Genetic polymorphisms and endometriosis: contribution of genes that regulate vascular function and tissue remodeling

Abstracts

A endometriose é uma doença ginecológica benigna caracterizada pela presença e crescimento de células endometriais fora do útero. Fatores genéticos, endócrinos, imunológicos e ambientais têm sido sugeridos em sua patogênese. Um grande número de estudos tem relacionado polimorfismos genéticos como um fator que contribui para o desenvolvimento da endometriose. Nesta revisão, apresentamos uma descrição detalhada da contribuição de polimorfismos genéticos nos genes que regulam a função vascular e o remodelamento do tecido em endometriose (AHSG, EGFR, EGF, VEGF, endostatina, PAI-1, ACE e MMPs). Alguns polimorfismos dos genes VEGF (-460 C/T, +405 G/C, +936 C/T), PAI, MMP-1, 2 e 3 foram amplamente estudados, enquanto outros dos genes AHSG, EGF, endostatina e VEGF (-1154 G/A, -2578 A/C), não. Nesse último caso, estudos adicionais tornam-se necessários para confirmar os achados encontrados pelos poucos trabalhos que analisaram esses polimorfismos de único nucleotídeo (SNP). Além disso, os estudos que encontraram associação positiva ou negativa do SNP com endometriose enfatizam a importância de estudos com grande número de casos-controles para confirmar os achados por eles publicados. A análise por haplótipo foi realizada apenas para os genes VEGF (-460, +405, -1154 e -2578), ACE (-240/2350) e MMP-1, 2, 3 e 9, e, na maioria deles, não houve associação com endometriose. Dos oito trabalhos que analisaram haplótipos do gene VEGF, cinco deles não os associaram à endometriose. Os haplótipos dos genes ACE e MMP-2 não foram associados à endometriose, enquanto aqueles dos genes MMP-1, 3 e 9 foram relacionados a risco elevado da doença.

Endometriose; polimorfismos genéticos; fator de crescimento endotelial vascular; metaloproteinases da matriz; inativadores de plasminogênio; peptidil dipeptidase A

REVIEW ARTICLE

PhD Student in Genetics; Associate Professor of Genetics at Universidade Federal do Triângulo Mineiro, Uberaba, MG, Brazil

Correspondence to

SUMMARY

Endometriosis is a benign gynecological disease characterized by the presence and growth of endometrial cells outside the uterus. Genetic, endocrine, immunological, and environmental factors have been suggested in its pathogenesis. A great number of studies have related genetic polymorphisms as a factor that contributes to the development of endometriosis. This review presents a detailed description of the contribution of genetic polymorphisms in genes that regulate vascular function and tissue remodeling in endometriosis (alpha 2-HS glycoprotein [AHSG], epidermal growth factor receptor [EGFR], vascular endothelial growth factor [VEGF], endostatin, plasminogen activator inhibitor 1 [PAI-1], angiotensin I-converting enzyme [ACE], and matrix metalloproteinases [MMPs]). Some polymorphisms of the VEGF (-460 C/T, +405 G/C, +936 C/T), PAI, MMP-1, 2, and 3 genes were widely studied, while polymorphisms of the AHSG, EGF, endostatin, and VEGF (-1154 G/A, -2578 A/C) genes were not. In this latter case, additional studies are required to confirm the findings of the few studies that have analyzed these single nucleotide polymorphisms (SNPs). Additionally, studies that found a positive or negative association of SNP with endometriosis emphasize the relevance of studies with a large number of control cases to confirm their findings. The haplotype analysis was performed only for the VEGF (-460, +405, -1154 and -2578), ACE (-240/2350) and MMP-1, 2, 3, and 9 genes, and in most of them, there was no association with endometriosis. Of the eight works that analyzed haplotypes of the VEGF gene, five did not associate them with endometriosis. Haplotypes of ACE and MMP-2 genes were not associated with endometriosis, while those of MMP-1, 3, and 9 genes were related to a high risk for the disease.

Keywords: Endometriosis; genetic polymorphisms; vascular endothelial growth factor; matrix metalloproteinases; plasminogen activator inhibitors; peptidyl dipeptidase A.

