarians in the prevalence of specific genotypes and sometimes in their associated protein activities.…”