Molecular Human Reproduction, Vol. 9, No. 8, 491-495,
August 2003
© 2003 European Society of Human Reproduction and Embryology
Article |
Evaluation of germline sequence variants within the promoter region of RANTES gene in a cohort of women with endometriosis from Spain
Submitted on March 4, 2003; accepted on April 14, 2003
1 Unidad de Genética Médica y Diagnóstico Prenatal, 2 Unidad de Reproducción and 3 Servicio de Ginecología, Hospitales Universitarios Virgen del Rocío, Avda. Manuel Siurot s/n. 41013, Seville, Spain
4 To whom correspondence should be addressed. e-mail: guillermo.antinolo.sspa{at}juntadeandalucia.es
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ABSTRACT |
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The RANTES (regulated upon activation normal T cells expressed and secreted) chemokine, is known to be expressed in endometriotic lesions in a concentration correlating with the severity of endometriosis. Since it has been widely demonstrated that endometriosis has a genetic basis, we postulated that the gene encoding RANTES could be a good candidate gene for the disease. We have used fluorescence resonance energy transfer (FRET) technology to genotype and evaluate the role of the variants –403G
A and –28CG, located within the promoter region of the gene, as susceptibility factors in a cohort of Spanish women with endometriosis. No differences have been found in the allelic frequencies of both variants nor in the haplotype/ genotype distribution between patients and controls. These data are consistent with the lack of association between these polymorphisms and endometriosis in our population. They do not exclude completely a possible role of other variants within RANTES gene in this pathology. Key words: endometriosis/genetics/polymorphisms/RANTES/susceptibility factor
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Introduction |
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Endometriosis is a prevalent gynaecological condition that affects between 5 and 15% of women of reproductive age (Goldman and Cramer, 1990). Although no single theory can fully account for the diverse clinical presentations of endometriosis, it is generally accepted that endometrial cells and fragments, desquamated during the menstrual period and transported through the Fallopian tubes into the peritoneal cavity, implant, proliferate and develop into endometriotic lesions (Sampson, 1925). Irrespective of the mechanisms involved, there is increasing evidence suggesting that the disease may have a genetic basis, since (i) there is familial clustering in humans and rhesus monkeys (Kennedy et al., 1995; Hadfield et al., 1997a; Stefansson et al., 2002); (ii) concordance has been reported in monozygotic twins (Moen, 1994; Hadfield et al., 1997b; Treloar et al., 1999); (iii) the age at onset of symptoms is similar in affected, non-twin sisters (Kennedy et al., 1996); (iv) the prevalence of the disease is 6–9-fold greater in first-degree relatives of affected women compared with the general population (Simpson et al., 1980; Coxhead and Thomas, 1993; Moen and Magnus, 1993); and (v) disease prevalence may be as high as 15% in the sisters of women with severe disease (Kennedy et al., 1998).
Although the aetiology of endometriosis is unknown, it has been suggested that deficient immunity against retrograde endometrium during menstruation may be involved in the pathophysiology of the disease and natural killer (NK) cells may subserve this role (Lebovic et al., 2001a). In this way, some authors have demonstrated that peritoneal fluid from women with endometriosis contains significantly greater NK cell suppressive activity than peritoneal fluid from fertile controls (Oosterlynck et al., 1991). A wide pattern of cytokines has also been shown to play a critical role in immunological surveillance, recognition and destruction of ectopic endometrial cells and possible facilitation of the implantation of ectopic endometrial tissues (Schall and Bacon, 1994; Ben-Baruch et al., 1995; Butcher and Picker, 1996; Strieter et al., 1996; Barcz et al., 2000). One of these cytokines is RANTES (regulated on activation, normal T-cell expressed and secreted), a potent chemoattractant for eosinophils, lymphocytes, monocytes, and basophils, at the site of inflammation (Schall et al., 1990; Kameyoshi et al., 1992; Alam, 1997). Khorram et al. showed that RANTES is detectable in the peritoneal fluid of women with endometriosis and its concentration increases with the severity of disease. These authors postulated that after T-cell activation in peritoneal fluid, secretion of RANTES may lead to the recruitment of peritoneal macrophages and more T-lymphocytes, further contributing to the progression of endometriotic lesion (Khorram et al., 1993). Hornung et al. (1997) found predominant immunolocalization of RANTES in the stromal compartment of normal endometrium. Recently, the same authors found that transcription of RANTES mRNA is up-regulated by interleukin (IL)-1ß via nuclear factor (NF)-
B response element in the proximal RANTES gene promoter. These results demonstrated a feed-forward regulatory loop in the pathogenesis of endometriosis by which IL-1ß produced from activated macrophages can lead to further macrophage recruitment via RANTES production in endometriotic stromal cells (Lebovic et al., 2001b).