INTRODUCTION

Endometriosis is a complex gynecological condition characterized by endometrial tissue outside the uterus. Main clinical symptoms include dysmenorrhea, chronic pelvic pain, deep dyspareunia, infertility, and cyclic bowel and urinary symptoms, such as pain or bleeding when defecating/urinating during the menstrual period^1,2. A study performed by Bellelis et al.³ showed that the main complaint reported by patients with endometriosis was dysmenorrhea, with a prevalence of 62.2%. Nonetheless, when all symptoms reported were considered, chronic pelvic pain was the most prevalent symptom, followed by deep dyspareunia, reported by 56.8% and 54.7% of the patients, respectively. Infertility was reported by 39.8% of the 892 patients. A study aiming at understanding the Brazilian gynecological practices regarding the diagnosis of endometriosis showed early detection of endometriosis when the patient complained of infertility or chronic pelvic pain⁴. An interesting finding of this study was that the time elapsed until indication of a diagnostic procedure was lower in case of doctors that had participated in congresses and lectures on gynecological endoscopy and endometriosis, thus evidencing that better-informed gynecologists detect the disease earlier⁴.

Endometriosis is similar to cancer, as the implantation of endometrial cells requires neovascularization in order to establish, grow, and invade tissues. Additionally, theories on the etiopathogenesis of endometriosis involve growth factors and cytokines associated with the regulation of cell multiplication and neoangiogenesis that may act in carcinogenesis. It is estimated that 1% of endometriosis cases are related to cancer and, for some types of endometriosis, its benign nature has been questioned^5,6.

Although the final diagnosis of endometriosis requires needs a surgical intervention, videolaparoscopy, several findings in the physical, image, and laboratory examinations can already predict, with a high degree of reliability, that the patient has this disease. During this surgical procedure, it is possible to view lesions suggestive of the disease and to obtain a tissue sample for anatomopathological analysis and confirmation of the endometriosis diagnosis⁷. The classification used for endometriosis is that of the American Society of Reproductive Medi-cine/ASRM, revised in 1996, which classifies this disease into four stages: minimal (stage I), mild (stage II), moderate (stage III), or severe (stage IV)⁸. Currently, the most widespread treatments are surgery, ovarian suppression therapy, or the combination of both^5,7.

The cause of endometriosis remains unknown. Nonetheless, there are evidences of immunological^9,10, environmental¹¹, and genetic^12-14 factors involved in its pathogenesis.

Regarding the immune response, the role of cytokines in the development of endometriosis¹⁵ is emphasized; high levels of many cytokines were found in patients with endometriosis^16-18. The same group of researchers, in independent works, assessed the levels of cytokines involved in immune response patterns Th1 [interleukin (IL)-2, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma] and Th2 (IL-4 and IL-10) in patients with endometriosis (n = 65) and in those without the disease (n = 33)^16-18. Podgaec et al. noted an increase in the levels of IFN-gamma and IL-10 in patients with endometriosis, evidencing the co-existence of both responses¹⁶. However, when considering the ratio between cytokine levels and these responses, there was a predominance of IL-4 and IL-10, thus reflecting a potential change of the Th2 immune response component. In the subsequent study, cytokine levels were associated with the clinical symptoms of endometriosis¹⁸. Patients with endometriosis that presented deep dyspareunia and infertility showed high levels of TNF-alpha and IL-2, respectively. These cytokines are related to the Th1 immune response, and almost 70% of the patients that presented these results had severe endometriosis. The authors concluded that, when specific clinical data are associated with a high production of certain cytokines, there is a Th1 response pattern that may be related to severe endometriosis. The induction of the Th1 immune response was also reported by Fairbanks et al., who demonstrated high levels of IL-12 in patients with severe endometriosis¹⁷.

The contribution of environmental factors to the development of endometriosis was reviewed by Bellelis et al., who related the influence of these factors, together with the diet, on the genesis of this disease¹¹. The authors concluded that the mechanism by which dioxin and dioxin-like compounds (2,3,7,8-tetrachlorodibenzo-p-dioxin[TCDD] and polychlorinated biphenyls [PCBs]) act and change the endometrial physiology is uncertain and speculative. They also affirm that there is insufficient evidence as to the use of specific diets as preventive or even adjuvant factors in the treatment of endometriosis.

