**3. Endometriosis and genetic polymorphism**

A number of polymorphisms in candidate genes have been studied to identify the genes responsible for the etiology of endomeriosis. It was only since 2000, that reports were published establishing an association of genetic polymorphism with endometriosis.

Transforming growth factor beta (TGF-β) family members are multi-functional cytokines that play a key role in cellular growth, proliferation, and differentiation (Hsieh YY et al, 2005). It has been shown that an association of endometriosis with TGF-β 1-509 gene polymorphism exists. T homozygote and T allele for TGF-β1 are associated with higher susceptibility to endometriosis. Arg448Gly, a common polymorphism located within nuclear receptor interacting protein 1 (NRIP1) gene, is associated with endometriosis. NRIP1 gene variants, separately or in combinations, might act as predisposing factors for human endometriosis (CaballeroV, et al., 2005).

A significant linkage on chromosome 10q26 and another region of suggestive linkage on chromosome 20p13 as susceptibility loci, has been associated with endometriosis (Treloar SA et al, 2005).

It has been hypothesized that dysregulation of the normal apoptotic process takes place in the endometrium. One of the apoptotic pathways playing a crucial role in the programmed cell death within the endometrium is the Fas-FasL system. Three polymorphisms within FAS (-1377G>A and -670A>G) and FASL (-843C>T) genes, as susceptibility factors for endometriosis have been analysed. However, the differences in the distribution of the polymorphic variants were not statistically significant (Fernandez,R.M.et.al,2005). The angiotensin I-converting enzyme (ACE) A2350G and A-240T gene polymorphism has been suggested as markers of susceptibility in endometriosis as the genotypes and alleles are associated with higher susceptibility to endometriosis and might be associated with endometriosis development ( HseihYY etal, 2005).

#### **3.1 Environmental toxin genes**

Endometriosis shows significantly elevated frequency in industrial areas and there is a possible genetic pre-disposition (Kennedy S et al. 2001). The glutathione-S-transferases (GSTs) constitute a family of xenobiotic-detoxifying phase-II enzymes catalyzing the conjugation of glutathione to a variety of electrophilic compounds including polycyclic aromatic hydrocarbons (PAH), which are widely present in the human environment and known to be carcinogenic.

Several GSTs are polymorphic and some allelic variants causing enzyme activity impairment are suspected to increase susceptibility to malignancies associated with environmental PAH, particularly colorectal cancer (Strange RC & Fryer AA, 1999). A very small portion of endometriosis develops into cancer later, but endometriosis itself is not a malignant disease. It has many characteristics similar to cancer, for example progressive growth, invasive growth, estrogen-dependent growth, recurrence and a tendency to metastasis (van Gorp T et al. 2004).

Environmental toxic compounds like *dioxin* may increase the risk of endometriosis. Previous association studies implicated GALT gene (a gene involved in galactose metabolism, located on chromosome 9), glutathione S transferases (GSTM 1), (GSTT1), cytochrome p 450 ( CYP1A1) and N- acetyltransferase 2 ( NAT2) genes, which encode for detoxification enzymes, as possible disease susceptibility genes ( Zondervan KT et al, 2001; Hadfield RM et al, OXEGENE collaborative group, 2001; Deguchi M et al, 2005). The diversity of biological effects resulting from exposure to dioxin may reflect the ability of this environmental pollutant to alter gene expression by binding to the Aryl hydrocarbon receptor (AHR) gene and related genes (Watanabe T et al, 2001).

One of the genes previously implicated in endometriosis is CYP17; this encodes the enzyme P450c17alpha, which plays a vital role in steroid biosynthesis in the ovary. However, the CYP17 MspA1 polymorphism has not been associated with endometriosis in either the UK or the Japanese population(Asghar,T.et.al,2005).

A study of the association between endometriosis and polymorphisms in the Nacetyltransferase 1 (NAT1) and N-acetyltransferase 2 (NAT2) genes has previously demonstrated a positive association with NAT2 polymorphisms in a UK population. However, polymorphisms in NAT1 and NAT2 were not associated with an increased risk of endometriosis in the Japanese population (Deguchi M et al, 2005).A case control study suggested no association between endometriosis and NAT2 in South Indianwomen(Arvind-Babu,K.et.al.2005).

Glutathione S-transferases (GSTs) are enzymes involved in the metabolism of many diseasecausing carcinogens and mutagens that are present in human environments. An association between the incidence of endometriosis and the GST genotypes of patients has been suggested. The study inferred that GSTM1, GSTT1 and GSTP1 genetic polymorphisms are not associated with the development of endometriosis in Korean women (Hur.S.E.et.al, 2005).
