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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.

Human apolipoprotein E is the most important supplier of the cholesterol precursor for steroid hormone production in steroidogenic tissues and therefore could play a role in the regulation of steroid hormone function and influence human reproduction. This hypothesis has been confirmed by studies describing a differential fertility associated with common apolipoprotein (APOE) genotypes in two European populations. In the present investigation the impact of APOE genetic variation on fertility was studied in two Ecuadorian populations, African-Ecuadorians (57 women) and Cayapa Indians (27 women). In addition some biodemographic variables concerning women's fertility were investigated (124 African-Ecuadorian women; 40 Cayapa women) to better understand the APOE-fertility relationships in these pre-industrial populations. General fertility rates in both populations were very high (6.5 and 6.2 for the African-Ecuadorians and for the Cayapa respectively). When considering only women near the end of reproductive life ($40 years), a more marked difference was observed between the two groups (9.1 versus 7.7, P 5 0.09). In both communities, the highest number of children was found to be associated with the e*4/e*3 genotype; the e*4/e*3 genotype frequency (0.50) in the African-Ecuadorian women with 9-17 children was about three times that of the women with 0-8 children (0.14) (P 5 0.02). The present findings are at variance with those observed in European populations, where e*3/e*3 was the genotype associated with the highest reproductive efficiency. A possible explanation for this inconsistency could be due to the different functional properties associated with the e*3 and e*4 alleles and to genotype interactions with environmental factors including reproductive strategies.

BACKGROUND: In the wide-ranging debate about the potential monitors of population fertility, twinning rate has been considered a candidate. In the developed countries, a decline in spontaneous twinning rate began around 1950 and continued until the late 1970s. The decrease in mean maternal age at delivery and the number of children per family have been considered as possible reasons for the decrease. The rise in twinning rates, which began in the 1980s, is probably due to the spread of assisted reproduction, at least for older mothers. METHODS: The temporal trend in twinning rate and the relationship with maternal age at delivery and birth order in the Italian population were analysed. RESULTS: The recent increase in twinning rate can be mainly attributed to the recourse to assisted reproduction techniques, as demonstrated by the twinning frequency among older primiparae. The twinning rate recently observed in young mothers approximates to the value of the 1950s, which is assumed to represent a ‘natural’ fertility condition. CONCLUSIONS: On the assumption that twinning is an indicator of fertility, and hence of population fitness, the present data seem to suggest that natural fertility has been slightly increasing in the Italian population.

The effect of stabilizing and directional selection on birth weight has been analyzed for Italian births from 1954 to 1994, a period of rapid improvement in environmental conditions. The population of newborns was subdivided according to gestational age, one of the main covariates of birth weight. In the last cohort of births, no selection at all (neither stabilizing nor directional) was found in full-term babies, which represent more than 95% of total deliveries. Preterm babies are still selected against, even if at lower rates than in the past. It can therefore be claimed that improved and widely available prenatal and neonatal care has dramatically changed the selection patterns previously associated with birth weight in the majority of the Italian population. The mortality rates associated with birth-weight variations lying in a wide interval (2.5 kg-4.5 kg) are nowadays very similar, and both stabilizing and directional selection have practically disappeared.

In industrialized countries, male excess is generally found in early deaths, despite the overall decrease in mortality. We studied the association between sex and some factors generally considered crucial for babies' survival, such as mother's age and education, birth order, and gestational age, in order to gain insight into the causes underlying the persisting higher vulnerability of male sex in early life. The analysis was performed on babies dying during the perinatal period. These were subdivided into those who were stillborn and those who died during the first week of extrauterine life. A higher male excess among babies dying during the neonatal period than among those who were stillborn was always found in all classes of all factors. The finding of such generalized male overmortality in the early extrauterine period of life, together with the patterns shown by the temporal sex ratio in stillbirths and in early deaths, supports the hypothesis of a postponement of male risk from late fetal into neonatal life.

We have studied the impact of natural selection through stillbirth on the Italian population, taking into account the socio-economic heterogeneity of the country. The results suggest that older age at delivery and lower cultural level of the mothers, indicators of critical biological and socio-economic conditions, even at present increase stillbirth risk. Moreover, in the less favourable environment of the southern regions, selection is still sex-specific.

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.

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.

