Genetic variability within Adenosine Deaminase gene and uterine leiomyomas.

OBJECTIVE: The recent observation of an association of colon cancer with two polymorphic sites within the Adenosine Deaminase (ADA) gene suggests an involvement of these polymorphisms in the development of solid tumors. This prompted us to search for a similar association in uterine leiomyomas. STUDY DESIGN: We have studied 181 women admitted to the hospital for leiomyomas requiring surgical intervention and 248 women of comparable age without clinical signs of leiomyomas. All women were from the White population of Rome and gave verbal consent to participate in the study. The genotypes of three polymorphic sites (ADA1, ADA2, ADA6) of ADA gene were determined by DNA analysis. RESULTS: A higher proportion of ADA2*1/*1 genotype and of carriers of the ADA6*1 allele was observed in women with leiomyomas as compared to controls. This parallels the association found in colon cancer. CONCLUSIONS: This pattern is identical to that previously observed in colon cancer making the possibility of mere sample chance artifact unlikely and supporting the hypothesis that genetic polymorphisms within the ADA gene could be involved in the susceptibility to solid tumors. Genetic variability within the ADA gene may influence adenosine concentration and in turn the immune response by lymphocytes in solid tumors. On the other hand ADA molecules acting as ecto-enzyme may be involved in the transduction of signals in the cell surface with important effects on tumor development.

The effect of ACP1, ADA6 and PTPN22 genetic polymorphisms on the association between p53 codon 72 polymorphism and endometriosis.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Allergy and Uterine Leiomyomas: Cooperative Interaction with ACP1 Genetic Polymorphism.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

PTPN22 and uterine leiomyomas.

OBJECTIVE: It has been suggested that the development of uterine leiomyomas is positively influenced by an immune system in a chronically inflammatory state and that a lower level of regulating T cell (Treg cells) would play a central role. Since it has been suggested that the W620 variant of protein tyrosine phosphatase non-receptor type 22 (PTPN22) decreases the number of Treg cells, we investigated a possible relationship between PTPN22 polymorphism and uterine leiomyomas. STUDY DESIGN: We studied 203 white women from Rome who were hospitalized for symptomatic leiomyomas requiring surgical intervention. These women were considered in a previous paper regarding the relationship between ACP1 and dimension of leiomyomas. As controls we studied 355 healthy women from the same population with comparable age and without clinical evidence of leiomyomas. All women gave written informed consent to participate to the study. Chi square test of independence and T-test for difference between means were performed by SPSS package. RESULTS: Considering the whole sample, a borderline association between PTPN22 and leiomyomas was observed: the *C/*T genotype is more frequent in cases than in controls. This association is marked and statistically significant in younger women only. The main diameter of tumor is significantly greater in *C/*T than in *C/*C women. This effect is present in younger women only. The *C/*T genotype also shows a higher tendency to intramural localization, but no effect of age is observed upon this association. CONCLUSIONS: The data suggest a positive effect of *C/*T genotype on susceptibility to leiomyomas in younger women. In these women a *C/*T genotype favors the growth of leiomyomas.

Is there an association between uterine leiomyomas and acid phosphatase locus 1 polymorphism?

OBJECTIVE: Platelet derived growth factor (PDGF) is involved in the development of leiomyomas. The low-molecular-weight phosphoprotein-tyrosine-phosphatase (LMWPTP), controlled by the highly polymorphic acid phosphatase locus 1 (ACP1), is able to dephosphorylate the PDGF receptor. Therefore, we searched for a possible association between ACP1 and leiomyomas. STUDY DESIGN: We studied 172 women hospitalized for symptomatic leiomyomas requiring surgical intervention and 164 healthy women without clinical evidence of leiomyomas from the same white population. The chi(2) test of independence, Pearson correlation, analysis of variance, and post hoc test for difference between means were performed. RESULTS: The distribution of ACP1 genotypes among patients does not differ significantly from that of healthy women. However, leiomyoma size was negatively correlated with ACP1 F isoform concentrations. Leiomyoma size was smaller among carriers of the *B/*B genotype, which has the highest concentration of the F isoform, than among carriers of *A/*A, *C/*B, and *C/*C genotypes, which have the lowest concentration of the F isoform. CONCLUSION: High ACP1 F isoform concentration, through dephosphorylation of the PDGF receptor, may negatively regulate cell proliferation and growth of leiomyomas.

Acid phosphatase locus 1 genetic polymorphism, endometriosis, and allergy.

Recent studies suggest that acid phosphatase locus 1 (ACP1) could be involved in T-cell antigen receptor signaling and in immune disorders. The present study shows that the ACP1( *)C allele, which is associated with elevated enzymatic activity, is significantly more common in women with endometriosis than in healthy women, but is less common in allergic than in nonallergic subjects. These findings suggest that carriers of high activity ACP1 genotypes are more susceptible to endometriosis but less susceptible to allergic manifestations than carriers of other ACP1 genotypes.

Association of p53 codon 72 polymorphism with endometriosis.

OBJECTIVE: To study the association of endometriosis with p53 codon 72 polymorphism in the population of central Italy and to search for possible interaction with the PTPN22 polymorphism. DESIGN: Study of p53 and PTPN22 polymorphisms in women with endometriosis. Analysis of PTPN22 genotype distribution in relation to p53 genotypes. SETTING: Department of Obstetrics and Gynecology of the University of Rome "Tor Vergata." PATIENT(S): The study included 129 women with endometriosis and 147 controls from the Caucasian population of central Italy. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Evaluation of risk for endometriosis. RESULT(S): No significant difference in the distribution of p53 codon 72 genotypes was observed between endometriosis patients and controls. An interaction between p53 and PTPN22 was observed: a protective action by the Arg/Arg genotype against endometriosis seems to be present only in carriers of the ( *)T allele of PTPN22. CONCLUSION(S): The negative association between the Arg/Arg genotype of p53 codon 72 found in Chinese people has not been observed in Japanese and Italian populations. Interaction with genes showing different allele frequencies among ethnic groups could be responsible for the differences reported among human populations concerning the relationship between p53 and susceptibility to endometriosis.

Association between PTPN22 and endometriosis.

PTPN22 is currently one of the few known shared-autoimmunity genes and is therefore a candidate marker for endometriosis. Our data show that female carriers of the PTPN22( *)T variant are significantly more susceptible to endometriosis than controls.