The genetic and hereditary basis for endometriosis was evidenced in the study by Bellelis et al.³, in which approximately 5.3% of the patients reported first-degree family history of endometriosis. Familial aggregation, a high concordance rate among monozygotic twins, and a risk of 4% to 7% for first-degree relatives support the contribution of genetic factors to the pathogenesis of this disease¹⁴. In this context, the identification of genetic variants or single nucleotide polymorphisms (SNPs) responsible for susceptibility to endometriosis has been researched in recent years^19-21. Different classifications have been proposed for the genes responsible for susceptibility to endometriosis (Box 1).

This bibliographic review presents a detailed description of the contribution of genetic polymorphisms in genes regulating vascular function and tissue remodeling into the pathogenesis of endometriosis. Genes belonging to this category include: alpha 2-HS glycoprotein (AHSG), epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), endostatin, plasminogen activator inhibitor 1 (PAI-1), angiotensin I-converting enzyme (ACE), and matrix metalloproteinases (MMPs).

For this purpose, a bibliographic research was performed in PubMed, with no time limitation, using the following terms (n = number of articles retrieved):

1 - endometriosis and AHSG polymorphisms (n = 1);

2 - endometriosis and EGFR polymorphisms (n = 2);

3 - endometriosis and VEGF polymorphisms (n = 19, 14 articles were selected for reading);

4 - endometriosis and endostatin polymorphisms (n = 1);

5 - endometriosis and PAI-1 polymorphisms (n = 6,

4 articles were selected for reading);

6 - endometriosis and ACE polymorphisms (n = 4);

7 - endometriosis and MMPs polymorphisms (n = 11, 9 articles were selected for reading).

Articles were selected based on titles and summaries, and the full texts or summaries of those related to the topic were analyzed. An aggregate of 35 publications on polymorphisms in these genes were included in this review. Table 1 summarizes the main results of these studies.

Excluded articles associated polymorphisms in these genes to other types of disease/sample (adenomyosis, pterygium, and placenta, n = 4), or endometriosis to polymorphism in another gene (IL-10, n = 1), or were included in the review category (n = 3), or were published in Chinese and the abstract was not available (n = 1).

Articles addressing general information on endometriosis or mentioned in the references of the studies retrieved from PubMed were also researched due to their relevance to this review.

AHSG AND ENDOMETRIOSIS

The alpha-2 Heremans Schmid glycoprotein (AHSG) is a protein present in human plasma secreted by the liver. The AHSG gene appears in the endometrium of women with endometriosis, and these women showed high levels of AHSG in serum and peritoneal fluid, in addition to anti-AHSG antibodies^22-24.

The AHSG gene is located at 3q27-29²⁵ and consists of seven exons and six introns²⁶. Two polymorphisms, termed AHSG1 and AHSG2, have been described and occur in exons 6 and 7, respectively. Allele 1 is characterized by a replacement of cytokine for thymine, i.e., the triplet ACG (threonine) at position 230 was modified to ATG (methionine), resulting in the missense mutation p.T230M (rs4917). Allele 2 corresponds to a change from cytokine to guanine, with the respective missense mutation at position 238 of the protein, from threonine (ACC) to serine (AGC), i.e., p.T238S (rs4918)²⁷.

Considering the possibility of associating these SNPs to endometriosis, Kim et al.²⁸ investigated these polymorphisms in 79 Korean women with endometriosis and 105 women without the disease. They observed that those not carrying the AHSG2 allele had twice the risk of developing endometriosis than those with at least one copy of this allele, thus evidencing a positive association between endometriosis and polymorphisms in the AHSG gene in this population.

EGFR, VEGF, ENDOSTATIN AND ENDOMETRIOSIS

Endometriosis shows characteristics similar to neoplasias, such as invasiveness and neovascularization, the latter considered an important phenomenon for the implantation of endometrial cells in ectopic sites. Thus, growth and other angiogenic factors, such as the VEGF and EGFR, could be related to the development of endometriosis^29-32.

