Fulvia Gloria-Bottini

Adenosine modulates cardiovascular functions reducing blood pressure and heart rate. Adenosine deaminase (ADA) by the irreversible deamination of adenosine to inosine contributes to the regulation of adenosine concentration in body fluids. We have studied the interaction between smoking and ADA genetic variability concerning their effects on blood pressure. We have studied 344 subjects admitted to the hospital for cardiovascular diseases. The genotypes of two polymorphic loci within the ADA gene were determined: ADA₁ and ADA₂. Both loci show two alleles: ADA₁*1 and ADA₁*2 in ADA₁ locus and ADA₂*1 and ADA₂*2 in ADA₂ locus. In the absence of smoking, the proportion of subjects with hypertension tends to be lower in carriers of the ADA₁*2 allele. In smoking subjects, the pattern is reversed and the proportion of those with hypertension tends to be higher in carriers of the ADA₁*2 allele. A similar pattern is observed for ADA₂ locus. Smoking increases the proportion of subjects showing hypertension: such effect is more marked in those carrying the ADA₁*2 allele as compared to subjects with ADA₁*1/*1 genotype. The same pattern of association is observed for ADA₂ locus. The two loci show an additive effect. The odds ratio for hypertension in smokers vs nonsmokers is 1.450 in subjects carrying ADA₁*1/*1 and ADA₂*1/*1 genotypes, while it is 11.200 in subjects carrying the *2 alleles in both loci. From a practical point, a view of our results suggest that smokers carrying both ADA₁*2 and ADA₂*2 alleles have a higher risk of hypertension.

Fetal genetic adaptation to environment of aging women could result in positive selection of genes that during extrauterine life increases the risk of type 1 diabetes mellitus (T1DM). We have examined the distribution of three genetic polymorphisms (acid phosphatase locus 1 [ACP₁], p53 codon 72, and PTPN22) involved in T1DM risk in relation to maternal age at delivery. p53 codon 72 was determined in 281 T1DM children, ACP₁ in 207 children, and PTPN22 in 216 children. Controls (blood donors) were 351 for ACP₁, 271 for PTPN22, and 730 for p53 codon 72. Genotypes were determined by DNA analysis. The proportions of the three genotypes associated with T1DM are much greater in T1DM children from older mothers than in those from young mothers and in controls. The data support the hypothesis that advanced maternal age favors a positive selection of genes more adapted to the uterine environment of older women: these genes predispose to T1DM during extrauterine life.

The possible association between allergy and neoplastic disorders has been the subject of many investigations but no general relationship has been determined. Little attention, however, has been paid to the possible role of allergy in the clinical manifestations of these diseases. In this study, the role of allergy in the susceptibility to uterine leiomyomas and in their growth was investigated. Interaction with ACP1, a genetic polymorphism associated with the growth of leiomyomas, has been also considered. Two hundred and three White woman from the population of Rome hospitalized for symptomatic leiomyomas requiring surgical intervention have been studied. One hundred thirty eight healthy women have been considered as controls. Allergy has been evaluated by prick test. T-test for equality of means, analysis of variance and linear correlation analysis has been performed. The level of statistical significance was set at 0.05. The frequency of allergic manifestations in women with leiomyomas does not differ from healthy women. The dimension of leiomyomas is lower in allergic than in non allergic women (p=0.004). The ACP1 *B/*B genotype and allergy cooperate in lowering the dimension of leiomyomas; the proportion of woman with small leiomyomas (<10 percentile) is much higher in allergic women carrying the *B/*B genotype as compared to other women (p<0.001). About 8% of variance of leiomyomas dimension is attributable to the joint effect of ACP1 and allergy. Allergic women with high concentration of ACP1 f isoform (*B/*B genotype) are protected from excessive leyomioma growth. If confirmed in other clinical settings, our observation may have practical importance in identifying women at risk of more severe clinical manifestations.

Association of P53 Codon 72 with Colon Cancer: the Role of Genetic Factors

Association between p53 codon 72 and endometriosis has been observed in populations of East Asia but not in those of European descent. Genetic polymorphisms could interact with p53 codon 72 influencing its association with endometriosis, thus explaining these differences among populations. 130 women hospitalized for endometriosis and a sample of 250 women without endometriosis have been studied. All women were from the White population of Rome. ACP₁, PTPN22, ADA₆ and p53 codon 72 genotypes were determined by DNA analysis. Statistical analysis was performed by SPSS package. Three-way contingency table analyses were performed by a log linear model according to Sokal and Rohlf. There is an epistatic interaction among ADA₆, p53 codon 72 and endometriosis resulting in a positive association between carriers of *Pro allele of p53 codon 72 and endometriosis in women carrying the ADA₆ *1 allele. PTPN22 and ACP₁ show an additive effect with p53 codon 72 concerning their effect on endometriosis. The strength of association between p53 codon 72 and endometriosis is positively correlated with the number of the three factors considered. ADA₆, PTPN22 and ACP₁ are involved in immune reactions: since endometriosis has an autoimmune component, a cooperative interaction among these genetic systems appears biological plausible. The present result could contribute to explain the differences observed among populations concerning the association between p53 codon 72 and endometriosis.