Search

The acid phosphatase locus 1 (ACP1) codes for a low molecular weight phosphotyrosine protein phosphatase that has the important action of dephosphorylating tyrosine phosphorylated proteins and peptides and a second important role in modulating flavin cofactor levels and the activity of flavo-enzymes. These functions significantly influence cell division, differentiation, and growth. Two alleles (ACP1*A and ACP1*B) reach polymorphic frequencies at the ACP1 locus in all human populations, while the ACP1*C and ACP1*R alleles reach polymorphic frequencies in restricted geographical regions. The worldwide distribution of these alleles, and data from several clinical studies, strongly suggest that the ACP1 locus functions to modulate growth and that selection at this locus is a component of the selective processes influencing body mass and human population adaptation to thermal stress. The ACP1*A allele reaches highest frequencies at extreme latitudes and appears to be associated with maximizing body mass and adaptation to cold stress, whereas the ACP1*B allele reaches highest frequencies in tropical and subtropical environments and appears to be associated with minimizing body mass and adaptation to heat stress. The high frequency of the ACP1*C allele at northern latitudes, where ACP1*A allele frequencies are elevated, may be a mechanism for limiting fetal and maternal complications associated with fetal macrosomia and adult obesity in populations where protein and calorie intake are relatively high. Am. J. Hum. Biol. 12:688-701, 2000. Copyright 2000 Wiley-Liss, Inc.

Background: The recent discoveries about the structure of Rh protein that suggest a transport function and the recent observations of a positive correlation between Rh(D) protein and glycosylated hemoglobin levels in non-insulin-dependent diabetes mellitus prompted us to review our data on diabetic pregnancy to evaluate the perinatal consequences of maternal-fetal Rh blood group interactions in a metabolic perspective., Subjects and Methods: One hundred thirty-two women with gestational diabetes and 120 women with preexisting insulin-dependent diabetes mellitus were examined. Three hundred eighty-seven consecutive nondiabetic puerperae from the same population were considered control subjects., Results: In both gestational and insulin-dependent diabetes mellitus, an increased proportion of mother Rh(+)/newborn Rh(-) and a decreased proportion of mother Rh(-)/newborn Rh(+) joint phenotype has been observed. No deviation has been observed for joint phenotypes in which mother and newborn are similar [ie, Rh(+)/Rh(+) and Rh(-)/Rh(-)]. In the situation of mother Rh(+)/newborn Rh(-), there is a relatively lower rate of fetal loss and a decreased tendency to high birth weight. On the contrary, in pairs mother Rh(-)/newborn Rh(+) the fetus shows an increase of fetal loss and of tendency to high birth weight., Conclusions: The results are compatible with the hypothesis that when the density of Rh protein in the mother is higher than that in the fetus, the conceptus is relatively protected against the toxic effect of glucose. In the opposite genotypic combination (ie, density of Rh protein higher in the fetus than in the mother), the fetus is relatively more susceptible to these effects.

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.

The possible association of human growth hormone (hGH) and insulin (INS) gene regions with metabolic control in diabetes was investigated in 98 subjects with non-insulin-dependent diabetes mellitus (NIDDM); 54 control subjects from the same population were also studied. Two polymorphic restriction sites in the region of the hGH cluster (BGLIIA and BGLIIB) show significant association with both glycemic and hemoglobin A1c (HbA1c) levels. Mean values for plasma glucose and HbA1c show a maximum in the BGLIIA *1/*1 genotype and a minimum in the BGLIIA *2/*2 genotype. Mean values for plasma glucose and HbA1c show a maximum in the BGLIIB *1/*2 genotype. The BGLIIA*2/BGLIIB*1 haplotype shows a negative correlation with plasma glucose and HbA1c levels. Since the two markers are located in the area surrounding the hGH-V locus, the expression of this gene in NIDDM warrants further investigation.

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.

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.