EGFR is a transmembrane glycoprotein that plays important roles in controlling cell growth, differentiation, and motility. The EGFR gene is located at 7p12 and a polymorphism characterized by exchange of base A for T at position 2073 of exon 21 has been observed³³. This modification changes the stop codon (TGA) by synthesis of the amino acid cysteine (TGT). Aiming at assessing whether the EGFR +2073A/T SNP could be used as a susceptibility flag for endometriosis, Hsieh et al. assessed 122 Taiwanese women with this pathology and 139 controls, and associated the TT and AT genotypes and the T allele to high risk for the disease³⁴. However, subsequent studies did not associate this SNP to endometriosis in Japanese people³⁵.

VEGF induces endothelial cell proliferation, migration, differentiation, and formation of capillaries, which contribute to the pathogenesis and progression of endometriosis. Additionally, studies have shown high levels of VEGF in the peritoneal fluid, serum, mRNA expression, and proteins of patients with endometriosis^36-42. These data reinforce the role of VEGF in the pathogenesis of endometriosis.

The VEGF gene is located at 6p21.3⁴³, consists of eight exons, and shows alternative splicing, which is responsible for forming several proteins. At least 30 SNPs were described in this gene⁴⁴. In order to determine a genetic predisposition to endometriosis, some studies were developed to investigate polymorphisms of the VEGF gene in women with endometriosis. These studies were conducted in China^45-47, Korea^48,49, India⁵⁰, Japan⁵¹, Italy⁵², Spain⁵³, Turkey^54,55, Australia⁵⁶, Estonia⁵⁷, and Iran⁵⁸. Assessed SNPs were -460 C/T (rs833061), +405 G/C (also known as -634 G/C, rs2010963), +936 C/T (rs3025039), -1154 G/A (rs1570360), and -2578 A/C (rs699947).

-460 C/T polymorphism was researched in several studies^{45-48,50,51,53-56,58}. Only the study of Hsieh et al.⁴⁵ associated the TT genotype and T allele to high risk for endometriosis.

With respect to +405 G/C polymorphism, no association between this SNP and endometriosis was reported by Ikuhashi et al.⁵¹, Zhao et al.⁵⁶, Cosin et al.⁵³, and Lamp et al.⁵⁷, but a significant association was reported in six other studies^{48,50,52,54,55,58}. However, these studies showed conflicting results regarding the relation between genotypes and alleles and endometriosis. Considering genotype and allele, Kim et al.⁴⁸, Gentilini et al.⁵², Attar et al.⁵⁵, and Emamifar et al.⁵⁸ associated +405 CC and therefore the C allele, to endometriosis; Bhanoori et al.⁵⁰ and Altinkaya et al.⁵⁴ related the +405 GG and +405 GC genotypes to the disease, respectively. Thus, some works associated the C allele with endometriosis^48,52,55,58, while other works associated the G allele^50,54 with the disease. A positive association between endometriosis and SNP at position 405 became evident, suggesting an effective contribution of such polymorphism to the pathogenesis of endometriosis. The discrepancy regarding the results of analysis of +405 G/C VEGF SNP among the published works could be explained by the different populations studied, whose ethnic differences would explain the causes of these conflicting findings.

The studies by Ikushashi et al.⁵¹ and Cosin et al.⁵³ investigated the same polymorphisms (-460 C/T, +405 G/C and +936 C/T) in populations with different ethnic origins. Both reported a positive association with respect to VEGF 936 T allele in women with endometriosis, while other authors^46,49,56,57 did not confirm this association.

-1154 G/A polymorphism was assessed by Liu et al.^46,47 and by Lamp et al.⁵⁷. Studies by the same group of researchers^46,47 showed different results, as the AA genotype was associated with reduced risk for endometriosis⁴⁶, and the GG genotype was associated with high risk for the disease⁴⁷. Different alleles of the -2578 C/A SNP were associated with reduced risk for endometriosis. The A allele of this polymorphism was reported to be protective in relation to the development of endometriosis⁴⁶; Lamp et al.⁵⁷ associated this protection with the C allele. This polymorphism was not associated with endometriosis in a study by Zhao et al.⁵⁶.

