G yn ec ol E nd oc ri no l D ow nl oa de d fr om in fo rm ah ea lt hc ar e. co m b y U ni ve rs it y of S yd ne y on 0 7/ 09 /1 2 F or p er so na l u se o nl y. ynecological Endocrinology, 2012; 28(4): 305–309 Copyright © 2012 Informa UK, Ltd.
ISSN 0951-3590 print/ISSN 1473-0766 online DOI: 10.3109/09513590.2011.631624
ENDOMETRIOSIS
XRCC1 399*Arg-related genotype and allele, but not XRCC1
His107Arg, XRCC1 Trp194Arg, KCNQ2, AT1R, and hOGG1
polymorphisms, are associated with higher susceptibility of
endometriosis
Yao-Yuan, Hsieh
1,2, Chi-Chen Chang
2, Shih-Yin Chen
3, Chih-Ping Chen
4, Wen-Hsin Lin
5& Fuu-Jen Tsai
3,61School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan, 2Division of Infertility Clinic,
Hsieh Yao-Yuan Women’s Hospital, Taichung, Taiwan, 3Graduate Institute of Chinese Medical Science, China Medical University,
China Medical University Hospital, Taichung, Taiwan, 4Department of Obstetrics and Gynecology, Mackay Memorial Hospital,
Taipei, Taiwan, 5School of Pharmacy Undergraduate Program Department of Medicine, China Medical University, Taichung,
Taiwan, and
6Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan
X-ray repair cross-complementing group 1 (XRCC1) and human 8-oxoguanine glycosylase 1 (hOGG1) play important roles in base excision repair. KCNQ genes comprising voltage-gated ion-channels related with cell stability. Angiotensin II type 1 receptor (AT1R) is related with angiogenesis, which influence endometri- osis growth, invasion and regression. We aimed to investigate whether these polymorphisms were associated with endo- metriosis susceptibility. Women were divided [1]: endometriosis (n = 136 [2]); non-endometriosis groups (n = 112). XRCC1 (codon
107, 194, 399), hOGG1, KCNQ2, AT1R polymorphisms were amplified by PCR and detected by electrophoresis after restric- tion enzyme (RsaI, HpaII, MspI, Fnu4HI, Ava II, Dde I) digestions. Genotypes and allelic frequencies in both groups were compared. Proportions of XRCC1
Arg399Gln*GG/GA/AA and G/A allele between both groups were [1]: 41.9/53.7/4.4% and 68.8/31.2% [2]; 30.4/54.5/15.1% and 57.6/42.4% (p < 0.05). Other 5 polymorphisms (XRCC1 codon 107 and 194, hOGG1, KCNQ2, and AT1R) between both groups were non-significantly different. Proportions of XRCC1 107*AA/AG/GG and XRCC1
194*TT/TC/CC between both groups were [1]: 3.7/27.2/69.1% and 5.8/34.6/59.6% [2]; 2.6/21.4/75.8% and 11.6/37.5/50.9%. HOGG1*CC/CG/GG, KCNQ2*AA/AC/CCC and AT1R*AA/AC/CC were [1]: 14.8/42.6/42.6, 14/41.9/44.1 and 92.6/7.4/0% [2]; 11.6/50/38.4, 17/50/33 and 100/0/0%. We concluded that XRCC1 399 Arg-related genotype and allele are correlated with higher susceptibility to endometriosis, which suggested its associa- tion with endometriosis pathogenesis. XRCC1 107 and 194,
hOGG1, KCNQ2, and AT1R are not associated with endometriosis susceptibility.
prevalence of endometriosis is around 10% in the general popu-lation [1]. Endometriosis displays some features of malignancy, including altered morphology, disregulated growth, local inva-sion and aggressive spread to distant organs. Endometriosis might be caused by an interaction between multiple genes as well as environmental factors. Altered or defected DNA-repairing system is essential for the self-defense against tumorigenesis. Angiogenesis might be also related with the development of endometriosis.