We have studied the pattern of association between the season of conception and cytosolic low molecular weight phosphotyrosine phosphatase (ACP1) genetic polymorphism in 329 consecutively newborn infants from the population of Penne and 361 consecutively newborn infants from the population of Rome. In addition, 329 mothers were studied in the population of Penne. A concordant, highly significant association was observed in the two populations between ACP1 parameters and the season of conception of newborn infants. The total activity of ACP1 shows a minimum in infants conceived in January-February and a maximum in those conceived at the end of the solar year. Analysis of the joint mother-newborn ACP1 distribution in relation to the season of fertilisation has shown that among mothers carrying ACP1*A (the allele showing the lowest activity), the proportion of newborns carrying this allele is higher in those conceived in the first months of the year than in those conceived subsequently. Since ACP1 probably functions as a phosphotyrosine phosphatase and as a flavin mononucleotide phosphatase, low activity could enhance the metabolic rate and would be advantageous in a cold environment. The cycle of variation of ACP1 in infants follows the cycle of solar illumination. It is possible that individuals who have a genetic background allowing them to adapt easily and readily to seasonal demand are more successful in reproducing themselves. The population of zygotes conceived in a given season would therefore reproduce the pattern of gene combination more fit for that season.

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.

Low-molecular-weight acid phosphatase (ACP1) is a polymorphic protein-tyrosine phosphatase present in all human tissues, including adipocytes. A positive association between the low-activity ACP1*A/*A genotype and extreme body mass index has previously been shown by us in obese subjects from the population of Rome. We have now studied a sample of 265 subjects with non-insulin-dependent diabetes mellitus (NIDDM) from another Italian population. There is a significant interaction between ACP1, body mass index, and blood lipid level. A highly significant positive association between ACP1*A/*A and high body mass index similar to that previously observed in obese subjects from the population of Rome is present only in those NIDDM subjects with blood lipid levels within the normal range. In NIDDM subjects the low-activity ACP1*A/*A variant seems to favor the increase of body mass or blood lipid levels or both. The pattern of association is independent of sex, age at survey, age at onset of diabetes, duration of disease, and therapy.

The relationship between human placental alkaline phosphatase (PLAP) genotype and birth weight is investigated in a sample of white, black and Puerto-Rican new-born infants from New Haven, Connecticut (total 710 subjects). Black and Puerto-Rican infants show a higher incidence of growth retardation and a higher frequency of ALPp*1/*1 genotype as compared to whites. The proportion of newborns with a low birth weight (below the 10th percentile) is lower in infants with ALPp*1/*1 genotype than in those with other PLAP genotypes, especially among non-whites. It is argued that the higher frequency of ALPp*1 allele among non-whites might be, at least in part, a consequence of their adaptation in the past to environmental conditions adverse to optimal intrauterine development.

Low molecular weight acid phosphatase encoded by the highly polymorphic locus ACP1 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 the last trimester of pregnancy appear to be significantly associated with the ACP1 genotype, and correlate positively with ACP1 enzymatic activity. The data suggest that quantitative variations of ACP1 may influence the clinical manifestations of diabetic disorders, and call for further studies on the role of this enzyme in the modulation of insulin-receptor phosphotyrosine pathways.

Human red cell acid phosphatase (ACP1) is a polymorphic enzyme closely related to cytosolic low molecular weight acid phosphatases, a protein family broadly conserved among eukaryotes. Two different functions have been proposed for ACP1: flavin mononucleotide (FMN) phosphatase and phosphotyrosine phosphatase (PTPase). Given that genetic variants of ACP1 activity are common, the enzyme could have a role in regulating a large spectrum of cellular functions and, in turn, disease susceptibility. In the present paper we report a study of ACP1 genetic polymorphism in 1088 normal subjects and in 1267 subjects from the population of Rome admitted to hospital for a number of common diseases. All ACP1 parameters investigated show highly significant differences among samples, suggesting that the enzyme may have a significant role in some of the diseases considered. In particular, consistent associations of ACP1 with developmental disturbances and with hemolytic favism have been observed. In the majority of diseases showing association with ACP1, only one of the two ACP1 isoforms, f and s, is involved, supporting the hypothesis of a functional differentiation between the two enzymatic fractions.

