Journal of Gynecology & Obstetrics

Case Report Open Access

Association with ACP1 genotypes has been observed in immune Cytosolic Low Molecular Weight disorders such as T1D, Chron’s disease and allergy [10-12]. Protein Tyrosine Phosphatase In the present paper we have investigated a possible effect of

high activity ACP1 genotypes on some clinical manifestations of and Clinical Manifestations of endometriosis. Endometriosis Material & Methods We have studied 113 women from the White population of Fulvia Gloria-Bottini*, Adalgisa Pietropolli, Anna Neri, Andrea Rome admitted consecutively to the Hospital with the diagnosis of Magrini and Egidio Bottini Department of Biomedicine and Prevention, University of Rome Tor Vergata, endometriosis. The disease was diagnosed during laparoscopy and the Rome, Italy criteria for the inclusion in the study were those proposed by Holt and Weiss [13]. All subjects gave verbal informed consent to partecipate in *Corresponding author: Fulvia Gloria-Bottini, Email: [email protected] the study that was approved by the Council of Department. Received: 28 October 2016; Accepted: 26 December 2016; Published: 06 January 2017 Controls were blood donors without manifestation of endometriosis.

ACP1 genotye was determined by DNA analysis as previously Abstract described [12]. Chi square test of Independence and Odds Ratio analysis were carried out by SPSS programs [14]. We have previously observed that high activity ACP1 (Acid Phosphatase locus 1) genotypes are more frequent in endometriosis. The number of subjects is not the same for all clinical manifestations considered due to lack of reliable information for some manifestations. ACP1 encodes for cytosolic Low Molecular Weight Protein Tyrosine Phosphatase (cLMWPTP), an enzyme present in all tissue that is composed by two isoforms that have different biochemical properties, Results different concentration among genotypes and probably different Table 2 shows the proportion of high activity *C/*A and *C/*B functions in the cell. In the present paper we have investigated a ACP1 genotypes in endometriosis and in controls. The proportion of possible effect of high activity ACP1 genotypes on some clinical *C/*A and *C/*B genotypes is higher in endometriosis than in control manifestations of endometriosis. (p=0.0158, O.R.=1.930). We have studied 113 women from the White population of Table 3 shows the proportion of high activity *C/*A and *C/*B Rome admitted consecutively to the Hospital with the diagnosis of genotypes in presence and in absence of some clinical manifestations in endometriosis. ACP1 genotye was determined by DNA analysis. Chi women with endometriosis . Chi square test of independence and Odds square test of independence and Odds Ratio analysis were carried out Ratio are calculated comparing the proportion of *C/*A and *C/*B in by SPSS programs. endometriosis with that of controls reported in Table 2. For all clinical variables examined the proportion of high activity The proportion of high activity ACP1 genotypes is significantly *C/*A and *C/*B genotypes is higher in the presence of more severe higher in presence of severe lesions, of disturbance of menstrual cycles, manifestation than in its absence.*C/*A and *C/*B ACP genotypes 1 of recurrence of endometriosis and of pharmacological treatment as show a higher total concentration of the enzyme and a higher S isoform compared to the proportion of controls. concentration as compared to other ACP1 genotyes suggesting that S isoform is associated to higher susceptibility to endometriosis and to Table 1: F and S isozyme concentration in relation to ACP1 higher frequency of severe clinical manifestations. genotypes. The quantities of enzyme are given in ml of packed of If confirmed in other clinical settings the observation may allow cells [7,8]. the identification in advance of subjects at risk of endometriosis and of Total quantity of F (µg/ml RBC) Total quantity of S (µg/ml RBC) severe complications. *B/*B 16.4 *C/*C 20.6 *A/*B 12.0 *A/*C 12.7 Introduction *B/*C 11.3 *B/*C 12.1 Endometriosis is a chronic gynecologic disease associated with *A/*A 7.9 *B/*B 3.9 autoimmune disorders,atopic diseases, pelvic pain, infertility and *A/*C 7.5 *A/*B 3.4 cancer [1,2]. An association with heart diseases has been also recently *C/*C 5.7 *A/*A 3.3 reported [3]. We have previously observed that high activity of ACP1 genotypes are more frequent in endometriosis [4]. Table 2: The proportion of high activity *C/*A and *C/*B ACP1 genotypes in endometriosis and in controls. ACP1 (Acid Phosphatase locus 1 ) encodes for cytosolic Low

Molecular Weight Protein Tyrosine Phosphatase (cLMWPTP), an % Proportion of high activity *C/*A and *C/*B ACP1 genotypes enzyme present in all tissue [5,6] that is composed by two isoforms % Total n° that have different biochemical properties, different concentration ENDOMETRIOSIS 20.35% 113 among genotypes (Table 1) and probably different functions in the cell. CONTROLS 11.7% 744 ACP shows a genetic polymorphism with three codominant alleles: 1 Chi square test of Indepen- χ2 = 5.825 p = 0.016 *A,*B,*C. Correspondingly there are six genotypes with activity dence increasing in the order *A/*A<*A/*B<*B/*B ≤*A/*C<*B/*C<*C/*C O.R. 1.930 C.I. 1.122-3.301 [5-8]. The enzyme dephosphorylates a negative regulatory Odds Ratio analysis phosphorylation site of ZAP 70 (Zeta-chain-associated protein kinase 70 ) that belongs to a family of protein kinases (PTK) closely related to Src and plays a critical role in the events involved in initiating T-cell Copyright © 2017 The Authors. Published by Scientific Open Access responses by the antigen receptor [9]. Journals LLC. Bottini et al. Volume 1, Issue 1 J Gynec Obstet 2017; 1:003