DNA damage plays a major role in mutagenesis, carcinogenesis and aging. Repairing DNA damage is critical for cell proliferation and prevention of cell malformations. The integrity of damaged genome is typically restored as a consequence of the action of certain DNA-repairing enzymes. The sensitivity to mutagens and efficacy of DNA repair are affected by variation in several genes, including X-ray repair cross-complementing group 1 (XRCC1) and human 8-oxoguanine glycosylase 1 (hOGG1) genes. XRCC1 is a base excision repair protein that plays a central role in the repair of oxidative DNA base adducts, and also a negative regu- lator of apoptosis [2]. The hOGG1 gene encodes glycosylase of base excision repair and specifies a key protein in homologues recombination repair. The hOGG1 gene encodes a DNA glycosy- lase involved in the excision repair of 8-hydroxy-2′-deoxyguanine (8-OH-dG) from oxidatively damaged DNA [3]. The hOGG1 is a key component of the base excision repair pathway and catalyzes the removal of 8-OH-dG [4].
The KCNQ gene family comprises voltage-gated potassium channels, which were expressed in epithelial tissues (KCNQ1,5), inner ear structures (KCNQ1,4) and the brain (KCNQ2-5 [5]). The M channels, important regulators of neuronal excitability, Keywords: AT1R, Endometriosis, hOGG1, KCNQ2, polymorphism,
XRCC1
Introduction
Endometriosis is a pathologic gynecologic entity typical of women in reproductive age, associated with many polygenic/ multifactorial alterations but its etiology remains unclear. The
are voltage-gated potassium channels composed of KCNQ2-5 subunits. KCNQ2 is crucial for their functions in controlling neuronal excitability. Mutations in KCNQ2 genes might be asso- ciated with benign familial neonatal convulsions, dominantly inherited epilepsy and myokymia. Mutations in KCNQ2 genes have been found to be correlated with some instability for neurona excitability, such as benign familial neonatal convulsions, domi- nantly inherited epilepsy and myokymia [6].
with higher susceptibility of endometriosis.
Correspondence: Fuu-Jen Tsai, M.D., Ph.D., Department of Medical Genetics, China Medical University Hospital, No. 2 Yuh-Der Road, Taichung, Taiwan. Tel: 886-4-22052121; ext. 2041. Fax: 886-4-22033295. E-mail: d0704@m a i l .c m u h. o r g .tw
306 Y.-Y. Hsieh et al. Gyneco l ogical Endocrinology G yn ec ol E nd oc ri no l D ow nl oa de d fr om in fo rm ah ea lt hc ar e. co m b y U ni ve rs it y of S yd ne y on 0 7/ 09 /1 2 F or p er so na l u se o nl y. T ab le I . T he p ri m er s eq ue nc es , p ol ym er as e ch ai n re ac ti on a nd r es tr ic ti on f ra gm en t le ng th p ol ym or ph is m ( P C R -R FL P ) co nd it io ns f or X R C C 1, h O G G 1, K C N Q 2, a nd A T 1R g en e po ly m or ph is m s. R es tr ic ti on D N A f ra gm en t si ze ( bp ) 66 0 + 2 10 87 0 33 8 21 9 + 1 19 24 2 14 7 + 9 5 20 0 10 0 + 1 00 24 6 15 1 + 5 3 + 4 2 15 1 10 0 + 5 1 Po ly m or ph is m s (l oc at io n s) X R C C 1 co do n 10 7 P ri m er s se qu en ce s (5 ′-> 3′ ) F : T T G A C C C C C A G T G G T G C T R : A G T C T G C T G G C T C T G G G C T G G F: CA G A C A A A G A T G A G G C A G A G G R : T C A G A C C C A G G A A T C T G A G C F : C C C C A A G T A C A G C C A G G T C R : T G T C C C G C T C C T C T C A G T A G F : A C T G T C A C T A G T C T C A C C A G R : G G A A G G T G C T T G G G G A A T F: C A T G G A G T T C C T G C G G C A R : T C G G A G T C G G T G T C T G A C T C T C F : T T G A G G T T G A G T G A C A T G T T C G A R : C G G T T C A G T C C A C A T C C T G C A D en at ur e (° C /s ec ) 94 /3 0 A nn ea li ng ( °C /s ec ) 63 /3 0 E xt en si on ( °C /s ec ) 72 /3 0 en zy m e (° C /m in )* R sa I( 37 °C /1 h ) S N P se qu en ce A G T C G A C G A C A C A lle lic v ar ia nt s H is A rg T rp A rg A rg G ln Se r C ys Pro Pro A de Cyt X R C C 1 co do n 19 4 94 /3 0 58 /3 0 72 /3 0 H pa II (3 7/ 3 h) X R C C 1 co do n 39 9 95 /4 0 55 /4 0 72 /4 0 M sp I (3 7° C /3 h ) hO G G 1 co do n 32 6 94 /3 0 60 /3 0 72 /3 0 Fn u4 H I (3 7° C /1 h ) K C N Q 2 co do n 71 8 94 /3 0 58 /3 0 72 /3 0 A va I I (3 7° C /1 h ) A T 1R c od on 1 16 6 94 /3 0 58 /3 0 72 /3 0 D de I ( 37 °C /1 h ) *F a nd R in di ca te f or w ar d an d re ve rs e pr im er s.
