{"paper_id":"570123fc-8baa-459d-828a-db15474135b5","body_text":"SHORT COMMUNICATION\nLack of an association human dioxin detoxification gene\npolymorphisms with endometriosis in Japanese women: results\nof a pilot study\nYasunari Matsuzaka • Yukie Y. Kikuti • Kenichi Goya •\nTakahiro Suzuki • Li-yi Cai • Akira Oka • Hidetoshi Inoko •\nJerzy K. Kulski • Shun-ichiro Izumi • Minoru Kimura\nReceived: 15 December 2011 / Accepted: 28 March 2012 / Published online: 1 May 2012\n/C211The Japanese Society for Hygiene 2012\nAbstract\nObjectives Endometriosis is a chronic disease caused by\nthe presence of endometrial tissue in ectopic locations outside\nthe uterus. Chronic exposure to the environmental pollutant\ndioxin has been correlated with an increased incidence in the\ndevelopment of endometriosis in non-human primates. We\nhave therefore examined whether there is an association\nbetween the polymorphisms of ten dioxin detoxification\ngenes and endometriosis in Japanese women.\nMethods This was a pilot study in which 100 patients\nwith endometriosis and 143 controls were enrolled. The\nprevalence of five microsatellite and 28 single nucleotide\npolymorphism markers within ten dioxin detoxification\ngenes ( AhR, AHRR, ARNT, CYP1A1, CYP2E1, EPHX1,\nGSTM1, GSTP1, GSTT1, NAT2) was examined.\nResults Taking into account that this analysis was a\npreliminary study due to its small sample size and genetic\npower, the results did not show any statistically significant\ndifference between the cases and controls for any of the\nallele and genotype frequency distributions examined. In\naddition, no significant associations between the allele/\ngenotype of all polymorphisms and the stage (I–II or III–\nIV) of endometriosis were observed.\nConclusion Based on the findings of this pilot study, we\nconclude the polymorphisms of the ten dioxin detoxifica-\ntion genes analyzed did not contribute to the etiology of\nendometriosis among our patients.\nKeywords Endometriosis /C1Dioxin detoxification genes /C1\nSingle nucleotide polymorphisms /C1Microsatellite /C1\nAssociation study\nIntroduction\nEndometriosis (MIM131200) is an estrogen-dependent\ninflammatory disease that is characterized histologically by\nthe presence of endometrial glands and stroma outside the\nuterine cavity. Approximately 6–10 % of women of repro-\nductive age have been reported to suffer from this condition\n[1, 2]. In a study of the genetic influence on the risk of endo-\nmetriosis among twins in Australia, the risk ratio of affected\nversus population prevalence was 3.58 for monozygotic twins\nand 2.32 for dizygotic twins [3]. A strong familial occurrence,\nElectronic supplementary material The online version of this\narticle (doi:10.1007/s12199-012-0281-y) contains supplementary\nmaterial, which is available to authorized users.\nY. Matsuzaka ( &) /C1Y. Y. Kikuti /C1A. Oka /C1H. Inoko /C1\nJ. K. Kulski /C1M. Kimura ( &)\nDivision of Basic Molecular Science and Molecular Medicine,\nSchool of Medicine, Tokai University, Bohseidai, Isehara,\nKanagawa 259-1193, Japan\ne-mail: yasunari.matsuzaka@helmholtz-muenchen.de\nM. Kimura\ne-mail: kimura@is.icc.u-tokai.ac.jp\nPresent Address:\nY. Matsuzaka\nInstitute of Experimental Genetics, Helmholtz Zentrum\nMu¨nchen, German Research Center for Environmental Health,\nNeuherberg, Germany\nK. Goya /C1T. Suzuki /C1L. Cai /C1S. Izumi ( &)\nDepartment of Obstetrics and Gynecology, School of Medicine,\nTokai University, Bohseidai, Isehara, Kanagawa 259-1193,\nJapan\ne-mail: s-izumi@is.icc.u-tokai.ac.jp\nJ. K. Kulski\nCentre for Forensic Science, The University of Western\nAustralia, Nedlands, WA 6009, Australia\n123\nEnviron Health Prev Med (2012) 17:512–517\nDOI 10.1007/s12199-012-0281-y\n\nin which the incidence of the disease is approximately sev-\nenfold higher in relatives of women with endometriosis than in\nthose without family history, supports a genetic role [4, 5].