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.

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.

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.

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.

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.

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.

Further studies on acid phosphatase in obese subjects.

Low activity genetic variants of acid phosphatase (ACP1) are positively associated with extreme body mass deviations in obese subjects. The same pattern has been found in non-diabetic children, in diabetic pregnant women, and in non-diabetic adult subjects. Low activity variants of ACP1 also show a positive association with family history of obesity, supporting the hypothesis of an enhancing action of these variants on expressivity of obesity.

Phosphotyrosine-protein-phosphatases and human reproduction: an association between low molecular weight acid phosphatase (ACP1) and spontaneous abortion.

ACP1 (low molecular weight acid phosphatase) genetic polymorphism has been studied in 173 women with a history of two or more consecutive spontaneous abortions and in 1508 control subjects, including 482 normal pregnant women. The proportion of carriers of ACP1*C allele (*A/ *C, *B/*C) in women with a history of repeated spontaneous abortion is lower than in normal pregnant women and other control groups. Women with repeated spontaneous abortion show a specific decrease of ACP1 S isoform concentration as compared to normal pregnant women. The other component of ACP1 activity, the F isoform, does not show a significant difference between the two groups. The data suggest that women with ACP1 genotypes showing a high concentration of S isoform are relatively 'protected' against spontaneous abortion. Preliminary analysis of a sample of 352 normal puerperae along with their newborn babies supports this hypothesis.

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.

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.

Foetal macrosomia and erythrocyte acid phosphatase (ACP1) polymorphism in diabetic and normal pregnancy.

Both in diabetic and in normal pregnancy the proportion of macrosomic fetuses is much lower among newborns carrying Pc allele of erythrocyte acid phosphatase (ACP1) than among other ACP1 genotypes. In diabetic pregnancy the well known increased incidence of fetal macrosomia has been observed only among fetuses which do not carry this allele. ACP1 probably functions as a flavin-mononucleotide phosphatase. Since Pc allele is associated with the highest enzymatic activity it is likely that subjects carrying this gene may have a relatively lower concentration of flavin-mononucleotide cofactors and in turn a reduced rate of metabolic activities controlled by flavoenzymes. It is possible that in fetuses carrying Pc, flavo-enzyme activities are regulated at a level that does not allow a full response to stimuli (both genetic and/or environmental) aimed to maximize fetal growth.

Serum haptoglobin appearance during neonatal period is associated with acid phosphatase (ACP1) phenotype.

Erythrocyte acid phosphatase (ACP1) is a polymorphic enzyme found in many tissues and acts in vivo as a flavin-mononucleotide phosphatase. We have recently observed a relation between this enzyme and length of gestation. The present study shows that the pattern of appearance of serum haptoglobin during the neonatal period is associated with ACP1 phenotype suggesting some important function of this polymorphic enzyme in human development.

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.

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.

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.