Angiotensin (Ang) is a well-known activator of smooth muscle in the vasculature. Ang II is locally produced in various tissues; whereas its role upon the regulation of tissue metabolism is still indefinite. Ang II type 1 receptor (AT1R) is related with the regulation of vascular tone. Ang II signaling contributes to cell proliferation and inhibition of the insulin signaling pathways through AT1R [7]. Activation of AT1R stimulates catecholamine systems within both central and peripheral tissues that are associated with blood pressure control [8]. Recent studies have revealed the role of AT1R in the control of energy homeostasis and lipid metabolism [9].
Genetic variations in DNA-repairing (XRCC1, hOGG1), ion-channels, cell stability (KCNQ2), and vascular-related (AT1R) genes might be involved in the pathogeneses of endometriosis. In this study, we firstly aimed to evaluate whether these gene poly- morphisms are attractive markers for predicting the susceptibility of endometriosis. To the best of our knowledge, this is the first survey in this field.
Patient and methods
Pre-menopausal Taiwan women with surgically and histologi-cally diagnosed endometriosis were included. All patients were divided into two groups [1]: severe endometriosis (revised American Fertility Society classification stage IV, n = 136 [2]); endometriosis group (n = 112). The non-endometriosis statuses were confirmed after detail ultrasonography. All women accepted the peripheral blood sampling for genotype analyses. The genomic DNA was prepared from peripheral blood leukocytes using a genomic DNA isolation kit (Blossom, Taipei, Taiwan). A total of 50 ng genomic DNA was mixed with
20 pmol of each polymerase chain reaction (PCR) primer in a total volume of 25 μl containing 10 mM Tris-HCL pH 8.3, 50 mM potassium chloride, 2.0 mM magnesium chloride, 0.2 mM each deoxyribonucleotide triphosphate, and 1 U DNA polymerase (Amplitag; Perkin-Elmer, Foster City, CA, USA). The PCR primer sequences and conditions of each primer were listed in Table I.
After PCR amplification, the XRCC1 (codon 107, 194, and 399), hOGG1 codon 326, KCNQ2 codon 718, AT1R codon 1166 gene polymorphisms were analyzed by restriction digestion with restriction enzymes (RsaI, HpaII, MspI, Fnu4HI, Ava II, Dde I, New England Biolabs, Inc, Beverly, MA). The reaction was then incubated at 37°C, and then 10 μl of the digested products were loaded into a 3% agarose gel with ethidium bromide staining and separated by electrophoresis. The individual PCR conditions, following electrophoreses and base pairs for their wild and SNP types were listed in Table I. Genotypes and allelic frequencies for XRCC1, hOGG1, KCNQ2, and AT1R gene polymorphisms in both groups were compared. Correlations of these gene poly- morphisms and endometriosis were evaluated. Allelic frequencies are expressed as a percentage of the total number of alleles. The SAS package with χ2 and Fisher’s extract tests were utilized for statistical analyses. A p value < 0.05 was considered statistically significant.