Endometriosis is likely to be a complex trait, in which multiple gene loci conferring susceptibility to the condition interact with each other and the environment to produce the phenotype (Kennedy, 1999). For that reason, we decided to investigate the role played by RANTES polymorphisms in susceptibility to endometriosis. Other studies have revealed that two RANTES variants at positions –28 and –403 in the human RANTES promoter may have significance in the development of certain diseases, such as atopic dermatitis (Nickel et al. 2000), bronchial asthma (Fryer et al., 2000), polymyalgia rheumatica, rheumatoid arthritis (Makki et al., 2000), or sarcoidosis (Takada et al., 2001), as well as in the context of HIV infection (Hajeer et al., 1999; Liu et al., 1999; McDermott et al., 2000; Marshall, 2001). Therefore we have investigated these two specific polymorphisms in a series of Spanish patients with endometriosis and control subjects.
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Materials and methods |
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Study participants
In the present study we have included the following three groups: (i) 63 sporadic cases of endometriosis with surgical and histological confirmation of endometriosis in stage II–IV (American Fertility Society, 1995), undergoing surgery at Hospitales Universitarios Virgen del Rocío; (ii) 36 pre-menopausal women aged ≥45 years, with a normal pelvis at hysterectomy, also undergoing surgery at the Hospitales Universitarios Virgen del Rocío; and (iii) 110 women with an average age of 36 years who came to the hospital for other reasons, and did not present symptoms of endometriosis. All the subjects included in this study were Caucasian–Mediterranean women from the South of Spain.
Informed consent was obtained from all participants in accordance with the regulations of the institutional review board for human subjects’ protection.
Analysis of RANTES variants
Genomic DNA was obtained from peripheral venous blood samples from each participant using standard protocols (Dracapoli et al., 1994). The polymorphisms –403GA and –28CG within the RANTES promoter were analysed by fluorescence resonance energy transfer (FRET) using specific probes and the LightCyclerTM system (Roche Molecular Biochemicals, Germany). Primers used to obtain the amplicons containing the polymorphic variants have been previously described (Gonzalez et al., 2001), and sequences of internal probes are shown in Figure 1.
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This method has two steps: (i) real time PCR and (ii) melting curve determination. During the melting curve annealing step, two different oligonucleotides (Anchor and Sensor probes) hybridize to adjacent regions of the target DNA, making possible the FRET reaction (Figure 1). During the temperature curve determination, we measured the melting point of the sensor probe, which depends on the presence/absence of a mismatch along the sequence. The amplicon containing the two polymorphic loci was obtained in a LightCycler system under the following conditions: each 10 µl PCR contained 25 ng of genomic DNA, 1 µl of Fast Start LC-master mix (Roche Molecular Biochemicals), 12.5 mmol/l MgCl2, 2 pmol of each Sensor and Anchor probes and 10 pmol of each primer. An initial denaturation step for 7 min at 95°C was followed by 55 cycles of amplification (95°C for 0 s, 65°C for 15 s and 72°C for 30 s). Amplification was followed by a melting curve (from 36°C to 95°C, with a 0.4°C/s slope), while fluorescence was measured on channels F2 (640 nm)/F1 (520 nm) for –403G
A variant, and F3 (705 nm)/F1 (520 nm) for –28CG polymorphism.
Statistical analysis
Allelic frequencies of the analysed RANTES polymorphisms were determined and then compared between patients and controls. Comparisons were performed using either 
2-analysis with the Yates’ correction, or Fisher’s two-tailed exact test when appropriate. P < 0.05 was considered statistically significant. Estimations on the power calculations were performed using the SamplePower application of the SPSS program.
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Results |
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Genotyping of the two specific polymorphic variants within RANTES promoter was performed with fluorescence monitoring during the melting curve experiment in the LightCyclerTM system. This process comprised a temperature ramp coupled to a continuous fluorimetric register. In each case, fluorescence melting peak analysis revealed different melting temperatures (Tm) for amplicons containing the wild-type sequence and for products with the polymorphisms. Our results show that the experiments designed detect both variants in the sequence, with specific Tm for each one (Figure 1). This technique was previously validated by the sequencing method in both the sense and antisense strands, which allowed us to select the internal genotyping controls (homozygous and heterozygous individuals for each variant) included in every genotyping procedure. Our method allows us to test the two sequence variants in a fast, simple, reliable, and efficient way, using two different pairs of probes after the performance of only one PCR reaction.
We have analysed 63 unrelated cases of women with endometriosis compared respectively to 110 women without symptoms of the disease, and to 36 confirmed unaffected women, for the frequency of two polymorphic variants within the gene encoding RANTES chemokine. The frequency data for each group are shown in Table I. Our results show that the differences in the frequencies of both polymorphic variants are not statistically significant when the group of patients is compared to the other two groups (Table I). In the specific case of the variant –28CG, the frequencies obtained for the polymorphic allele were very low in each of the groups. Taking into account that the frequency for this variant in our normal control group is 2.7% (which is in accordance with the frequencies reported for other populations) and given our current sample size, we have calculated that for a value of 
= 5% (type I statistical error) and a maximum value of ß = 20% (type II statistical error), the difference in the frequency for both groups should be >12% to consider association of the variant with the development of the disease. Since the frequency obtained for the group of women with endometriosis is very similar to the controls, we can assume that this variant is not related to endometriosis. The generation of haplotypes based on the combination of the two variants showed that the haplotype distributions in patients and both groups of controls were not significantly different (Table II). Furthermore, no statistical significance was obtained after comparing the distribution of genotypes (pairs of haplotypes) between the groups (Table II).
