A. Amante

Both Maternal and Foetal Genetic Factors Contribute to Macrosomia of Diabetic Pregnancy

The study of 230 diabetic mothers along with their newborn babies has shown that foetal macrosomia is associated with two specific genomic sites: phosphoglucomutase locus 1 (PGM1)-Rhesus blood group (Rh) linkage group (chromosome 1) and HindIII restriction fragment length polymorphism (RFLP) linked to insulin-like growth factor 1 (IGF1) (chromosome 12). In PGM(1)2-1 mothers carrying the E allele, there is a proportion of 8.7% of macrosomic newborns as compared with 39.6% in mothers with other genotypes. The relationship between the maternal PGM1-RhE genotype and neonatal macrosomia does not depend on the type of diabetes. The proportion of macrosomic infants is much lower among newborns carrying the IGF1HS allele of the HindIII RFLP linked to IGF1 (20%) than among IGF1F/IGF1HF newborns (55%).

Phosphotyrosine protein phosphatase and diabetic pregnancy: an association between low molecular weight acid phosphatase and degree of glycemic control

Low molecular weight acid phosphatase encoded by the highly polymorphic locus ACP 1 is a member of the protein-tyrosin phosphatase family (PTPases) which plays an essential role in the control of receptor signalling through phosphotyrosine pathways. Recent experiments have shown that purified rat liver ACP, corresponding to human ACP1, is able to hydrolyze a phosphotyrosine-containing synthetic peptide corresponding to the 1146–1158 sequence of the human insulin receptor, and shows a high affinity for it. This prompted us to analyze the degree of glycemic control in relation to ACP1 genetic variability in a sample of 214 diabetic pregnant women including IDDM, NIDDM and gestational diabetes. The ACP1 genotype was also determined in 482 non-diabetic pregnant women. In diabetic women glycemic levels in thelast trimester of pregnancy appear to be significantly associated with the ACP1 genotype, and correlated positively with ACP1 enzymatic activity. The data suggest that quantitative variations of ACP1 may influence the clincal mainifestations of diabetic disorders, and call for further studies on the role of this enzyme in the modulation of insulin-receptor phosphotyrosine pathways.

A possible genetic component of obesity in childhood. Observations on acid phosphatase polymorphism

Phenotypes of acid phosphatase with low enzymatic activity (ACP1 A and BA) are correlated with the highest degree of body mass increase observed in a sample of obese children. Since acid phosphatase probably functions as a flavin-mononucleotide phosphatase, differential modulation of flavo-enzyme activity and energy metabolism due to acid phosphatase genetic variability may explain the observed association.

Intrauterine growth: Association with acid phosphatase genetic polymorphism

Acid phosphatase (ACP1) is an enzyme found in the cytoplasm of many tissues and probably functions as a flavin mononucleotide-phosphatase. Therefore the highest concentration of flavin-mononucleotide cofactors is expected in ACP1 phenotypes with the lowest enzymatic activity (A and BA) and the lowest concentration of these cofactors is expected in phenotypes with the highest activity (CB and C). Accordingly, metabolic activities related to flavoenzymes should attain maximal levels in A and BA phenotypes and minimal levels in CB and C phenotypes. In the present study we have analyzed possible effects of ACP1 genetic variability on intrauterine growth in a sample of 609 newborns collected from three consecutive series in Rome. An association between ACP1 and birth weight is observed. The association is present only among male infants. ACP1 phenotypes with low enzymatic activity (A and BA) show a clear tendency to higher rates of intrauterine growth. A linear negative correlation is also observed between enzymatic activity and quartile class. The relation is significant only in male infants. The data suggest that in fetuses with low ACP1 activity, metabolic activity may be regulated at a level allowing a full response to specific genetic stimuli maximizing fetal growth.

Maternal-fetal interaction in the ABO system: a comparative analysis of healthy mothers and couples with recurrent spontaneous abortion suggests a protective effect of B incompatibility.