The study by Zhao et al.⁵⁶ that assessed VEGF -460 C/T, +405 G/C, -2578 A/C, and +936 C/T SNPs (the latter also investigated by Kim et al.⁴⁹), was the only study that did not associate these SNPs with endometriosis. Despite the conflicting results regarding some SNPs, at least one polymorphism was associated with endometriosis in the abovementioned works.

The 4349 G/A polymorphism of the endostatin gene was assessed by Kim et al.⁴⁹. Endostatin is a specific endogenous anti-angiogenic factor derived from the proteolysis of type XVIII collagen, and it induces inhibition of endothelial cell proliferation, migration, and apoptosis. Studies have demonstrated the role of endostatin in endometriotic lesions in animal models^59,60. This SNP was not related to endometriosis, but the endostatin level in serum was negatively correlated with the development of this disease⁴⁹.

In addition to the individual analysis of the VEGF gene per SNP, some studies carried out the research per haplotypes. The -460/+405 haplotype was not associated with endometriosis in the studies by Kim et al.⁴⁸, Ikushashi et al.⁵¹, and Cosin et al.⁵³. The -460T/+405C haplotype showed lower frequency in women with endometriosis⁵⁰; in another study, it was associated with high risk for this disease⁵⁵. Other haplotypes not related to endometriosis were -2578/-460/+405⁵⁶ and -2578/-1154/+405⁵⁷. -460C/1154A/-2578A, -460T/-1154A/-2578A, and -460T/1154A/-2578C haplotypes were associated with reduced risk for endometriosis, while -460C/-1154A/-2578C was associated with high risk for the disease⁴⁶. Therefore, only eight out of 14 studies that assessed the VEGF gene performed analyses per haplotype, with result of positive association with endometriosis in only three studies.

PAI-1 AND ENDOMETRIOSIS

The plasminogen activation system includes plasminogen activators and their inhibitors, which are involved in tissue degradation and remodeling under normal and pathological conditions. Two plasminogen activator inhibitors (PAIs), termed PAI-1 and PAI-2, regulate the plasminogen activation system^61,62. The main PAI is PAI-1, also known as endothelial cell PAI, which also plays an important role in signal transduction, cell adherence, and cell migration⁶³.

The PAI-1 gene, whose official symbol is SERPINE1, is located at 7q21.3-q22 and contains 9 exons. A guanine (G) insertion/deletion polymorphism in the promoter region of the PAI-1 gene at position -675, termed 4G/5G, has been described and is involved in regulating the synthesis of this inhibitor. In vitro studies have showed that the 4G allele is associated with increased gene expression from its binding to an activator protein, while the 5G allele contains an additional binding site for the DNA-binding protein acting as a transcriptional repressor^64-66.

Four studies were performed in women with endometriosis from Canada⁶⁷, Spain⁶⁸, Italy⁶⁹, and Brazil⁷⁰. A positive association for PAI-1 4G/5G SNP was reported by Bedaiwy et al.⁶⁷ and Gonçalves-Filho et al.⁷⁰. According to Bedaiwy et al., patients with 4G/5G and 4G/4G genotypes are 38 and 441 times more likely to have endometriosis than those with a 5G/5G genotype, respectively⁶⁷. In this study, 118 women were assessed (75 with endometriosis and 43 controls) and the 4G allele frequency was significantly higher in those with endometriosis. Nonetheless, these findings were not replicated in two studies involving a large number of patients and controls, one with 389 women (170 with endometriosis and 219 controls)⁶⁸, and the other with 204 women with endometriosis and 164 controls⁶⁹. Therefore, according to studies of Ramon et al.⁶⁸ and Gentilini et al.⁶⁹, the predisposition to endometriosis did not involve the 4G/5G PAI-1 polymorphism.