The estrogen receptor (ER) plays an important role in mediating estrogen action on target tissues. ER-alpha, the most abundant, is found in all human reproductive tissues and studies on alpha-ER knockout mice have highlighted its role in reproduction. ER-alpha gene (ESR1) polymorphisms have been associated with a variety of disorders including human infertility. In this study, we examined the association of ESR1 PvuII and XbaI polymorphisms with fertility in two populations with different reproductive patterns and precisely in a sample of healthy Italian men and women (n 5 178) and in a sample of healthy African-Ecuadorian women (n 5 57). ESR1 xx and ppxx genotypes among the Italian men were found to be associated with an above-median number of children (P 5 0.01 and P 5 0.004, respectively). ESR1 pp genotype among the Italian women showed a tendency to be associated with a lower number of abortions (P 5 0.04), whereas ESR1 pp and ppxx genotypes among African-Ecuadorian women were associated with a higher number of children (P 5 0.02 and P 5 0.03, respectively). These results are consistent with previous observations indicating a role of ESR1 genotypes in human infertility and give insight into the complex interactions between genotypes and reproductive behaviours in human populations.

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.

We studied the relaxation of natural selection affecting the newborn population in Italy between 1930 and 1993 due to the decrease in the stillbirth (mortality) rate and the simultaneous changes in women's reproductive behavior (strategies). Results show that, apart from a drastic overall reduction, the stillbirth rate has varied among different groups of neonates. The present stillbirth rate of less than 5 per thousand, observed in 8 of the 20 phenotypic classes defined on the basis of maternal age at delivery and neonate birth order, most likely represents an unavoidable biological or genetic cost. A 9 per thousand stillbirth rate, about twice the potential minimum, exists among neonates born to women delivering at advanced age (or = 35): the risk they face at the first or, in adverse living conditions, the fourth pregnancy could, however, be decreased by a policy aimed at countering the tendency to delay maternity and improving antenatal care in economically disadvantaged areas of the country.

We have studied the impact of natural selection on the Italian population, analysing the relationship between stillbirth and three related variables: birth weight, birth order and maternal age. A progressive relaxation of selection with time has been demonstrated by the reduction of the Haldane index calculated with respect to the three variables.

We have chosen four Italian regions with different degrees of industrialization and socioeconomic levels to study environmental differences in the sex ratio. The improvement in living and sanitary conditions during the last century has led to a progressive reduction in early male extramortality, and the sex ratio at birth has been almost unchanged at least to the first year of life and probably up to reproductive age. To investigate whether socioeconomic, cultural, or biological factors still influence the sex ratio at birth, we studied the stillbirth rate and the relations between newborn viability and sex composition as a function of maternal age and educational level. Our results suggest that in less favorable environments early selection against male newborns is almost twice that against female newborns when the mothers are the least favored for socioeconomic status, cultural level, and biological conditions (older than 39 years).

Several studies have shown that the human secondary sex ratio is affected by a wide range of biological and environmental factors. Here, we describe a partitioning of the sex ratio variability as observed in the Italian population over the last two generations. This period has seen drastic changes in the environmental conditions of Italy. As a consequence, demographic and biological variables that can affect the sex ratio have also changed dramatically. In an attempt to isolate any specific effect, we used a stepwise multiple regression to analyze the covariation over time of the sex ratio and of relevant parameters, such as stillbirth rate, maternal age, firstborn proportion, and birth order. The results show that a quadratic function of the firstborn proportion and mother's age is a fairly good predictor of sex ratio values.

We studied the sex ratio (M/F) in representative populations of the main human ethnic groups, namely, US whites, US blacks, and Japanese. The data cover a period of over 50 years. For intra-ethnic comparison, we included analogous data on Italians. The populations studied show heterogeneous patterns: the US white and Italian populations are the most similar, with no drastic variations in live-birth sex ratio throughout the period. Comparison of sex ratio data for live-borns and 1-year-old infants yields a similar pattern in all groups; the differences between the two sex ratio values are constantly reducing. It can be hypothesized that in the near future the sex ratio observed at birth will be maintained up to reproductive age. If this value is stabilized by natural selection, as is likely, new relationships between the sex ratio and selection are expected to evolve in the populations of developed countries.

In the course of the last century industrialized countries have experienced significant changes in mortality rates. Since the sex ratio of a population may be considered a function of, among other factors, differential mortality in the two sexes, it is expected to correlate with changes in sex-specific mortality rates. In this paper secular changes in the sex ratio at birth and after the action of relevant components of early selection (stillbirth, mortality within the first month and within the first year of life) have been studied in the Italian and in the USA White populations. The results can be summarized as follows. (i) In the past, extra male-specific mortality appeared to reduce the relatively large values of the sex ratio observed at birth, and this held true in both populations. (ii) In more recent times, male-specific mortality has been decreasing in all age groups, and the sex ratios before and after the action of early selection now tend to identical values. Therefore, it can be envisaged that in the near future the sex ratio observed at birth will be maintained up to the reproductive age. If the reproductive value is stabilized by natural selection, as is likely, new relationships between sex ratio and selection may be expected to develop in a relatively short time.