\nLigand-bound AhR translocates to the nucleus, where it\nheterodimerizes with ARNT.T h e AhR–ARNT heterodimer\nbinds to xenobiotic response element sequences and indu-\nces the activation of the target genes that encode the\ncytochrome P450 enzymes CYP1A1 and CYP2E1 [ 6]. In\nthis heterodimer formation, the AhRR competes with AhR\nto repress the expression of AhR regulatory genes [ 7].\nCrosstalk between dioxin-activated AhR and the functional\nestrogen receptor (ER) has been reported [ 8]. Dioxin has\nalso been shown to induce a dose-dependent increase in the\nseverity of endometriosis in rhesus monkeys [ 9].\nIn order to gain a better understanding of the association\nbetween detoxification genes and endometriosis in Japanese\nwomen, we performed a case–control study of endometriosis\nas pilot study involving 100 cases and 143 controls.\nMethods\nSubjects\nAll patients and controls were female and had given their\nwritten informed consent (IC), following an explanation of\nthe laparoscopy and histological examination, to participate\nin this study, which was performed at the Department of\nObstetrics and Gynecology, Tokai University School of\nMedicine. The rate of approval was almost 100 % after a\nreflection period between the explanation and admittance to\nthe hospital. The patients with endometriosis were diagnosed\nby laparoscopy and histological examination, and the severity\nof disease was staged according to the revised classifica-\ntion of the American Society of Reproductive Medicine\n(r-ASRM) [10]. Of the 100 endometriosis cases (mean age of\npatient 38 ± 4.8 years), 27, 10, 31, 32 cases were classified\nas stage I, II, III, and IV levels of disease, respectively. The\n143 healthy controls (mean age 43 ± 12.3 years) were\npatients of unexplained infertility who had undergone a\ndiagnostic laparoscopy that proved the absence of endome-\ntriosis (Table 1). Patients with apparent disease(s) were\nexcluded from the control group. Ethics approval for this\nstudy was obtained from the Institutional Review Board at\nTokai University School of Medicine.\nDNA extraction\nGenomic DNA samples were isolated from peripheral blood\nleukocytes that were drawn from each subject into tubes\ncontaining heparin by using the Qiagen DNA Extraction kit\n(Qiagen, Tokyo, Japan) after lysis with proteinase K and\n0.5 % sodium dodecyl sulfate at 37 /C176C for 1 h.\nAnalysis of microsatellite polymorphisms in the AhR\nand ARNT gene regions\nTo determine the number of repeat units of the microsat-\nellite loci exhibiting polymorphisms in the AhR and ARNT\ngenes, we synthesized unilateral primers by labeling the 5\n0\nend with the fluorescent reagent 6-FAM (PE Biosystems,\nFoster City, CA). Two and four PCR primer sets were used\nfor the amplification of two and four microsatellite loci in\nAhR and ARNT gene regions, respectively [Electronic\nSupplementary Material (ESM) Table 1]. PCR amplifica-\ntion and GenScan (Applied Biosystems Japan, Tokyo,\nJapan) detection of these microsatellites were carried out as\npreviously described [ 11].\nGenotyping\nTo examine the distribution of the alleles and genotype\nfrequency of each single nucleotide polymorphism (SNP)\nand deletion, we performed direct sequencing analysis of\nten endometriosis candidate genes using 25 pairs of oli-\ngonucleotide PCR primers (ESM Table 2). The reaction\nmixture (20 ll) contained 2 ml of dNTP mixture (2.5 mM\neach of dATP, dCTP, dGTP, and dTTP), genomic DNA\n(5 ml; 2 ng/ ll), 2 ml of 10 9 buffer (100 mM Tris–HCl,\npH 8.3, 500 mM KCl, 15 mM MgCl\n2), 20 pmol of forward\nand reverse primers, and 0.5 U of r Taq (TaKaRa Bio,\nShiga, Japan). PCR amplification was performed in a\nGeneAmp PCR system 9700 automated