Association between ACP(1) genetic polymorphism and favism.

An association between favism (a hemolytic reaction to consumption of fava beans), glucose-6-phosphate dehydrogenase deficiency (G6PD(-)) and acid phosphatase locus 1 (ACP(1)) phenotypes has been reported; the frequency of carriers of the p(a) and p(c) ACP(1) alleles was found to be significantly higher in G6PD(-) individuals showing favism than in the general population. Here, we investigated the hypothesis that favism is caused by toxic Vicia faba substances, which in some ACP(1) phenotypes cause increased phosphorylation and consequently increased glycolysis, with strong reduction in reduced glutathione production, resulting in hemolysis. It has been demonstrated that ACP(1) f isoforms have physiological functions different from those of s isoforms and are responsible for most of the phosphatase activity, in addition to being less stable in the presence of oxidizing molecules. Thus, the C, CA and A phenotypes, characterized by lower concentrations of f isoforms, could be more susceptible to damage by oxidative events compared to the other phenotypes. To test this hypothesis, the (f+s) enzymatic activity of different ACP(1) phenotypes with and without added V. faba extract was analyzed. Enzymatic activities of ACP(1) A, -CA, -C groups (low activity) and -B, -BA, -CB groups (high activity) were significantly different after addition of V. faba extract. Phenotypes A, CA and C had extremely low enzymatic activity levels, which would lead to low levels of reduced glutathione and bring about erythrocyte lysis.

Coronary artery disease: a study on the joint role of birth weight, adenosine deaminase, and gender.

An inverse relationship between birth weight and coronary artery diseases is well documented but it remains unclear which exposure in early life might underlie such association. Recently it has been reported an association between adenosine deaminase genetic polymorphism and coronary artery diseases. Gender differences in the degree of this association have been also observed. These observations prompted us to study the possible joint effects of BW, ADA, and gender on the susceptibility to coronary artery diseases. 222 subjects admitted to hospital for nonfatal coronary artery diseases, and 762 healthy consecutive newborns were studied. ADA genotypes were determined by DNA analysis. A highly significant complex relationship has emerged among ADA, birth weight, and gender concerning their role on susceptibility to coronary artery diseases in adult life. Odds ratio analysis suggests that low birth weight is more important in females than in males. ADA( *)2 allele appears protective in males, while in females such effect is obscured by birth weight.

Atopic and nonatopic asthma in children.

In 155 asthmatic children we have studied the relationship between prick test positivity and a set of genetic factors previously found to be associated with bronchial asthma. Among these factors, MN system (p = 0.009) and age at onset of symptoms (p = 0.05) are the most important variables separating prick test negative from prick test positive children. MN and age at onset influence independently prick test positivity pointing to an additive effect of the two variables. M phenotype appears correlated positively with an increased susceptibility to nonallergic asthma in all age groups, whereas N phenotype appears correlated positively with age at onset but in allergic asthma only. The MN system codifies for glycophorin A, a sialoglycoprotein that represents a major ligand for several bacteria and viruses that recognize the N-acetylneuraminic acid present in this protein. The present data suggest that genetic variability in this system might influence bacterial and viral competition and mucosal damage influencing susceptibility to asthmatic reactions in absence of IgE hyperproduction.

Intrauterine development and MNSs blood groups in repeated spontaneous abortion.

OBJECTIVES: To determine whether the maternal MNSs genotype has an effect on the birth weight and gestation duration of the live offspring of women with repeated primary spontaneous abortion (RSA). METHODS: The study sample consisted of 239 healthy white women who had been delivered of a live infant, and 137 women with a history of primary RSA-54 of whom had recently been delivered of a live infant and 83 who had had a spontaneous abortion. Maternal MNSs phenotypes were determined by standard serological methods, and the results were analyzed for relationships between these phenotypes and the mothers' reproductive status and the infants' birth weight and gestational age. Analysis of variance, the chi(2)-test of independence, and the Mantel-Haenszel test for linear association were performed for data analysis. RESULTS: Infants born to mothers with the Ss genotype showed significantly lower birth weight and gestational duration compared with the infants of mothers with other genotypes. Additionally, the MNSs haplotype was found to be associated with birth weight. CONCLUSIONS: Previous studies have shown that the MNSs system influences the gestational age of aborted fetuses in cases of RSA. The present study supports the hypothesis that this genetic factor influences intrauterine growth and development in women experiencing RSA.

The genetics of signal transduction and the outcome of diagnostic tests in growth retardation.