Pharmacological reduction of S isoform activity could be useful Table 3: The proportion of high activity *C/*A and *C/*B ACP1 genotypes in absence and in presence of clinical characteristics of in endometriosis and its manifestations. The limitation of our study subjects with endometriosis. Comparisons with the proportion of high is represented by the relatively small number of subjects examined. activity ACP genotypes in controls reported in Table 2. If confirmed in other clinical settings the observation may allow the 1 identification in advance of subjects at risk of endometriosis andof % Proportion of high activity *C/*A and *C/*B severe complications. ACP1 genotypes % Total n° % Total n° References Surgical Severe Non severe 1. Nothnick WB. Treating endometriosis as an autoimmune disease. Fertil Classification 38.1% 21 25.9% 27 Steril. 2001; 76:223-31. χ2 = 10.774 Chi square test of χ2 = 3.690 p = 0.055 2. Matarese G, De Placido G, Nikas Y, Alviggi C. Pathogenesis of endometriosis: p = 0.001 Independence natural immunity dysfunction or autoimmune disease? Trends Mol Med. Odds Ratio O.R 2.643 C.I.0.983- 2003; 9:223-8. O.R. 4.647 C.I. 1.706- analysis 6.844 3. Mu F, Rich-Edwards J, Rimm EB, Spiegelman D, Missmer SA. Endometriosis 12.419 and Risk of Coronary Heart Disease. Circ Cardiovasc Qual Outcomes. 2016; Disturbance of Present Absent 9:257-64. Menstrual cycles 33.3% 45 11.1% 54 4. Ammendola M, Pietropolli A, Saccucci P, Piccione E, Bottini E, Gloria- χ2 = 15.783 p = Chi square test of χ2 = 0.008 p = 0.928 Bottini F. Acid phosphatase locus 1 genetic polymorphism, endometriosis, and 0.00007 Independence allergy. Fertil Steril. 2008; 90:1203-5. doi: 10.1016/j.fertnstert.2007.10.014. Odds Ratio O.R 0.944 C.I.0.352- O.R. 3.766 C.I. 1.854- 5. Hopkinson DA, Spencer N, Harris H. Red cell acid phophatase variants: a analysis 2.383 new human polymorphism. Nature. 1963; 199:969-971. 12.419 Recurrence of Yes No 6. Bottini N, Bottini E, Gloria-Bottini F, Mustelin T. Low-molecular-weight Endometriosis 24.4% 45 20.5% 53 protein tyrosine phosphatase and human disease: in search of biochemical mechanisms. Arch Immunol Ther Exp (Warsz). 2002; 50:95-104. Chi square test of χ2 = 5.244 p = 0.022 χ2 = 0.854 p = 0.355 Independence 7. Dissing J. Immunochemical characterization of human red cell acid Odds Ratio O.R. 2.443 C.I. 1.120- O.R 1.545 C.I.0.676- phosphatase isozymes. Biochem Genet. 1987; 25:901-18. analysis 5.233 3.425 8. Dissing J . Human red cell acid phosphatase (ACP1): genetic, catalytic and Pharmacological Yes No molecular properties. PhD thesis. Kobenhavn Universitat, 1993. Treatment 30.0% 40 21.9% 73 9. Bottini N, Stefanini L, Williams S, Alonso A, Jascur T, Abraham RT, et al. χ2 = 9.930 Activation of ZAP-70 through specific dephosphorylation at the inhibitory Chi square test of χ2 = 5.413 p = 0.030 p = 0.002 Tyr-292 by the low molecular weight phosphotyrosine phosphatase Independence (LMPTP). J Biol Chem. 2002; 277:24220-4. Odds Ratio O.R 2.120 C.I.1.114- O.R. 3.236 C.I. 1.492- analysis 3.991 10. Bottini E, Bergamaschi A, Magrini A, Spina C, Ammendola L, Grassi S, et 6.923 al. Allergy and ACP1 genetic polymorphism. Allergy Asthma Proc. 2007; 28:87-92. Discussion 11. Bottini N, Gloria-Bottini F, Lucarini N, Ronchetti PG, Fontana L. Inflammatory bowel disease: Are there gender differences in the genetics of *C/*A and *C/*B ACP1 genotypes show a higher total concentration of the enzyme and a higher S isoform concentration signal transduction? A preliminary study of cytosolic low molecular weight protein tyrosine phosphatase. Dis Markers. 2000; 16:163-166. as compared to other ACP1 genotyes (Table 1) suggesting that S isoform is associated to higher susceptibility to endometriosis and to 12. Bottini N, Meloni GF, Borgiani P, Giorgini A, Buzzetti R, Pozzilli P, et al. higher frequency of severity of clinical manifestations. The increased Genotypes of cytosolic low-molecular-weight protein-tyrosine-phosphatase activation of the protein ZAP 70 associated with enhanced signaling correlate with age at onset of type 1 diabetes in a sex-specific manner. Metabolism. 2002; 51:419-422. from T cell antigen receptor due to high ACP1 activity could be involved in the susceptibility and severity of clinical manifestation 13. Holt VL, Weiss NS. Recommendations for the design of epidemiologic of endometriosis. Further investigations, however, could clarify the studies of endometriosis. Epidemiology. 2000; 11:654-659. possible causal relationship between high ACP1 activity and severe 14. SPSS/PC+ Version 5, Chicago. SPSS Inc., 1992. manifestations of endometriosis.

Citation: Gloria-Bottini F, Pietropolli A, Neri A, et al. Cytosolic Low Molecular Weight Protein Tyrosine Phosphatase and Clinical Manifestations of Endometriosis. J Gynec Obstet 2017; 1:003.