ACE AND ENDOMETRIOSIS

The ACE catalyzes the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor. Thus, ACE activity is associated with angiogenesis, which plays a key role in the pathogenesis of endometriosis. The presence of angiotensin receptors in the endometrial tissue has been demonstrated. Angiotensin II in endometrial stromal cells was mediated via angiotensin I receptors⁷¹, and could increase the intracellular calcium concentration by interaction with the angiotensin receptor in endometrial stromal cells⁷². These findings suggest a contribution of ACE to the development of endometriosis and the endometrium.

The ACE gene is located at 17q23.3 and three SNPs were assessed to verify association with endometriosis: -240 A/T (promoter region - rs4291), 2350 A/G (alteration in exon 17, Thr776Thr - rs4343), and one insertion/ deletion (I/D) of one Alu sequence (287 pb) in intron 16.

Hsieh et al.⁷³ and Lamp et al.⁵⁷ investigated polymorphisms at position 240 and 2350 and found conflicting results. In 2005, Hsieh et al. assessed 150 women with endometriosis and 159 controls from Taiwan/China⁷³. They observed that genotypes and alleles related to ACE 2350G (heterozygous AG, homozygous GG, and G allele) and ACE-240T (heterozygous AT, homozygous TT, and T allele) were associated with high susceptibility to endometriosis in this population. However, in 2010, Lamp et al. did not identify an association between these two SNPs and endometriosis in 150 women with endometriosis and 199 controls from Estonia⁵⁷. These same researchers investigated -240/2350 haplotypes and did not associate them with endometriosis.

Regarding polymorphism in the ACE I/D gene, the genotypes and alleles related to the ACE I were strongly associated with endometriosis in 125 patients with endometriosis and 128 controls⁷⁴. However, Kowalczynska et al.⁷⁵ investigated this same SNP in 121 women with endometriosis and 122 without endometriosis, and did not associate it to the disease. Therefore, only studies in Taiwanese/Chinese subjects^73,74 have demonstrated positive associations of the ACE polymorphism at position 2350, 240, and ACE I/D with endometriosis. When such polymorphisms are assessed in people of other ethnic origins, the results of positive association were not confirmed^57,75.

MMPS AND ENDOMETRIOSIS

MMPs belong to a large group of 23 proteases that regulate tissue remodeling by degrading the structural components of the extracellular matrix (ECM). MMPs also control basic cellular functions (proliferation, differentiation, motility, apoptosis), as they regulate the ECM proteins that interact with cells⁷⁶.

High levels of MMPs were found in ectopic endometrium when compared to eutopic endometrium in women with endometriosis. Therefore, the overexpression of MMPs may contribute to the development of endometriosis^77-84.

Genetic polymorphisms located in the promoter region of the MMPs genes could increase the levels of gene expression, and may be associated with genetic predisposition to various diseases^85-87.

Thus, polymorphisms in the MMP-1^88-91, MMP2^91-94, MMP-3^88-91, MMP-7^91,95, MMP-9^94-96, MMP-12⁹¹, MMP-13⁹¹, and TIMP-2^92,93 genes were investigated to verify whether they contribute to the development of endometriosis.

An I/D of guanine in the promoter region of the MMP1 (-1607 1G/2G) (rs112925) gene was associated with increased risk for endometriosis in Chinese women according to Kang et al.⁸⁸ and Shan et al.⁸⁹. Both studies showed a role of the 2G allele in the pathogenesis of endometriosis in 100 women with endometriosis and 150 controls. Polymorphisms in this gene were not associated with endometriosis in Italian⁹⁰ and French⁹¹ women.

Four SNPs in the promoter of the MMP-2 gene have been described: -735 C/T (rs2285053), -790 T/G (rs243864), -1306 C/T (rs243865), and -1575 G/A (rs243866). -735 C/T polymorphism was investigated by Zhao et al.⁹², Kang et al.⁹³, and Saare et al.⁹⁴. Only in the study of Saare et al. was the -735CC genotype associated with increased risk for stage I-II endometriosis⁹⁴. The -790 T/G SNP investigated by Saare et al.⁹⁴; the -1306 C/T investigated by Zhao et al.⁹², Kang et al.⁹³, and Bhorghese et al.⁹¹; and the -1575 G/A analyzed by Bhorghese et al.⁹¹ and Saare et al.⁹⁴ showed no significant association with endometriosis.