thermal cycler\n(Applied Biosystems Japan) under the following PCR\nreaction conditions: an initial denaturation for 5 min at\n96 /C176C, followed by 30 amplification cycles of 45 s at\n96 /C176C, 45 s at various temperatures depending on the\nTable 1 Characteristics of cases of endometriosis and controls\nStudy cohort Cases Controls\nNumber of patients 100 143\nAge (years)a 38 ± 4.8 43 ± 12.3\nEndometriosis stageb\nStage I 27 (27.0)\nStage II 10 (10.0)\nStage III 31 (31.0)\nStage IV 32 (32.0)\nSmoking (%)\nc 14.7 14.7\nBody mass index d 20.6 ± 3 21.5 ± 3\na Mean and standard deviation (SD) of 100 cases and 143 controls\nb Number of patients, with the percentage (of 100 cases) given in\nparenthesis\nc Smoking rates for 34 cases and 34 controls\nd Mean and standard deviation for 32 cases and 30 controls\nEnviron Health Prev Med (2012) 17:512–517 513\n123\n\nprimers used (ESM Table 2) for annealing, and 2 min at\n72 /C176C, with a final extension of 7 min at 72 /C176C. Each PCR\nproduct was purified by exonuclease I and then sequenced\nusing an ABI 3100 automated sequencer (Applied Bio-\nsystems Japan).\nStatistical analyses\nAllele and genotype frequencies were determined by direct\ncounting. The significance of differences in the distribution\nof alleles and genotypes between the patients and controls\nwas tested using a case–control design by the Fisher’s\nexact probability test ( P value test). A P\nc of\\0.05, which\nindicates significant corrections for multiple testing, such\nas the Bonferroni method [ P 9 L 9 (n - 1)], was con-\nsidered to indicate statistical significance for all allelic and\ngenotypic frequencies where P, L, and n indicate the\nP value, number of loci examined, and the number of\nalleles examined, respectively. The odds ratio (OR) and\n95 % confidence interval (CI) were also calculated for all\nSNPs. The program Haploview (MIT/Harvard Broad\nInstitute, Cambridge, MA) was used to estimate pairwise\nlinkage disequilibrium (LD) and haplotype frequency [ 12].\nThe Genetic Power Calculator was used to calculate a\ngenetic power for association study ( http://pngu.mgh.\nharvard.edu/*purcell/gpc/).\nResults\nAssociation of microsatellite markers around the AhR\nand ARNT genes with endometriosis\nA total of 100 Japanese patients with endometriosis and\n143 healthy controls were enrolled in our analysis aimed at\ninvestigating the association between genetic variations in\nthe AhR and ARNT genes and endometriosis. To this end,\nwe used six microsatellites found in close proximity and\nwithin the region of the AhR and ARNT genes (Table 2).\nThe two microsatellites with the dinucleotide repeat\n(AC)n and (CA) n were positioned 1,206 and 882 bp\nupstream of the exons 2 and 3 in the AhR gene region,\nrespectively. The other four microsatellites, with di- to\npentanucleotide repeats (TG) n, (TAA), (ATTT) n, and\n(TTTTG)n, were positioned 9,907 and 10,880 bp upstream\nof the first methionine of exon, 16,306 bp upstream of exon\n2, and 2,642 bp upstream of exon 14, respectively, in the\nARNT gene. As shown in Table 2, the microsatellite with\nthe CA repeats, at intron 2 of the AhR gene and the four\nmicrosatellites in the ARNT gene region had no statistically\nsignificant association with endometriosis. The other\nmicrosatellite with the dinucleotide repeat (AC) n in the\nAhR gene region was not polymorphic (data not shown).