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Discussion |
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TopABSTRACTIntroductionMaterials and methodsResultsDiscussionREFERENCES |
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Endometriosis is a common disorder with poorly understood aetiology and pathogenesis. There is increasing evidence that endometriosis is inherited as a complex genetic trait, implying that multiple gene loci interact with each other and environmental factors to produce the phenotype.
It has been widely demonstrated that cytokines, which are produced by many cell types in peritoneal fluid, play a diverse role in constructing the peritoneal environment that induces the development and progression of endometriosis and endometriosis-associated infertility (Harada et al., 2001). In this sense, genes encoding cytokines represent good candidate genes for endometriosis. Some authors have already evaluated the role of certain polymorphisms within genes encoding components of the cytokine network in the development of endometriosis (Harada et al., 2001; Hsieh et al., 2001; Kitawaki et al., 2002; Lee et al., 2002). However, this is the first study in which the involvement of genetic variants within the gene encoding RANTES chemokine in the pathogenesis of the disease has been evaluated. More specifically, we have investigated whether there is an association between endometriosis and the two variants located within the promoter of RANTES gene, namely –28CG and –403GA. Our hypothesis was based on the facts that (i) RANTES is found at high levels in the peritoneal fluid of women with endometriosis (Schall et al., 1990), and that (ii) in addition to the regulation of leukocyte migration and function, it has been found that RANTES displays specific roles in endometrial angiogenesis, apoptosis, proliferation, and differentiation (Kayisly et al., 2002). Thus, it would be plausible that variants within the promoter region of the gene encoding RANTES could affect its transcription and expression, contributing to the development of this complex trait. In fact, the point mutation at base pair –403 results in a new consensus binding site for the GATA transcription factor family. In addition, it has already been demonstrated that IL-1ß induction of RANTES expression in endometriotic stromal cells depends on a NF-B site in the proximal promoter. More specifically, the promoter region of RANTES contains two NF-B binding sites at positions –54 and –40. In endometriotic stromal cells, IL-1ß induces the RANTES promoter via an NF-B cis-acting binding site located within the –40 to –31 region of the RANTES promoter, a region very close to the location of one of the studied variants (Lebovic et al., 2001b).
According to our data, neither –403GA, –28CG, nor the haplotypes generated by the combination of both variants, or the genotypes comprising haplotype pairs, seem to be involved in the susceptibility to endometriosis in our population. Given the heterogeneous nature of this disease, it is possible that a bias in the selection of cases and controls could be hiding a putative association between the polymorphisms and endometriosis. In fact, several other case– control studies centred on the evaluation of the same parameters have obtained different results, due in part to differing case definitions and subject selection strategies (Holt and Weiss, 2000). For this reason, the selection of cases in this study was based on the definition of the pathological condition by a consensus panel of European gynaecologists in 1991, as ‘the presence of ectopic endometrium, in association with evidence of cellular activity in the lesions and of progression, such as the formation of adhesions, or by its interference with normal physiological processes’ (Audebert et al., 1992; Holt and Weiss, 2000). Because physical, ultrasound, and magnetic resonance imaging examinations have relatively low sensitivity in ascertaining the presence of ectopic endometriotic tissue, diagnosis of endometriosis was made by direct visualization of the pelvis during a laparoscopic surgical examination of excised tissue, and later a histological corroboration.
On the other hand, given that the prevalence of asymptomatic endometriotic disease is estimated to be <2% (Sangi-Haghpeykar and Poindexter, 1995), only a small percentage of the control group composed of the 110 women without symptoms of endometriosis, was likely to have undiagnosed symptomatic or asymptomatic endometriosis, and so the estimated effect of this population-based study would be biased to only a very small degree. Nevertheless, in order to avoid the possibility of obtaining false conclusions from the study, we also compared the affected group with a control group made up exclusively of pre-menopausal women, with a normal pelvis at hysterectomy. All women belonging to this latter group were aged ≥45 years, avoiding younger women who might develop the disease in later life.
In addition, it has been stated that for the investigation of the impact of potential risk factors for endometriosis, such as genetic characteristics, the degree of bias is likely to be small or absent (Holt and Weiss, 2000). For these reasons, the bias performed in the selection of the groups in this study is expected to be almost non-existent.
Our results seem to indicate that the RANTES polymorphisms studied are not susceptibility factors for endometriosis. However, these data do not completely exclude the putative role of other variants within the RANTES gene in this pathology. Further mutational studies must be performed in order to rule out RANTES as a candidate gene in endometriotic disease.
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Acknowledgements |
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We would like to express our gratitude to the study participants affected by endometriosis and to the voluntary donors for their cooperation, essential for the completion of this study. This work was partially funded by the grant CAA 122/00 from the Consejería de Salud de la Junta de Andalucía, Spain.
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