The effects of 'normal' genetic variability of signal transduction on endocrine function may be more evident during stimulation tests than is observed in basal states, thereby contributing to a greater understanding of the possible role of signal transduction genetics in the pathogenesis of endocrine disorders. In the present study, we have studied the outcome of growth hormone (GH) stimulation testing by insulin in growth-retarded children in relation to the genotype of ACP1 (acid phosphatase locus 1; also referred to as cLMWPTP, cytosolic low molecular weight phosphotyrosine phosphatase). ACP1 is an enzyme, expressed as two distinct isoforms designated F and S, that down-regulates insulin receptor signal transduction and which shows a genetic polymorphism with strong quantitative enzymatic differences among genotypes. In this study, we examined 116 growth-retarded children of which 101 were genotyped for ACP1. We found that the basal level of GH is higher in ACP1 genotypes with low concentrations of the S isoform than in genotypes with high S isoform concentrations (P<0.02). Additionally, during GH stimulation with insulin, the genotypes with low S isoform concentrations were found to perform better (P<0.005) and to react more promptly than the genotypes with high S isoform concentrations (P<0.05). These findings suggest that high S isoform ACP1 activity slows down the effect of insulin, resulting in a retardation of its metabolic effect.

Birth weight and parental PGM1 alleles.

A deviation of the maternal-neonatal joint phosphoglucomutase locus 1 (PGM1) distribution from Hardy-Weinberg expectation has been reported. It was suggested that selection on PGM1 during intrauterine life might account for these deviations and that maternal and paternal PGM1 alleles might have different associations with intrauterine survival. This study considered possible associations between the joint mother-newborn PGM1 genotype and intrauterine growth. There was a significant association between birth weight percentile class and mother-newborn PGM1 genotype in infant females. Also, the paternal PGM1*2 allele was associated negatively with macrosomia, and this effect was significant only in female infants.

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.

The genetics of signal transduction and the effect of smoking on intrauterine growth.

We have studied cytosolic low molecular weight phosphotyrosine phosphatase (cLMWPTP or ACP1) in 364 healthy puerperae from the population of Penne, in 155 diabetic puerperae from the population of Rome and in 349 consecutive normal newborn infants from the population of Rome. The data from these independent samples point to a protective role of maternal ACP1 genotypes with medium-high activity against intrauterine growth retardation caused by smoking.

RH blood groups and diabetic disorders: is there an effect on glycosylated hemoglobin level?

Recent cloning of RH genes has elucidated their structure, suggesting that RH proteins are part of an oligomeric complex with transport function in the erythrocyte. This observation prompted us to investigate a possible relationship between the RH system and the glycosylated hemoglobin level (Hb A(1c)) in diabetes. This compound is considered an important indicator- of glycemic control in diabetic disorders. We studied 278 subjects with non-insulin-dependent diabetes mellitus (NIDDM) from the population of Penne, Italy. Glycemic and glycosylated hemoglobin (Hb A(1c)) levels are associated with RH phenotype. Glucose and Hb A(1c) levels are increased in DCcEe subjects and decreased in ddccee subjects as compared to the mean values for other genotypes. Sex, age at onset of disease, duration of disease, and age of patients were also considered. Correlation analysis suggests that these variables influence glycemia directly and Hb A(1c) indirectly. The RH system, on the other hand, seems to influence the Hb A(1c) level directly. Preliminary data on 53 children with insulin-dependent diabetes mellitus (IDDM) from Sardinia seem to confirm the relationship between RH and Hb A(1c) observed in NIDDM. Since glycosylated hemoglobin is found inside red blood cells, the relationship between RH genetic variability and Hb A(1c) level suggests that RH proteins may influence glucose transport through red cell membrane and/or hemoglobin glycation.

Adenosine deaminase-acid phosphatase association and the environment: A study in a continental Italian population.

Three hundred fifty newborns from Rome and 351 from Penne were studied in continental Italy. Medium high altitude above sea level and cold winters characterize the area of Penne, while low altitude and very mild winters characterize the area of Rome. An effect of environmental conditions on the association between adenosine deaminase (ADA) and acid phosphatase (ACP1), previously shown in Sardinia, has been confirmed in continental Italy. When compared with expected independent assortment, the proportion of ACP1*A/*A carrying the ADA*2 allele is lower than expected in the lowlands and higher than expected in highlands. In continental Italy there is an interaction among ACP1-ADA genotype, season of conception, and locality. The excess of *A/*A newborns carrying the ADA*2 allele is present only among those conceived in the first half of the year (January-June). Among newborns in Penne conceived in the Spring, the proportion of those with *A/*A genotype is increased and these infants show decreased intrauterine growth. The present data suggest that ADA and ACP1 interact during intrauterine life with effects on development and survival and that such effects are dependent on local environment and season of conception. Am. J. Hum. Biol. 12:214-220, 2000. Copyright 2000 Wiley-Liss, Inc.