During the last century, industrialized countries experienced such an improvement in socioeconomic conditions and in sanitation that it is likely that the selective forces active on human metric traits have been modified. Perinatal mortality as a function of birth weight is one of the clearest examples of natural selection in humans. Here, trends over time of stabilizing and directional selection associated with birth weight have been analyzed in Japan from 1969 to 1989. The population of newborns has been subdivided according to gestational age, which is one of the main covariates of birth weight. The results show that in full-term babies both stabilizing and directional selection are coming to an end, whereas in babies born after 8 months of gestation these selective forces are still active, even if at much lower levels than in the past. The peculiar results found in the 7-month-gestation population are probably due to grossly abnormal cases of immaturity.

The secular trend for stabilizing selection on birth weight has been analysed in Italy from 1954 to 1985 in order to study changes in the forces of natural selection which have occurred as a consequence of progress in health care. In previous papers we demonstrated a very rapid relaxation of stabilizing selection on birth weight. In this paper we show that in the last few years this kind of selection has been coming to an end for the vast majority of Italian newborns.

SummaryIn order to study the effect of mother's age on birthweight variance, data were collected from Official Vital Statistics of the USA, Japan and Italy. Birthweight means and variances were calculated for all single births and for live births only. The results demonstrated that birthweight variance regularly increases in babies born to mothers of increasingly older age (with the exception of the youngest mothers). Moreover, the higher the variance in all births, the more the variance diminishes after late fetal selection. Therefore, a feedback phenomenon takes place in the stabilizing component of selection, i.e. the difference between the variance of all births and that of live births. As a consequence, at least part of the higher number of fetal losses experienced by older mothers can be attributed to the increased birthweight variance of their children.

Differential mortality as a function of birth weight was studied in Japan in the years 1969, 1974 and 1984. During the 15-year interval of observation a progressive equalization of mortality in the birth weight classes near the mean was found both for perinatal mortality as a whole and for its two components, stillbirth and mortality within the 1st week of life. The relaxation of selection on this metric trait is confirmed by the analysis of the variation over time of intensity of selection. A comparison of the Japanese population with other populations so far studied is also presented.

The index of opportunity for selection proposed by Crow has been calculated for the Italian population during the last century. The evolution of its two components, the pre-reproductive mortality and the variance in fertility, has been also analysed and compared with similar data for the United States. The results clearly show the relevance of socio-economic changes to the evolution of selective patterns in our species; in particular the relative incidence of mortality and fertility to selection intensity: the total index has in fact been reduced by 75% during the last century, the relative amount due to fertility increasing from 57 to 89%. The probable different relevance of genetic factors in the two components has also been discussed.

Differential stillbirth rates as a function of birth-weight have been studied in all single births in Italy in the years, 1954, 1961, 1967 and 1974. In the course of the twenty year interval of observation the following changes were found: (i) a progressive equalization of mortality in birth-weight classes near the mean; (ii) a reduction of the directional component of selection which is parallel to the increase of mean birth-weight (in the case of 8 months of pregnancy); (iii) a reduction of the stabilizing component of selection which is parallel to the decrease of birth-weight variance (in the case of 9 months of pregnancy); (iv) a reduction of selection intensity, while selective mortality remains more or less unchanged. The modifications of natural selection associated with birth-weight as consequence of health care progress in this population are also discussed.

Secular changes of stature of adult Italian males were compared with trends of some relevant health and socio-economic variables: survivorship up to 19 years of age, protein intake, average income and illiteracy. The results indicate that during the pre-World War II period the relationships between each of these variables and stature were different from those of the post-war period. Also the effects on stature distribution appear to be different in these two periods: in the first one the curve tends to become normally shaped while in the second the mean values is increasing at a higher rate than before. In very recent years no significant modification was detected. These findings are discussed in terms of the possible full expression of the genetic endowment for stature achieved in the environmental conditions typical of a contemporary industrialized country.

Out of 989 Sardinian individuals, 16 Dia (NADH diaphorase) 2–1 phenotypes have been found. The estimate of the Dia2 frequency is, therefore, 0.0081 ± 0.0020, which is higher than that of the other pop

The differences of birth-weight distributions before and after selection by the different components of perinatal mortality were studied for all single babies born in Italy in 1974. It was found that: (i) In mature babies the selection is mainly stabilizing while the directional type is almost negligible. (ii) In immature babies both stabilizing and directional selection are at work, greatly modifying the birth weight distributions.

