Low Birth Weight and Allergy: Possible Pleiotropic Effect of ACP1

Abstract

The well-known relationship between low birth weight and allergies prompted us to investigate a possible pleiotropic effect of ACP1 on these conditions. ACP1 is a polymorphic enzyme that affects signal transduction of insulin and other growth factors, T-cell receptor signaling, and the regulation of flavoenzyme activity. Our aim was to compare the relationship between ACP1 and allergy with the relationship between ACP1 and birth weight. We studied 299 subjects from the Caucasian population of England, 124 subjects from the Caucasian population of central Italy, and 302 healthy puerperae and their newborn babies from the same Caucasian populations. ACP1 phenotype was determined by starch gel electrophoresis on RBC hemolysate and by DNA analysis. Subjects with high ACP1 activity (ACP1 C,B phenotype) show a lower level of IgE compared to subjects with low ACP1 activity (p = 0.01). The proportion of infants with a birth weight below the first quartile is lower among infants born to mothers with high ACP1 activity than among infants born to mothers with medium-low activity (p = 0.01). The data suggest a protective effect of high-activity ACP1 C,B phenotype from low birth weight and from allergic manifestations after birth.

KEY WORDS: BIRTH WEIGHT, ALLERGY, ACP1, CLMPTP, IGE LEVEL, ENGLAND, ITALY,

CAUCASIAN POPULATIONS.

The recent interest in the developmental origin of adult diseases (Gluckman et al. 2005), in particular, the relationship between low birth weight and asthma (Joseph et al. 2002; Potera 2003), prompted us to compare some data by our group concerning the relationship between ACP1 and IgE level to more recent observations on the relationship between maternal ACP1 phenotype and intrauterine growth.

ACP1 (also called cLMPTP) is an enzyme involved in the signal transduction of insulin and other growth factors, the regulation of flavoenzyme activity, and the phosphorylation status of band III of cytoskeleton (Spencer et al. 1964; Bottini et al. 2002a). More recently, a role for ACP1 in T-cell receptor signal transduction has been demonstrated. ACP1 specifically dephosphorylates the negative regulatory Tyr292 of ZAP70, thereby counteracting inactivation of ZAP70. This indicates that ACPl strengthens T-cell receptor signaling (Bottini et al. 2002e). The recently reported associations of ACP1 with serum IgE levels (Bottini et al. 2003) and with age at onset of type 1 diabetes (Bottini et al. 2002b) suggest an involvement of this polymorphism in Th1-Th2 balance.

ACP1 is controlled by a locus on chromosome 2 that shows three common codominant alleles ACP1 *A, *B, and *C. The enzyme shows great quantitative differences among common genotypes. Spencer et al. (1964) found in red blood cells the following activities (µmol p-nitrophenol produced in 30 min per gram of Hb at 37°C): ACP1*A/*A = 122.4, ACP1*B/*A = 153.9, ACP1*B/*B = 188.3, ACPl *C/*A = 183.8, and ACP1*C/*B = 212.3. The ACP1*C/*C genotype is rare (Spencer et al. 1964). ACP1 is present in all human tissues.

Materials and Methods

In this study we have reconsidered 299 subjects from the Caucasian population of England (sample 1) and 124 subjects from the population of central Italy (sample 2) (Bottini et al. 2003). In these samples, which include asthmatic and nonasthmatic subjects, we analyzed the relationship between IgE level and ACP1 phenotype. We also include in this study a consecutive sample of 302 healthy puerperae and their healthy newborn babies from the Caucasian population of central Italy (sample 3). In this sample we analyzed the relationship between birth weight and ACPl phenotype.

All subjects and the puerperae for the newborns gave verbal informed consent to participate in this study, which was approved by the Department of Biopathology and Imaging Diagnostics of the University of Rome Tor Vergata.

ACP1 phenotype was determined by starch gel electrophoresis on red blood cell hemolysate (Spencer et al. 1964) in samples 2 and 3. ACP1 genotype was determined by DNA analysis, as previously described (Iannaccone et al. 2005) in sample 1. In our laboratory no difference in results has been observed between the two methods.

The chi-square test of independence was performed using SPSS/PC programs (SPSS Inc. 1992).

Results

Table 1 (samples 1 and 2) shows the proportion of ACP1 genotypes in relation to IgE level (below and above the median). In subjects with an IgE level above the median the proportion of individuals with the ACP1*C/*B genotype is much lower than in subjects with IgE level below the median (p = 0.01). Similar results are observed for the mean level of IgE in relation to ACP1 phenotype (p = 0.01; data not shown).

Table 2 (sample 3) shows some maternal and neonatal parameters of the sample. Table 3 shows the proportion of ACP1 phenotypes in mothers and in newborns.

Table 4 shows the proportion of infants with a birth weight below the first quartile in relation to maternal and neonatal ACP1 phenotypes ordered according to their activity. The proportion of infants with a birth weight within the first quartile is low among infants born to mothers carrying the ACP1 C,B phenotype, which is associated with high ACP1 activity. There is a highly significant correlation between offspring birth weight and ACPl activity of the mothers (p = 0.009). In newborns a similar pattern is not observed.