AbstractWe investigated the possible differential effects of A and B blood group materno-fetal incompatibility on human fertility through a comparative analysis of couples with recurrent spontaneous abortion (RSA) and healthy mothers. ABO phenotype was determined in 5180 healthy mothers and their newborn babies from the population of Sassari (Sardinia) and in 1359 healthy puerperae (women who have just given birth) from the population of Rome. Mother-newborn joint ABO distribution in healthy mothers was compared with wife-husband joint ABO distribution in RSA couples. Distortions from expected distribution were evaluated by symmetry analysis. In both RSA couples and healthy mothers significant deviation from expected symmetry patterns were observed. Deviations in RSA are in the opposite direction to those observed in healthy puerperae. The most important difference observed concerned the symmetric joint phenotypes mother (women) A / infant (husband) B (B incompatible) and mother (women) B / infant (husband) A (A incompatible). A low number of B incompatible in RSA couples and a high number of B incompatible in healthy mothers was observed. The phenomenon is much more evident in women aged 24-28 years, a period of maximum fecundity. It is possible that the presence of anti-B immunoglobulin in the mother might have a protective effect against fetal loss in some cases of mother-infant ABO incompatibility.

Interaction at clinical level between erythrocyte acid phosphatase and adenosine deaminase genetic polymorphisms

SummaryThe effects of ACP1 phenotype on birth weight, neonatal jaundice, and obesity in children are dependent on ADA genotype. These phenomena may represent a clinical counterpart of the in vitro biochemical interactions between the two systems recently observed by our group.

Evidence of selective interaction between adenosine deaminase and acid phosphatase polymorphisms in fetuses carried by diabetic women

SummaryPossible selective interaction between genetic polymorphisms of acid phosphatase locus 1 (ACP1) and adenosine deaminase (ADA) has been investigated in a sample of 211 infants from diabetic women, and in 350 consecutive infants from normal women. Newborns from diabetic pregnancies carrying the ADA2 allele show a lower proportion of BA and CB phenotypes (heterozygotes for the main allele of ACP1 system), compared with both their mothers and normal infants. The observation suggests that, in a diabetic environment, intrauterine selection may act against double heterozygotes for the ACP1 and ADA systems.

Genetic and non genetic factors in the outcome of diabetic pregnancy.

In insulin-dependent diabetes mellitus, maternal Phosphoglucomutase genotype is a predictor of fetal macrosomia much more important than quality of metabolic control during pregnancy. In gestational diabetes and in non insulin-dependent diabetes, on the contrary, the most important predictor is the metabolic control of diabetes.

Haptoglobin development in newborn infants from diabetic mothers.

Haptoglobin (Hp) development during the neonatal period has been studied in 325 newborn infants from normal pregnancies and in 242 infants from diabetic mothers. In infants from diabetic mothers Hp development is delayed as compared to infants from normal pregnancies. This delay is associated with a change in the pattern of relationship between Hp development and the polymorphism of acid phosphatase (ACP1) (an enzyme which shows phosphotyrosine phosphatase (PTPase) activity). In infants from normal pregnancies who show ACP1 phenotypes with the highest activity, the appearance of Hp is accelerated as compared to other infants. In contrast, infants from diabetic pregnancies who have ACP1 phenotypes with the highest activity, show delayed Hp development.

Phosphoglucomutase genetic polymorphism and human fertility

We studied the phosphoglucomutase phenotype in relation to fertility parameters in a consecutive series of 204 women who had delivered a normal live-born child in Rome. A highly significant association was found between age of the women and phosphoglucomutase phenotype, suggesting a reduced rate of reproduction among women of phosphoglucomutase Type 1. Previous spontaneous abortion appears related to both age and phosphoglucomutase enzymatic type. An increased incidence of abortion in women of older ages was observed only in phosphoglucomutase Type 1. Gestational duration and fetal intrauterine growth rate are also significantly associated with maternal phosphoglucomutase phenotype. The pattern is complex, but also in this instance the influence of maternal age was evident. Considered altogether, the data suggest that phosphoglucomutase may have an important role in zygote development and survival through the whole span of intrauterine life.