Results
After the survey of 6 genetic polymorphisms, except for XRCC1 Arg399Gln, genotype proportions of other 5 gene polymorphisms (XRCC1 His107Arg, XRCC1 Trp194Arg, hOGG1, KCNQ2, and AT1R) between both groups were non-significantly different (Table II andIII). Distributions of
307
Copyright © 2012 Informa UK, Ltd.
Endometriosis n = 136 (%) Controls n = 112 (%) p value* the DNA damage resulted from mutagenic and carcinogenic envi-ronment. Genetic variants of DNA-repair genes might contribute to tumorigenesis. Some polymorphisms involved in the repair of alkylating DNA adduct and DNA base damage might be associated with modulating or decreasing the cancer risks [11]. Endometriosis involves a complex interaction or hOGG1 326
C/C 20 (14.8%) 13 (11.6%) NS*
C/G 58 (42.6%) 56 (50%)
G/G 58 (42.6%) 43 (38.4%)
Allele C 98 (36%) 82 (36.6%) NS* between cell metapasia, genetic defect, DNA repair, cell stability
Allele G 174 (64%) 142 (63.4%) and angiogenesis [12]. Deficient DNA-self repairing or defense
KCNQ2 718 process against peritoneal/ovarian metaplastic cells or retrograde
AA 19 (14%) 19 (17%) NS* endometrial cells during menstruation might be involved with
AC 57 (41.9%) 56 (50%) the pathophysiology of endometriosis.
CC 60 (44.1%) 37 (33%) Compromised DNA-repair capacity may play an important
Allele A 95 (34.9%) 94 (42%) NS* role in the pathogenesis of endometriosis. Amongst DNA-repair Allele C 177 (65.1%) 130 (58%) genes, XRCC1 play an important role in the excision or repair
AT1R 1166 of both damaged bases and single-strand breaks of DNA after
AA 126 (92.6%) 112 (100%) NS† chemical or other carcinogen exposure [11,13]. XRCC1 protein
AC 10 (7.4%) 0
DNA strand breaks [14]. XRCC1 is essential for the excision or
CC 0 0 repair of both damaged bases and single-strand breaks of DNA
Allele A 262 (96.3%) 224 (100%) NS†
after chemical or other carcinogen exposure [13]. Cells lacking Allele C 10 (3.7%) 0 the XRCC1-related activity are hypersensitive to DNA damage.
*χ2 test; †Fisher’s extract test.
Genetic variations in DNA-repair genes, such as XRCC1, might lead to inter-individual variation in DNA-repair capacity and 308 Y.-Y. Hsieh et
al.
Gyneco l
Table II. Genotypes and allelic frequencies for XRCC1 His107Arg, Try194Arg, and Arg399Gln gene polymorphisms in women with and w ithout endometriosis. Endometriosis n = 136 (%) Controls n = 112 (%) p value* XRCC1 107 AA 5 (3.7%) 3 (2.6%) NS AG 37 (27.2%) 24 (21.4%) GG 94 (69.1%) 85 (75.8%) Allele A 47 (17.3%) 30 (13.3%) NS Allele G 225 (82.7%) 194 (86.6%) XRCC1 194 TT 8 (5.8%) 13 (11.6%) NS TC 47 (34.6%) 42 (37.5%) CC 81 (59.6%) 57 (50.9%) Allele T 63 (23.2%) 65 (30.4%) NS Allele C 209 (76.8%) 153 (69.6%) XRCC1 399 GG 57 (41.9) 34 (30.4) 0.007 GA 73 (53.7) 61 (54.5) AA 6 (4.4) 17 (15.1) Allele G 187 (68.8) 129 (57.6) 0.01 Allele A 85 (31.2) 95 (42.4) *χ2 test.
Table III. Genotypes and allelic frequencies for hOGG1 Ser326Cys, KCNQ2 Pro718Pro, and AT1R Ade1166Cyt genes polymorphisms in women with and without endometriosis.