Inflammatory bowel disease: Are there gender differences in the genetics of signal transduction? A preliminary study of cytosolic low molecular weight protein tyrosine phosphatase.

The phenotype of cytosolic Low Molecular Weight Protein Tyrosine Phosphatase (cLMWPTP or ACP1), an enzyme involved in signal transduction of insulin, PDGF and T-cell receptors, has been determined in 71 patients with Crohn's Disease (CD: 37 males and 34 females), 49 patients with Ulcerative Colitis (UC: 27 males and 22 females) and 358 consecutive newborns (194 males and 164 females). cLMWPTP phenotypes showing a high concentration of F isoforms are associated with CD in females and with UC in males. Since PTPases counteract the effects of protein tyrosines kinases, a high concentration of F isoform of cLMWPTP may influence the mucosal response to pathogenic factors, increasing susceptibility to CD in females and to UC in males.

Haptoglobin genotype and natural fertility in humans.

OBJECTIVE: To study the possible relation between human natural fertility and haptoglobin (Hp) genotype. DESIGN: Prospective study. SETTING: Maternity departments of local hospitals in two Italian localities. PATIENT(S): Healthy women who had just given birth in the maternity departments of two local hospitals (n = 679). INTERVENTION(S): Venous blood collection for determination of Hp genotype with the use of starch gel electrophoresis of hemoglobin-supplemented serum. MAIN OUTCOME MEASURE(S): Distribution of Hp genotypes in relation to age of puerperae. RESULT(S): In both populations, the proportion of young mothers was much higher among women who were homozygous for the Hp*1 allele (the Hp*1/*1 genotype) than among women who had other Hp genotypes. In addition, the proportion of multiparous women among the older mothers was higher among those with the Hp*1/*1 genotype than among those with other Hp genotypes. CONCLUSION(S): The data suggest that women with the Hp*1/*1 genotype reproduce at an earlier age and have higher natural fertility potential than women with other Hp genotypes.

Phosphotyrosine-protein-phosphatase and diabetic disorders. Further studies on the relationship between low molecular weight acid phosphatase genotype and degree of glycemic control.

We have studied a new sample of 276 NIDDM patients from the population of Penne (Italy). Comparison of the new data with those of 214 diabetic pregnant women from the population of Rome reported in a previous paper has shown that the pattern of association between low molecular weight acid phosphatase genotype and degree of glycemic control is similar in the two classes of diabetic patients. Among nonobese subjects the proportion of ACP1*A (the allele showing the lowest enzymatic activity) is lower in diabetic patients with high glycemic levels (mean value greater than 8.9 mmol/l) than in diabetic patients with a low glycemic level (mean value less than 8.9 mmol/l). Among obese subjects no significant association is observed between glycemic levels and ACP1. Among nonobese subjects the concentration of f isoform of ACP1 is higher in patients showing a high glycemic level than in patients showing a low glycemic level. No significant difference is observed for s isoform.

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. METHOD OF STUDY: Adenosine deaminase phenotype has been determined in 209 women with repeated episodes of unexplained spontaneous abortion (RSA) and their husbands, as well as in 115 healthy pregnant women from the population of Rome. An independent sample of 286 puerperae along with their newborn infants in the population of Penne was also studied. RESULTS: The proportion of carriers of ADA*2 allele, which is associated with the lowest enzymatic activity, is lower among women with RSA than among healthy pregnant women from the same population of Rome. Preliminary observations suggest a protective effect of ADA*2 against the development of autoantibodies in RSA. Such an effect seems to be mediated by an interaction with AB0 blood groups. In the population of Penne the proportion of women carrying ADA*2 allele is higher among those who have had two or more previously born children than among women with only one or no children. CONCLUSIONS: The data suggest that women carrying the ADA*2 allele are better protected against the spontaneous loss of embryos and have a higher fertility rate.

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.

Diabetic complications and the genetics of signal transduction. A study of retinopathy in NIDDM.

Cytosolic low molecular weight acid phosphatase (ACP1) is a high polymorphic phosphotyrosine-protein-phosphatase involved in signal transduction. In NIDDM subjects we have found that ACP1 genotype is a highly significant predictor of retinopathy, suggesting that genetic variability of signal transduction may have an important role in the susceptibility to this complication. Adenosine deaminase, ABO blood groups and several clinical variables have been also considered. The results point out the importance of interactions between genetic systems. Among non-genetic variables dislipidemia and treatment with insulin are significantly associated with retinopathy.