E. Cosmi

Adenosine Deaminase and Human Reproduction: A Comparative Study of Fertile Women and Women with Recurrent Spontaneous Abortion

PROBLEM: We have investigated the possible role of adenosine deaminase (ADA) genetic polymorphism in human fertility through a comparative study of couples with recurrent spontaneous abortion (RSA) and healthy puerperae.

The Genetics of Signal Transduction and the Feto-Maternal Relationship. A Study of Cytosolic Low Molecular Weight Phosphotyrosine Phosphatase

Intracellular kinases mediate positive signalling from surface receptors by phosphorylating critical target proteins whereas phosphatases inhibit this process. Differential phosphatase activity at the feto-maternal interface could determine the appropriate relative growth and development on each side of the placenta. The highly polymorphic cytosolic low molecular weight phosphotyrosine-phosphatase (ACP1-cLMWPTPase) has been studied in 170 women who had at least two consecutive spontaneous abortions along with their husbands and in 352 normal puerperae along with their newborn babies. Symmetry analysis of joint wife/husband and mother/infant distribution suggests that when ACP1 activity is lower in the mother than in either her aborted fetus or her child, the probability of abortion is higher and the survival to term is lower as compared to pairs in which the ACP1 activity is higher in the mother than in her fetus. Further analysis has shown that the effect is due to S isoform: i.e. a high mother/fetus S isoform ratio favours intrauterine survival. Analysis of gestational duration and birth weight suggests that a high ACP1 maternal activity coupled with a low or moderate fetal activity favour fetal growth and developmental maturation. The present data indicate that maternal-fetal genetic differences in signal transduction could contribute significantly to variability of intrauterine developmental parameters and to pathological manifestation of pregnancy.

Is Delayed Childbearing Changing Gene Frequencies in Western Populations

Experimental data and clinical observations suggest that delaying childbearing influences the biology of the mother-fetus relationship, with a negative effect on fetal development and predisposition to severe diseases such as type 1 diabetes. We reason that advanced maternal age may influence intrauterine selection, favoring genotypes that are more adapted to the intrauterine environment of less young women. In the present study we have investigated the relationship of maternal age to HP genotype and PGM1-Rh area (chromosome 1) that have been previously found to be associated with fertility and developmental parameters. HP phenotype was determined in 679 consecutive puerperae from the population of central Italy. PGM1 phenotype and Rh C phenotype were determined in 222 puerperae and 200 newborns. The HP 1,1 phenotype decreases and the HP 2,2 phenotype increases with maternal age. The proportion of phenotypes carrying both the Rh C and PGM1*1 alleles is much higher in puerperae older than 36 years than in puerperae of age 22 years. The frequency of the PGM1*1–Rh C haplotype increases and the frequency of the PGM1*2–Rh C haplotype decreases with maternal age. The changes in these genetic systems with advancing maternal age are similar in mothers and newborns. The delay of childbearing age, associated in Western countries with the fertility transition in addition to detrimental effects on intrauterine development and increased susceptibility to severe disorders, could bring about changes in the genetic composition of a population.

Phosphoglucomutase genetic polymorphism of newborns

An association of the phosphoglucomutase locus 1 (PGM1) genetic polymorphism with repeated spontaneous abortion (RSA), with intrauterine development in both normal and diabetic pregnancies, and with fertility has been reported in previous studies. In view of the evolutionary interest and of a possible clinical relevance of PGM1 selection during intrauterine life, this study considers healthy puerperae, consecutive newborns, and couples with RSA as well as two alleles (PGM1*1 and PGM1*2). The joint maternal–neonatal PGM1 distribution in a sample from an Italian rural population is significantly different from that expected assuming Hardy–Weinberg conditions for equilibrium. Deviation is dependent on maternal age and parity. The joint mother–newborn PGM1 genotype distribution is significantly associated with a positive history of previous spontaneous miscarriage, suggesting that the presence of the PGM1*2 allele in the father predisposes to spontaneous abortion. This hypothesis is also supported by the observation that in couples with RSA, the delivery of a live born infant within 5 years from the first episode of miscarriage is negatively associated with the presence of a PGM1*2 allele in the husband. Altogether these observations suggest the hypothesis of PGM1 maternal selection at the reproductive level involving a differential role of PGM1*1 and PGM1*2 alleles of paternal origin. Am. J. Hum. Biol. 13:9–14, 2001.