(p = 0.01, Table II). These findings suggest that the Arg-related genotype and allele of XRCC1 Arg399Gln polymorphism are associated with higher susceptibility to endometriosis.
Furthermore, genotype proportions and allele frequencies between both groups were also non-statistically different in hOGG1 codon 326, KCNQ2 codon 718 and AT1R codon 1166 gene polymorphisms (Table III). Proportions of hOGG1 Ser326Cys*C homozygote/heterozygote/G homozygote and C/G allele in both groups were [1]: 14.8/42.6/42.6% and 36/64% [2]; 11.6/50/38.4% and 36.6/63.4%, respectively (Table III). Proportions of KCNQ2
Pro718Pro*A homozygote/heterozygote/C homozygote and A/C allele in both groups were [1]: 14/41.9/44.1% and 34.9/65.1% [2]; 17/50/33% and 42/58%, respectively (Table III). Distributions of AT1R Ade1166Cyt*A homozygote/heterozygote/C homozy-gote and A/C allele in both groups were [1]: 92.6/7.4/0% and 96.3/3.7% [2]; 100/0/0% and 100/0%, respectively (Table III).
Discussion
Endometriosis is a complex multifactorial disease associated with genetic alterations in neovascularization. This disease presents some characteristics of malignancy, such as development of local and distant foci and attachment to and invasion of other tissues with subsequent damage to the target organs [10]. Similar to tumor metastases, endometriotic implants require neovascularization to become established, grow and invade tissues. Neovascular processes are prominent in the endometriosic tissue.
G yn ec ol E nd oc ri no l D ow nl oa de d fr om in fo rm ah ea lt hc ar e. co m b y U ni ve rs it y of S yd ne y on 0 7/ 09 /1 2 F or p er so na l u se o nl y. 309
Copyright © 2012 Informa UK, Ltd.
might interact with DNA ligases in recognition and rejoining of
107*A homozygote/heterozygote/G homozygote and A/G allele in both groups were [1]: 3.7/27.2/69.1% and 17.3/82.7% [2]; 2.6/21.4/75.8% and 13.3/86.6%, respectively (non-significant difference, Table II). Proportions of XRCC1 194*T homozy-gote/heterozygote/C homozygote and T/C allele in both groups were [1]: 5.8/34.6/59.6% and 23.2/76.8% [2]; 11.6/37.5/50.9% and 30.4/69.6%, respectively (non-significant difference, Table II). In contrast, proportions of XRCC1 399*G homozy-gote/heterozygote/A homozygote and G/A allele in both groups were [1]: 41.9/53.7/4.4% [2]; 30.4/54.5/15.1%, respectively (p value = 0.007). Proportions of XRCC1 Arg399Gln*G/A allele between both groups were [1]: 68.8/31.2% [2]; 57.6/42.4%
modify the associations between exogenous and endogenous carcinogens and endometriosis risk. XRCC1 is thought to be involved with DNA single-strand beak (SSB) repair, and plays an important role in the base excision repair (BER) pathway. In coor- dinating BER, XRCC1 protein is proposed to interact with DNA ligase III in recognition and rejoining of DNA strand breaks.
XRCC1 gene is located on chromosome 19q13.2, which contains 17 exons as well as a large number of single-nucleotide polymorphisms (SNPs [15]). The XRCC1 gene of human, which encodes a protein that plays a central role in the single-strand break repair or base excision repair pathway [16], was identified by its ability to restore DNA repair [15]. XRCC1 and three other
ogical Endocrinology G yn ec ol E nd oc ri no l D ow nl oa de d fr om in fo rm ah ea lt hc ar e. co m b y U ni ve rs it y of S yd ne y on 0 7/ 09 /1 2 F or p er so na l u se o nl y.
