Association of CYP19 and ESR1 pleiotropic genes with human longevity.

Aromatase (CYP19) and estrogen receptor-alpha (ESR1) are involved in the metabolism of estrogens, which have a relevant role in female and male aging. Moreover, due to their influence on fertility, both genes may be part of the longevity-fertility trade-off mechanism. This investigation examines the association of ESR1 (PvuII and XbaI) and CYP19 (rs4646) polymorphisms with longevity. A sample of 258 individuals (mean age = 83.1 ± 5.7 years) was recruited in 2000. Based on mortality data collected in 2009, the sample was divided into two groups of participants surviving more than 90 years or not. The analysis showed that ESR1 PP (odds ratio = 2.2) and CYP19 genotypes carrying the T allele (odds ratio = 1.9) were significantly associated with longevity (survival to age more than 90 years). As the ESR1 PP genotypes were found associated with reduced fertility in the same sample, we may infer that ESR1 genotypes could exert an antagonistic pleiotropic effect on longevity and fertility.

Genetic variation of CYP19 (aromatase) gene influences age at onset of Alzheimer's disease in women.

BACKGROUND/AIMS: There is evidence for a higher prevalence of Alzheimer's disease (AD) in women, but whether this is due to their longer life expectancy or to biological gender-specific risk factors is unclear. One likely contributing factor is the reduced estrogen neuroprotective action following menopause. In this context, an AD risk gene could be CYP19, encoding aromatase, an enzyme involved in estrogen biosynthesis. METHODS: We analyzed the role of 3 CYP19 single-nucleotide polymorphisms (rs12907866, rs17601241, rs4646) in AD development and their possible influence on quantitative traits reflecting disease severity (age at onset and cognitive decline) in 319 patients and 110 controls. RESULTS: No association was observed between the CYP19 single-nucleotide polymorphisms and AD risk. Yet CYP19 genetic variation did seem to contribute to AD development in women as the rs4646 genotypes carrying the T allele were associated with an earlier onset age (p = 0.01) independently of a similar effect determined by the APOE e*4 allele (p = 0.005). Also, being present only in parous women (p = 0.01), the effect of rs4646 genotypes on onset age appeared to depend on past fertility. CONCLUSION: Together with gender-specific factors such as parity, genes controlling estrogen metabolism may play a relevant role in AD susceptibility in women.

Study on a possible effect of four longevity candidate genes (ACE, PON1, PPAR-gamma, and APOE) on human fertility.

The present study investigated for a possible effect on fertility of four longevity candidate genes (ACE, PON1, PPAR-gamma, APOE) in order to determine whether they have a pleiotropic action at different life ages. The study population was 151 healthy unrelated subjects. Only PPAR-gamma and APOE showed an effect on fertility. The PPAR-gamma Pro/Ala genotype, which had showed an association with longevity only in men, was found associated only in men with having produced more children (6.1+/-3.3) than the Pro/Pro genotype (3.3+/-1.9; P=0.001). APOE*2 allele, which has been consistently associated with longevity, was confirmed to be associated with the lowest fertility (P=0.03). The logistic regression analysis indicated that APOE and PPAR-gamma polymorphisms may be considered independent determinants of reproductive efficiency. These data suggest that the APOE*2 allele follows the model of antagonist pleiotropy, while the PPAR-gamma Pro/Ala genotype seems to exert beneficial effects both early in life and in advanced age in a gender-specific way.

Combined effect of apolipoprotein e genotype and past fertility on age at onset of Alzheimer's disease in women.

BACKGROUND: Various risk factors influence the development of Alzheimer's disease (AD). Apolipoprotein E (APOE) e*4 allele has a major role in AD susceptibility and its presence reduces age at AD onset. APOE is also thought to influence human reproduction, and common APOE genotypes seem to be associated with differential fertility. With this study, we investigated possible relationships between APOE genotype, past fertility, and AD onset age. METHODS: APOE genotypes were determined in a sample of 176 women with sporadic AD. The number of children each woman had delivered was recorded. RESULTS: A comparison of APOE genotype distribution in parous and nulliparous AD women confirmed that the e*3/e*3 genotype is associated with higher fertility and the e*4-carrying genotypes with lower fertility. When the combined effects of fertility and APOE genotypes on AD onset age were analyzed, parity was found to be associated with a significantly lower AD onset age (73.8 +/- 6.2 years) than nulliparity (80.7 +/- 5.0 years; p = 0.0007) among subjects carrying e*3/e*3 and e*3/e*2 genotypes. A similar effect was absent among e*4 carriers. Considering the high frequency of e*3/e*3 plus e*3/e*2 genotypes in Europe (range: 63-87%), past fertility may influence AD onset age in many women. CONCLUSION: Past fertility may have a relevant effect on AD onset age and this effect is influenced by APOE genotype.

Environmental factors and the proportion of males at birth in Italy.

A significant decline in the proportion of male births has been observed in recent decades in several western countries, and several researchers have raised the question of the possible role of environmental pollution in this trend. In the present analysis, the authors examined the effect of environmental factors (pollution from pesticides, urban pollution, and industrial pollution) on the sex ratio (proportion of males) of Italian singleton 1st births for the years 1989-1993, controlling for the age of the mother. The data show a slight increase in the sex ratio from north to south; however, no reduction in the proportion of males was seen in areas with higher pesticide consumption or intense industrial pollution. A small reduction in sex ratio was found in the major urban centers. The analysis was based on individual information on birth order and maternal age, as well as on ecological data on environmental pollution. No significant association was found between environmental pollution and the proportion of male births in Italy during the study period.

Trends in childbearing and stillbirth risk: heterogeneity among Italian regions.

In Italy, as in all Western countries, the almost monotonic decline in fertility observed since the 1960s has been paralleled until the beginning of the 1980s by a decrease in maternal age at delivery. Since then, age at marriage and at childbearing has been increasing and marital fertility has continued to decrease. By 1994 Italy showed extreme values of low total fertility rate (1.22) and of high mean maternal age at delivery (29.7). For the period between 1960 and 1994 we identified five U-shaped patterns in maternal age at delivery corresponding to five geographical areas, which differ socioeconomically and culturally. Since it is well known that an increase in the maternal age is accompanied by an increase in the risk of unfavorable pregnancy outcome, we estimated the stillbirth risk run by older (> or =35 years) mothers who delivered in 1994, with respect to their younger counterparts. The differences between the areas are reflected in the higher risk in southern compared to northern Italy: the maximum value occurred in Sicily (odds ratio 2.02, 95% confidence interval, 1.51-2.70) and the minimum value, even lower than in the north but not statistically significant, was found in Sardinia (odds ratio 1.25, 95% confidence interval, 0.81-1.91), known to be characterized by peculiar cultural and biological features.