hormone action, stimulation of growth of cultured cells, stimulation of the action of insulin, and involvement in development and growth. They appear to be autocrine regulators of cell proliferation. Consistent with this profile of metabolic actions, an association has been reported between a SNP in the 30 untranslated region of the IGF2 gene (ApaI) and BMI (O’Dell et al., 1997) that accounts for a small percentage of the population variance. A number of studies appear to confirm this initial finding between IGF2 ApaI G allele and BMI (Gaunt et al., 2001; O’Dell et al., 1997, 1999; Rice et al., 2002; Roth et al., 2002) including suggestive evidence from a recent genome scan for obesity (Gaunt et al., 2001; O’Dell et al., 1997, 1999; Rice et al., 2002; Roth et al., 2002). The mechanism by which IGF2 affects BMI is suggested in a recent study employing a 100 day overfeeding protocol conducted with pairs of monozygotic twins (Ukkola et al., 2001). In response to caloric surplus, fasting plasma insulin and OGTT (oral glucose tolerance test) increased more among the subjects with IGF2 Apa I GG than those with AA + AG in the insulin but not the glucose area. The changes were independent of changes in total fatness. The less common ApaI AA individuals also show lower serum levels of IGF2 (O’Dell et al., 1997) perhaps reflecting a role for the ApaI polymorphism in regulating transcription (Vafiadis et al., 1998). In the current study, we observed an increase in the A allele and the AA genotype in both Ashkenazi females and non-Ashkenazi males which is consistent with the findings that the AA genotype confers a slightly leaner body weight and may be preventative for developing insulin resistance and other metabolic-related diseases.

4.8. Leiden factor VII

The single current result that is not consistent with the risk profile of a polymorphism is an observed decrease in the A allele of the R353Q Leiden factor VII polymorphism in older Ashkenazi males corresponding to a reduced frequency of the QQ genotype (Gln/Gln). Wu and Tsongalis (2001) reviewed clinical studies that examined the role of single nucleotide polymorphisms in coagulation and platelet factors to determine if specific genotypes are correlated with a history of arterial thrombotic diseases (acute coronary syndromes or stroke). A meta-analysis was performed and showed that the combined RQ (arg/gln) and RR (arg/arg) genotypes of factor VII R353Q were correlated to a reduced risk for CVD in 2574 patients, whereas the QQ (gln/gln)

The potential link between aging and insulin/insulin- like growth factor-I (IGF-I) signaling has attracted substantial attention on the basis of several pieces of evidence showing that disruption of the insulin/IGF-I- signaling cascade can significantly extend life span in diverse species, including yeast, worms, fruit flies, and rodents (Barbieri et al., 2003). Intriguingly, long-lived mutants, ranging from yeast to mice, share some important phenotypic characteristics, including reduced insulin signaling, enhanced sensitivity to insulin, and reduced IGF-I plasma levels, with reduced oxidative damage of macromolecules and increased stress resistance being the likely final common pathway of these effects. Such genetic homologies and phenotypic similarities of insulin/IGF-I pathway mutants raise the possibility that the fundamental mechanism of aging may be evolutionarily conserved from yeast to mammals.

2003; Roberts et al., 1999), first findings for genetic studies are difficult to replicate especially across cultural and ethnic groups. Since longevity in humans is undoubtedly due to the cumulative effect of many common polymorphisms each of small effect size it is not surprising that replication is uneven except for a few genes.

Overall, some of the polymorphisms that have been associated with longevity in other studies or are associated with age-associated diseases likely to contribute to long- evity, were confirmed in the present study for a single outcome, survival to 75 years: apolipoprotein E, insulin-like growth factor 2, methylenetetrahydrofolate reductase, superoxide dismutase 2 and Leiden factor VII. However, none of the observed associations were observed uniformly across ethnic and gender categories. Additionally, the

Although in the current study, we examined the IGF2 receptor, it should be noted that IGF2 and IGF1 display similar physiological properties and are both components within a family of insulin-like growth factors (Le Roith,

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