Fulvia Gloria-Bottini

ACP1 and human adaptability. 1. Association with common diseases: a case-control study.

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.

Less Air Pollution Leads to Rapid Reduction of Airway Inflammation and Improved Airway Function in Asthmatic Children

OBJECTIVE. Air pollution can promote airway inflammation, posing significant health risks for children with chronic respiratory problems. However, it is unknown whether this process is reversible, so that limiting pollution will benefit these children. We measured the short-term response of allergic asthmatic children exposed to a real-life reduction in outdoor air pollution by using noninvasive biomarkers of airway inflammation and function. PATIENTS AND METHODS. Thirty-seven untreated allergic children with mild persistent asthma were recruited from a highly polluted urban environment and relocated to a less polluted rural environment. Air pollution, pollen counts, and meteorological conditions were carefully monitored at both sites. Nasal eosinophils, fractional exhaled nitric oxide, peak expiratory flow, and urinary leukotriene E4 were measured first in the urban environment and then again 7 days after relocation to the rural environment. RESULTS. One week after relocation to the rural environment, we measured, on average, a fourfold decrease in nasal eosinophils and significant decrease in fractional exhaled nitric oxide. We also noted an improvement in lower airway function, reflected by highly significant increase in peak expiratory flow. In contrast, mean urinary leukotriene E4 concentration remained unchanged after 1 week of exposure to the rural environment. CONCLUSIONS. Better air quality is associated with a rapid reduction of airway inflammation in allergic asthmatic children. Nasal eosinophils and fractional exhaled nitric oxide are sensitive indicators of this effect, and their rapid decline is paralleled by improved airway function measured by peak expiratory flow. Leukotriene synthesis has a more variable response to environmental modifications.

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.

Adenosine deaminase and body mass index in non—insulin-dependent diabetes mellitus

We studied 273 subjects with non-insulin-dependent diabetes mellitus (NIDDM) from the population of Penne, Italy. A low proportion of the adenosine deaminase (ADA)*2 allele is observed in NIDDM subjects with a body mass index (BMI) of 25 kg/m2 or less. On the contrary, a high proportion of this allele is observed in NIDDM patients with a BMI higher than 34 kg/m2. In the intermediate BMI class, the proportion of ADA*2 alleles does not differ significantly from that of normal subjects from the same population. No significant effect on the relation between ADA and BMI has been observed for the following variables: sex, age at the time of study, age at onset, therapy with insulin, and dyslipidemia. A borderline effect has been observed for the duration of disease. Several lines of experimental evidence suggest that an excess of adenosine A1 receptor activity may contribute to adiposity in NIDDM. ADA is a polymorphic enzyme that irreversibly deaminates adenosine to inosine, contributing to the regulation of intracellular and extracellular concentrations of adenosine. Since the activity of genotypes carrying the ADA*2 allele is lower than that of the more common genotype ADA*1/*1, genetic variability of the enzyme could contribute to degree of obesity in NIDDM. Our data also support attempts to ameliorate the metabolic control of diabetes through pharmacological modulation of adenosine receptors.

ABO/Secretor genetic complex and susceptibility to asthma in childhood

A positive association has recently been reported in adult subjects between O/nonSecretor phenotype and asthma. To confirm this association, this study investigated the joint ABO/Secretor phenotype in a cohort of 165 asthmatic children. Three-hundred and sixty-two consecutive newborn infants from the same population were also studied as controls. The proportion of O/nonSecretor in asthmatic children was higher than in controls, thus confirming the association found in adults. The association was more marked in males than in females. In males, the pattern of association between the joint ABO/Secretor phenotype and asthma is dependent on the age at on-set of symptoms. Since the oligosaccharide composition of cell membrane and mucosal secretions is controlled by the cooperative interaction of ABO and Secretor genes, and since such composition influences the adhesion of infectious agents, the age pattern could reflect a more general interaction between developmental maturation and oligosaccharide structure concerning their effects on susceptibility to viral and bacterial agents.

ACP1 genetic polymorphism and coronary artery disease: an association study.

Objectives: Assuming an immune component in the pathogenesis of atherosclerosis, we have investigated a possible association between coronary artery disease (CAD) and the acid phosphatase locus 1 (ACP1) genetic polymorphism, which has previously been found to be associated with immune disorders. Methods: 226 subjects admitted to the hospital for CAD, 358 consecutive newborn infants, 279 adult subjects with type 2 diabetes without CAD and 137 adults without diabetes and without CAD from the Caucasian population of Rome were studied. The ACP1 genotype was determined by DNA analysis. Statistical analyses were performed using the SPSS package. Results: CAD females showed an excess of ACP1 *A/*C and *B/*C genotypes and a deficiency of ACP1 *B/*B genotype compared to controls, while CAD males did not show significant differences. Among diabetic women the proportion of *C allele carriers was much greater in those with CAD than in those without CAD. This difference was much less evident in nondiabetic women. Conclusion: ACP1 may be involved in susceptibility to CAD. Since ACP1 has been found to be associated with immunological diseases, our observation reinforces the notion of an immune component in the pathogenesis of atherosclerosis.

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.

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 Crohns 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.

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.

ACP1 and Th class of immunological disease: evidence of interaction with gender.

Background: Data collected by our group in the past years indicate a relationship between ACP1 genetic polymorphism and susceptibility/resistance to immunological diseases. Recent observations suggest that through modulation of ZAP-70 activity, the enzyme may influence T cell activation. In view of the current interest in gender differences in autoimmune diseases we reviewed our data to enlighten possible effects of gender on the relationship between ACP1 and class of immunological disease. Methods: We studied three samples of subjects with allergic disorders of a total of 299 subjects, 71 subjects with Crohn’s disease and 188 children with type 1 diabetes. Three-way contingency tables were analyzed by a log linear model and two-way contingency tables by χ2 test. Results: There is an association between ACP1 and allergy (Th2 class) that depends on gender: the presence of the ACP1*A allele seems to make females more susceptible to allergic manifestations as compared to males. ACP1 is also associated with Crohn’s disease and type 1 diabetes: the relationship between this class (Th1) of immunological diseases and ACP1 depends on gender. The presence of *A allele seems to make females less susceptible to this class of diseases as compared to males. Conclusions: The ACP1*A allele which is associated with low ACP1 activity appears responsible for a complex relationship involving gender, ACP1 and Th1/Th2 orientation. Low ACP1 activity influencing ZAP-70 activity and in turn T cell activation seems to have opposite effects on Th1/Th2 orientation depending on gender.