DNA-repair enzymes are involved in the excision and repair of single-strand breaks and in recombinational repair pathways [17]: DNA ligase I at its 3′ end, DNA polymerase β, and poly adenosine diphosphate (ADP)-ribose polymerase (PARP). XRCC1 mutants display sensitivity to alkylating agents and ionizing radiation and exhibit elevated levels of sister chromatid exchange in the Chinese hamster ovary cell lines. Such alterations might be associated with increased cancer risk [14]. Furthermore, variants of XRCC1 gene might contribute to ionizing radiation susceptibility as measured by prolonged cell cycle G2 delay [18]. Many XRCC1 genetic poly- morphisms have been documented to be associated with alter- ative DNA-repair capacity [14].
HOGG1 is also essential for the base excision/repair pathway after DNA damage. Some investigators demonstrated the hOGG1
Ser326Ser and Ser326Cys genotypes were risk factors for super-ficial bladder cancer recurrence compared with the Cys326Cys genotype [19]. Patients with atrophic gastritis in conjunction with the hOGG1 Cys allele might have a higher susceptibility to gastric cancer [20]. KCNQ-type potassium channels generate the M-current voltage, which is essential in regulating neuron cells excitability. Ability of KCNQ channels is important in modulating cell excitability. KCNQ-potassium channels and M-currents could stabilize the neuronal resting potential and prevent repeti- tive firing of action potentials. Mutations in the voltage-gated potassium/M-channel KCNQ2 gene has been found to cause idio- pathic generalized epilepsy, the benign familial neonatal convul- sions, benign familial neonatal convulsions [6]. Impaired KCNQ2 channels cause neuronal hyperexcitability, manifested as epileptic seizures and myokymia. KCNQ2 genes have been emerged as novel targets for numerous cell-stability disorders [21].
Neoangiogenesis is prominent in endometrisic tissues, which suggested the affinity between vascular-related genes and endo-metriosis susceptibilities. Renin-angiotensin system is a central component of the physiological and pathological responses of cardiovascular system. Its primary effector hormone, Ang II, mediates not only immediate physiological effects of vasocon-striction and blood pressure regulation. Many evidences suggest an involvement in inflammation, endothelial dysfunction, athero- sclerosis, hypertension, and congestive heart failure. AT1R might influences Doppler blood flow parameters of carotid and brachial arteries in patients with myocardial infarction [22]. Defect in AT1R expression may further alter downstream signaling path- ways as well as responsible for the development of e hyperten- sion [8]. AT1R A1166C polymorphism is a potential genetic marker for increased susceptibility to renal complications in type
2 diabetes [23] and hypertensive heart disease [24].
XRCC1 polymorphisms were associated with numerous disor- ders, including breast cancer [25], lung cancer [26], squamous cell carcinoma of the head and neck [27], nasopharyngeal carcinoma [28], esophageal cancer [29] etc. However, the func- tional significance of XRCC1 SNPs upon endometriosis remains unknown. Despite the SNPs might not alter the transcript produc- tions, some investigator demonstrated the disequilibrium effects of certain genotypes might influence the related 3-dimensional structure and efficiency of the transcripts [30]. In this survey, our findings support the hypothesis that genetic variation in XRCC1 Arg399Gln might affect the susceptibility for endo- metriosis. XRCC1 399*G homozygote and allele are associated with higher susceptibility to endometriosis. We also observed a
lower percentage of Gln homozygote and allele in the women with endometriosis compared with the non-endometriosis group. The A and G alleles might be serving as markers of a functional variant in a nearby gene.
In conclusion, XRCC1 Arg399Gln polymorphism is correlated with higher susceptibility to endometriosis. This finding suggested that XRCC1 Arg399Gln polymorphism might be involved in the pathogenesis of endometriosis. In contrast, genetic variations for XRCC1 107 and 194, hOGG1, KCNQ2, and AT1R are not asso- ciated with endometriosis susceptibility. These findings provide a valuable insight into the pathogenesis of endometriosis. Some DNA-repairing, cell voltage/stability or vascular-related poly- morphisms might become useful markers to predict the future development of endometriosis as well as the modulating or inter- fering factors.
Declaration of interest: We confirm and declare that
all authors fulfilled the condition for authorship. There was no commercial support in the process of performing this study and submit- ting this manuscript. There were no conflicts of interest in our manuscript.
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