A total of 203 couples with unexplained habitual abortions and 364 consecutive normal puerperae along with their live-born babies were studied. The analysis of wife-husband joint ABO blood group distribution in couples with habitual abortion showed an excess of A incompatible mating type and a defect of B incompatible type as compared with expected proportions assuming random mating. The joint wife-husband ABO blood group distribution was further analysed in relation to the adenosine deaminase (ADA) genotype. A defect of O-A and A-O couples when the wife carries the ADA*1/*1 genotype and the husband carries the ADA*2 allele, and a defect of O-O and A-A when the wife carries the ADA*2 allele were observed. In the sample of normal puerperae, analysis of the joint mother-newborn ABO distribution in relation to the ADA genotype showed a pattern similar to that observed in couples with habitual abortion, i.e. there is a defect of O-A and A-O when the mother carries the ADA*1/*1 genotype and the newborn carries the ADA*2 allele and a defect of O-O and A-A types when the mother carries the ADA*2 allele. Altogether the data suggest an early loss of O-A and A-O zygotes when they carry the ADA*2 allele and an early loss of O-O and A-A zygotes when the mother carries the ADA*2 allele resulting in a deficit of these zygotic classes among both spontaneously aborted fetuses and live-born infants. The pattern of association observed in the mother-fetus type O-A (incompatible according to conventional terminology) appears similar to that observed for the reciprocal A-O type (compatible according to conventional terminology). Therefore strictly conventional immunological mechanisms cannot explain the whole pattern of associations. Cell to cell intereactions involving ABO antigens may have an important role at implantation: ADA, through the control of local adenosine concentration, could modulate these interactions influencing the probability of successful implantation.

The pattern of ACP1-ADA association in 12 Sardinian villages is dependent on altitude, suggesting that genetic and/or environmental factors may influence the interactions between the two systems. This may explain the variability of the association observed in human populations.

Ninety-nine pregnant women with insulin-dependent diabetes mellitus, 83 women with gestational diabetes, and a control sample of 315 nondiabetic consecutive puerperae have been studied along with their newborn infants. Neonatal macrosomia is less frequent among diabetic mothers with phosphoglucomutase (PGM1) genotype PGM1*1/*2 than among mothers with other PGM1 genotypes. In gestational diabetes the association is more evident among younger women than among older women. Diabetic women with the PGM1*1/*2 genotype show a reduced proportion of heterozygous PGM1*1/*2 offspring. The phenomenon is much more evident among women under 28 years of age and does not depend on the quality of metabolic control. The data suggest that when both mother and fetus share the PGM1*1/*2 genotype, the deleterious effects of a diabetic environment on fetal development are more severe, leading to an early loss of zygotes. This may contribute to a decrease incidence of macromosomia among live-born infants delivered by PGM1*1/*2 mothers.

Rh E-PGM1 (phosphoglucomutase locus 1) joint genotype frequencies (chromosome 1) have been determined in 90 women with gestational diabetes mellitus (GDM) and in 140 pregnant women with preexisting insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM). The pattern of Rh E-PGM1 association differs among types of diabetes. The distortion of the pattern tends to assume opposite values in GDM and NIDDM and this is particularly evident in PGM1*2,2 subjects. The proportion of PGM1*2,2 subjects homozygous for the Rh e allele is higher in GDM than in IDDM and NIDDM. IDDM women show an intermediate proportion and NIDDM women show the lowest proportion of this genotype. The opposite pattern is observed among PGM1*2,2 subjects carrying the Rh E allele. Genotype frequencies of the hypervariable region flanking the insulin gene (chromosome 11) have been determined in 77 women with GDM, in 52 pregnant women with preexisting diabetes (IDDM and NIDDM), and in 62 normal adults. In GDM and NIDDM subjects the frequencies are similar. In IDDM women the frequency of homozygotes for the class 1 allele is higher than the frequency found in GDM and NIDDM women. The data suggest a possible genetic basis for the differentiation of a subclass of GDM from both IDDM and NIDDM.

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.

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%).

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.

The blood glucose levels of pregnant women with insulin-dependent diabetes mellitus and the blood glucose levels of newborns during the first few hours of life show an association with maternal Rh genotype. Distortions of joint maternal-fetal Rh phenotype distribution have also been observed. Because a cluster of genes involved in glycide metabolism is located on the short arm of chromosome 1, the present observations may reflect the action of these genes.