Smoking, haptoglobin and fertility in humans

A prospective study on two samples of consecutive puerperae (total n° 667) from two populations has been carried out in order to investigate the possible effect of smoking habit on relationship between fertility and haptoglobin phenotype.In both populations the negative association previously reported between age of pueperae and Haptoglobin *1/*1 phenotype is present only in women with smoking habit pointing to an interaction between Hp and smoke on human fertility. This suggests that the effects of smoke on fertility are dependent on the Hp phenotype.

Evidence of decreased fertility in women carrying the gene for G6PD deficiency: a study in the Sardinian population

The current trend toward reduced feritility and delayed childbearing has stimulated an interest in the genetic and environmental factors capable of modifying fertility. The evaluation of fertility in G6PD-deficient females is of great theoretical interest in view of the proposed heterozygote advantage of G6PD deficiency in malarial environments. Toncheva and Tzoneva have reported population data from Bulgaria suggesting decreased fertility of women carrying the risk allele for G6PD deficiency. We have applied a model of maternal-age related differences within the distribution of ‘fertility-types’ among women, described by Gimelfarb and Bottini (1989) to a sample of 5182 Sardinian mothers. Mothers of infants with G6PD deficiency are underrepresented in the group of women having children at younger ages, suggesting a reduction of so-called ‘natural fertility’ among women carrying the risk allele for G6PD deficiency. Female infants with G6PD deficiency from young mothers have a lower birth weight compared to infants without G6PD deficiency from older mothers, suggesting that in younger mothers there is a negative effect of G6PD deficiency on intrauterine growth.

Smoking and the Genetics of Signal Transduction: An Association Study on Retinopathy in Type 1 Diabetes

BackgroundRecent studies suggest a complex association between smoking and retinopathy that probably depends on the interaction between many variables. We have reported an association between ACP1 phenotype and retinopathy in type 1 diabetes. Additionally, the deleterious effects of smoking on intrauterine growth are dependent on ACP1, a low-molecular-weight tyrosine phosphatase that modifies signal transduction. We examine here the interaction between smoking and ACP1 as a mediator of susceptibility to diabetic retinopathy in a sample of puerperae with type 1 diabetes. Subjects and MethodsSeventy-eight women who had just delivered live infants were studied. ACP1 phenotype was determined by starch gel electrophoresis. Three-way contingency tables were analyzed. ResultsThere is a significant epistatic interaction between smoking and ACP1 phenotype concerning their effects on retinopathy. In subjects with low ACP1 activity, frequency of retinopathy was slightly higher in smokers than in nonsmokers. However, in subjects with medium-high ACP1 activity, frequency of retinopathy was significantly lower in smokers than in nonsmokers. A logistic regression analysis using retinopathy as the dependent variable revealed that smoking, ACP1, and ACP1 by smoking interaction, as well as the interaction between smoking and age of the women, are the most robust predictors of retinopathy. ConclusionsThe effect of smoking on retinopathy in women with type 1 diabetes depends on many variables, which supports the hypothesis of complex interactions between smoking and other variables in the pathogenesis of this disease. Variability of genetic factors involved in signal transduction may affect endothelium proliferation through the regulation of growth factors and through regulation of glycemic levels. Because cigarette smoke influences signal transduction, its impact on diabetic retinopathy may be mediated by ACP1.

Maternal cigarette smoking, metabolic enzyme polymorphism, and developmental events in the early stages of extrauterine life,

The recent observation that maternal ACP1 genotype has an interactive effect with smoking on intrauterine development prompted us to search for a possible interaction effect between smoking and ACP1 genotype on haptoglobin (Hp) development in the neonatal period. ACP1 is a highly polymorphic protein tyrosine phosphatase involved in signal transduction of several growth factor receptors. The enzyme is composed of two isoforms, F and S. We studied 299 infants born in the Department of Obstetrics of the University Hospital of Rome La Sapienza. We found that an interaction between ACP1 genotype and smoking has an effect on haptoglobin development: A significant delay of haptoglobin development in infants born to smoking mothers is observed only in infants with the ACP1*B/*B genotype, which shows the highest concentration of the ACP1 F isoform. The results indicate that the ACP1 genotype modifies the deleterious effects of smoking on development not only during intrauterine life but also during the early stage of extrauterine life.