No association with endometriosis was reported for the -1612 5A/6A and -1171 5A/6A SNPs of the MMP-3 gene^88-91.

1G/6A, 1G/5A, 2G/6A, and 2G/5A haplotypes related to the MMP-1 and MMP-3 genes were investigated by Kang et al.⁸⁸ and Shan et al.⁸⁹. In both studies, the 2G/6A haplotype was associated with increased risk for endometriosis. For the -1306/-735 and -735/-790/-1575 haplotypes of the MMP-2 gene, no association with endometriosis was reported by Zhao et al⁹², Kang et al.⁹³, and Saare et al.⁹⁴.

Two polymorphisms in the promoter region of the MMP-7 gene (-153 C/T and -181 A/G) were investigated for association with endometriosis^91,95. Only the G allele of -the 181 A/G (rs1799750) SNP was associated with increased risk for endometriosis and adenomyosis in Chinese women⁹⁵.

R279Q (2678G>A), P574R (4859C>G), R668Q (5546G>A), and -1562 C>T (rs3918242) polymorphisms of the MMP-9 gene were investigated by Han et al.⁹⁶ and, in the analysis of individual SNP, showed no association with endometriosis. However, the AC (279Q/P574), GG (R279/574R) and CA (-1562C/668Q) haplotypes were significantly associated with endometriosis. In his research, Han et al.⁹⁶ concluded that haplotype analysis of the MMP9 gene was more informative than individual polymorphism analysis. Regarding the -1562 C> T SNP that had been previously investigated by Shan et al.⁹⁵, the result was consistent with the study of Han et al.⁸². However, a study by Saare et al.⁹⁴ showed that the -1562 TT and TC genotypes of the MMP-9 gene were associated with advanced stage endometriosis (III-IV).

The MMP-12 - MMP-13 A/GA/A combined genotype of MMP-12 and MMP-13 genes contributed to the development of superficial endometriosis in French women⁹¹.

Regarding the -418 G/C SNP of the TIMP-2 gene, the -418CC genotype was associated with reduced risk for endometriosis in the two studies^92,93, and the C allele was a protective factor against the development of endometriosis in Chinese women.

Regarding haplotype analysis, of nine studies on MMP genes, six assessed haplotypes, and a positive association between endometriosis and the haplotypes of MMP-1, 3, and 9^88,89,96 genes was reported, as well as a negative association for haplotypes of the MMP-2^92-94 gene.

FINAL CONSIDERATIONS

In this review, a detailed description of the contribution of genetic polymorphisms in genes that regulate vascular function and tissue remodeling into the pathogenesis of endometriosis has been presented. Some polymorphisms of the VEGF (-460 C/T, +405 G/C, +936 C/T), PAI, MMP1, 2, and 3 genes have been widely studied, while others of the AHSG, EGF, endostatin, and VEGF (-1154 G/A, -2578 A/C) genes were not. In the latter case, additional studies are required to confirm the findings by the few studies that have analyzed these SNPs. Additionally, studies that found a positive or negative association of SNP with endometriosis emphasize the relevance of studies with a large number of control cases to confirm their findings. Haplotype analysis was carried out only for the VEGF (-460, +405, -1154 and -2578), ACE (-240/2350) and MMP-1, 2, 3 and 9 genes, and in most studies, there was no association with endometriosis. Of the eight studies that analyzed haplotypes of the VEGF gene, five did not associate them with endometriosis. Haplotypes of ACE and MMP-2 genes were not associated with endometriosis, while those of MMP-1, 3, and 9 genes were related to a high risk for the disease. It is worth highlighting that studies involving polymorphisms are complex, since a genetic association, although valid for a specific ethnic population, may not be relevant to individuals of another ethnicity.

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Genetic polymorphisms and endometriosis: contribution of genes that regulate vascular function and tissue remodeling

Alessandra Bernadete Trovó de Marqui

Publication Dates

• Publication in this collection
  17 Oct 2012
• Date of issue
  Oct 2012

History

• Received
  13 Dec 2011
• Accepted
  11 May 2012