A series of genetic, developmental and environmental variables have been analyzed in a prospective sample of full-term newborn babies, compatible with their mothers in the major blood group systems, in order to attempt an evaluation of the effect of these variables on serum bilirubin level during the first few days of life. Three genetic factors (PGM1, ACP1 and ADA) and three non-genetic variables (rise of bilirubin level during the first day of life, a mother with a history of previous abortion, and use of alcoholic beverages by the mother) have a significant predictive value for the separation of newborns with clinically relevant jaundice from other infants.

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.

The ACP1*A allele of erythrocyte acid phosphatase (ACP1) has a lower enzymatic activity when compared to other ACP1 alleles and is associated with maximal rate of body growth during intrauterine life. In three different samples of obese subjects (total number = 218). ACP1*A was associated with extreme body mass deviations. No difference in ACP1 allele distribution was observed between obese and nonobese subjects. These data suggest that a genetically determined variability of ACP1 influences the degree of obesity, but only when obesity itself has been triggered by some other factors.

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.

In ABO incompatible infants, a strong association between Coombs test positivity and hyperbilirubinaemia in the first few days of life has been recorded in all samples studied. A remarkable variability between ethnic groups and between different series of infants from the same group has been also observed. A discriminant analysis carried out on several maternal and neonatal variables in two samples of ABO incompatible infants has shown that the Coombs test is the most important predictor of jaundice. Gestational age and birth weight in white and birth weight in black infants gave also important and independent contributions as discriminating variables. Among ABO incompatible black infants the incidence of hyperbilirubinaemia was higher than among ABO incompatible white infants. Discriminant analysis suggests the genetic and environmental factors which predispose to jaundice the ABO incompatible black infants may act mainly through immunological and developmental mechanisms accounted for by Coombs test, gestational length and birth weight.

Secondary sex ratio (SR) in man is influenced by various genetic and environmental factors. It has been observed that SR in subjects of blood group B compatible with their mothers is higher than in other subjects. The analysis of 676 newborns of the Rome population and 1,684 newborns of the New Haven (Connecticut) population have confirmed a higher SR in B group subjects compatible with their mothers. The data also indicate that placental alkaline phosphatase is another genetic factor influencing SR in man and that there is a strong interaction among ABO phenotype, fetomaternal ABO compatible status and PAP phenotype concerning their effects on SR.

Data on the offspring of 198 aunts and 179 uncles of 100 cystic fibrosis index cases were analyzed. Aunts showed higher average number of liveborn sons than uncles. No significant difference was observed in the number of liveborn female offspring. When the sample was subdivided with respect to family size, the proportion of liveborn sons of aunts appeared higher than that of uncles in all classes. The present observations suggest that a female carrier may have a higher probability of male offspring than a male carrier and that she may be mainly responsible for the sex ratio deviations previously reported in sibships of cystic fibrosis patients.

The pattern of associations between maternal phosphoglucomutase locus 1 (PGM1) and foetal macrosomia in diabetic pregnancy has been compared with that observed in normal pregnancy. In diabetic pregnancy a substantial increase of macrosomic infants, as compared to normal pregnancy, is observed only among women homozygous for PGM1(1) allele. Also neonatal hypoglycemia is much more frequent in newborns from PGM1(-1) mothers than in newborns from other mothers. Since enzymatic activity of PGM1(-1) phenotype is lower as compared to other PGM1 phenotypes, this may influence glycaemic level and/or its stability in diabetic pregnant women with unfavourable effects on the metabolic and developmental patterns of the foetus.

We investigated possible relations among four common neonatal manifestations of diabetic pregnancy (macrosomia, hypoglycemia, hypocalcemia, jaundice) and four enzyme polymorphisms (PGM1, ADA, AK1, ACP1 in a sample of infants born of diabetic mothers. The pattern of associations observed between the two sets of variables is consistent with known differences in enzymatic activity within phenotypes of each system, suggesting that low enzymatic activity may have unfavorable effects on fetal development and on adaptability of the neonate to the extrauterine environment, Some of the polymorphic enzymes studied influence fetal growth in normal pregnancy as well. Analysis of relations between genetic polymorphisms and the clinical pattern of common diseases may provide a better understanding of the genetic basis of the clinical variability of diseases within and between human populations.