Summary The secular trend of stabilizing selection on birth weight has been studied during the last decades in 17 countries, representative of America, Asia and Europe. A relaxation of the intensity of selection is regularly observed, which can probably be attributed to a progressive reduction of the environmental component of birth weight variance.

The mortailty and fertility components of the index of opportunity for selection (the Crow index) have been studied in the various Italian regions during the last century. To estimate the relevance of environmental factors on both components, their trends and those of their interregional variances have been compared with illiteracy. The results show that the selection opportunities due to mortality have decreased in a smiliar way in all the regions with a trend parallel to that of the national percentage of illiteracy, suggesting that this component is directly affected by the general socio-cultural level. As to the component due to fertility differentials, the regions, though scattered in the time scale, show a characteristic cycle of rise and fall. Moreover, the interregional variances of this component and of illiteracy are quite parallel, thus supporting the hypothesis that the reproductive pattern is strongly influenced by the individual cultural level.

Data from clinical records for 16,000 deliveries at the obstetric department of Rome University, Italy, are analyzed in order to identify the gestation times and birth weights associated with the lowest levels of perinatal mortality. The effects of mother's age, previous pregnancies and deliveries, and placental weight are also considered. The results show clearly that perinatal mortality increases with maternal age and is, in fact, equal to zero for mothers aged 15 to 19. (summary in ENG, FRE)

Summary The very large increase in adult stature during the last century is well documented for many countries and this phenomenon has been associated with the rapid improvement of environmental conditions. In the case of Italy, data relative to its regions and drawn from the military records of the last century showed a rapid normalization (i.e. elimination of both negative skewness and hyperkurtosis) of the distribution (1874–1938), followed by acceleration of the average increase (1938–57), which is now approaching a plateau (1957–64). Two different interactions between genotype and environment are hypothesized: the curve normalization is interpreted as being due to the elimination of extremely unfavourable conditions which inhibit growth, while the rapid stature increase is possibly due to the achievement of an environmental threshold, such as to permit a complete expression of the genetic potential. In fact, under the multifactorial model, a perfectly normal distribution is expected, unless there is differential selection before age 18.

Analyses of Vital Statistics from various industrialized countries have shown recent reduction of both the rate and sex-ratio of stillbirths. Two alternate explanations are conceivable for the finding: 1) the improvement of environmental conditions has actually reduced the male relative risk, 2) such an improvement has merely postponed late fetal mortality into early periods of extrauterine life. In order to discriminate between these two possibilities, both the secular trends of the sex-ratio of stillbirths and deaths in early infancy were analysed using Italian Vital Statistics. The results can be summarized as follows: 1) the sex-ratio of stillbirths continuously decreased during the examined period, from 1863 to 1979; 2) the sex-ratio of early deaths decreased until about 1920 and thereafter sharply increased. Therefore, Italian data seem to support the hypothesis of a postponement of late fetal deaths into early infant period.

Differential mortality as a function of birth weight was studied up to the 4th week of life in all single births in Italy in 1974. It was found that: (i) Both selection intensity and selective mortality are much higher with increasing immaturity. (ii) For babies born at term or after 8 months of pregnancy selection intensity tends to relax as early as one week after birth, while for those born after 7 months selection is at work for a longer period. (iii) Selective mortality, on the other hand, keeps increasing after birth but its relevance is relatively decreasing since average mortality after birth continues to decrease.

An analysis of genetic fitness was performed in Huntington's Disease (HD) and Spinocerebellar Ataxia 1 (SCA1) families. Two partially overlapping samples were used: clinically defined HD and SCA1 patients from families ascertained in definite geographical areas, and molecularly typed carriers of HD and SCA1 mutations (CAG trinucleotide expansions). In both cases, a control group of normal relatives was used. HD and SCA1 patients born before 1915-20 had more children than normal controls. Carriers of HD and SCA1 mutations, all in the low/medium expansion range (37-49 and 47-54 CAG repeats respectively), had a higher number of children than controls up to more recent times (1935-1950). The reproduction of heterozygotes for large expansions could be analysed only in subjects born after 1950 and provided indirect evidence of a lower than normal number of children. The above results fit a model based on a differential fitness according to the degree of expansion. Such a model predicts that 1) up to relatively recently the frequency of alleles in the low/medium range has been maintained or even increased by the increased fitness of their carriers, as well as by new mutations, and 2) the frequency of large expansions, part of which are lost at each generation, is maintained through further expansions of alleles in the low/medium expansion range. The implications of such a model on linkage disequilibrium and the possible spread of these diseases in future generations are discussed.

In a population sample of 333 unrelated individuals from Rome 2 variants, PHI 3-1 and PHI 5-1, were found.