\nAssociation of endometriosis candidate gene\npolymorphisms with endometriosis\nTwenty-eight SNPs in the AhR, AHRR, ARNT, CYP1A1\n,\nCYP2E1, EPHX1, GSTP1, and NAT2 genes were geno-\ntyped in all 100 patients with endometriosis and 143 con-\ntrols. The allele frequencies of each polymorphism are\nshown in Table 3. There was no significant association\nfound between the gene polymorphisms and the presence\nof endometriosis. However, the TT genotypes in intron 10\n(rs2106728) of the AhR gene showed a prominent—but not\nsignificant—association with the risk of developing endo-\nmetriosis (Table 4, P\nc = 0.087). To also test whether there\nwas an association between endometriosis and the gluta-\nthione S-transferase (GST) M1 and T1 null mutation, we\ngenotyped these genotype frequencies in 97 patients with\nendometriosis and 143 controls. No significant differences\nwere found between the cases and controls for the fre-\nquencies of the GSTM1 and GSTT1 null mutations\n(Table 4).\nWe evaluated the LD extension of approximately 42 kb\nof the AhR genomic region with 12 SNPs. For the LD block\nevaluation, we included SNPs with a minor allele fre-\nquency of [0.2, a genotype success rate of [0.8, and\nP[ 0.001 in the Hardy–Weinberg equilibrium test. All\nSNPs analyzed met the criteria, and the pairwise LD index\nTable 2 Results of the association tests for five microsatellite markers with endometriosis\nGene Location Position a Repeat unit Number of alleles Patients b Controlsb Odds ratio (90 % CI) P value\nAhR Intron 2 22,322 (CA) n 8 39 (24.1) 49 (20.9) 1.20 (0.74–1.93) 0.461\nARNT Promoter -10,880 (TAA) n 3 65 (50.8) 79 (44.9) 1.27 (0.80–2.00) 0.309\nARNT Promoter -9,907 (TG) n 14 20 (17.2) 20 (12.2) 1.50 (0.77–2.93) 0.235\nARNT Intron 1 11,774 (ATTT) n 2 20 (17.5) 21 (15.4) 1.17 (0.60–2.28) 0.655\nARNT Intron 13 55,880 (TTTTG) n 3 107 (75.9) 128 (68.8) 1.43 (0.87–2.34) 0.159\nCI, Confidence interval\na Position is the number of nucleotides from the first nucleotide (A) of the start codon\nb Data are presented as the number with the percentage in parenthesis\n514 Environ Health Prev Med (2012) 17:512–517\n123\n\nTable 3 Nucleotide variations within the human candidate genes and the significance of their association with endometriosis\nGene dbSNP\naccession no.\nLocation Allele a Amino acid\nsubstitution\nAllele frequencyb OR (90 % CI) P value Pc value\nPatients Controls\nAhR rs713150 Intron 1 C/g – 79 (40.7) 87 (30.4) 1.57 (1.07–2.30) 0.020 0.540\nrs2282886 Intron 1 A/g – 109 (69.9) 157 (66.5) 1.17 (0.75–1.80) 0.487 1.000\nrs2237299 Intron 1 T/c – 139 (73.2) 192 (68.1) 1.28 (0.85–1.92) 0.238 1.000\nrs2237298 Intron 1 T/c – 139 (73.2) 192 (68.1) 1.28 (0.85–1.92) 0.238 1.000\nrs3802083 Intron 1 T/c – 131 (68.2) 186 (65.5) 1.13 (0.77–1.67) 0.535 1.000\nrs2282883 Intron 2 T/c – 122 (69.3) 170 (65.9) 1.17 (0.78–1.76) 0.455 1.000\nrs1476080 Intron 2 T/g – 131 (68.2) 183 (66.3) 1.09 (0.74–1.62) 0.663 1.000\nrs2237297 Intron 2 G/a – 86 (45.7) 127 (45.4) 1.02 (0.70–1.02) 0.934 1.000\nrs3802082 Intron 5 A/t – 100 (52.6) 131 (52.0) 1.03 (0.70–1.50) 0.893 1.000\nrs2066853 Exon 10 G/a Arg/Lys 91 (47.9) 155 (45.8) 1.09 (0.75–1.57) 0.654 1.000\nrs2040623 Intron 10 C/a – 96 (49.5) 137 (47.9) 1.07 (0.74–1.53) 0.734 1.000\nrs2106728 Intron 10 T/c – 169 (87.1) 219 (76.6) 2.07 (1.26–3.39) 0.004 0.108\nAHRR rs2292596 Exon 6 C/g Pro/Ala 69 (37.5) 103 (36.8) 1.03 (0.70–1.51) 0.876 1.000\nARNT rs11204735 Intron 1 A/g – 84 (46.7) 112 (43.8) 1.13 (0.77–1.65) 0.547 1.000\nrs3768015 Intron 5 C/t – 127 (66.8) 164 (61.2) 1.28 (0.87–1.89) 0.216 1.000\nrs10305711 Intron 9 A/g – 127 (67.6) 177 (62.8) 1.24 (0.84–1.82) 0.287 1.000\nCYP1A1 rs3826042 Promoter G/a – 157 (89.2) 220 (84.6) 1.50 (0.84–2.68) 0.169 1.000\nrs3826041 Promoter T/g – 73 (41.5) 104 (40.0) 1.06 (0.72–1.57) 0.758 1.000\nrs4646421 Intron 1 C/t – 71 (37.0) 90 (31.9) 1.25 (0.85–1.84) 0.253 1.000\nrs4646422 Exon 2 G/a Gly/Asp 29 (14.9) 32 (11.3) 1.37 (0.80–2.35) 0.248 1.000\nrs1048943 Exon 7 A/g Ile/Val 46 (24.2) 61 (22.3) 1.12 (0.72–1.73) 0.624 1.000\nrs5030838 3\n0 flanking region T/c – 72 (37.1) 92 (32.4) 1.23 (0.84–1.81) 0.286 1.000\nCYP2E1 rs2070673 Promoter T/a – 95 (55.9) 133 (54.5) 1.06 (0.71–1.06) 0.782 1.000\nEPHX1 rs1051740 Exon 3 T/c Tyr/His 113 (58.2) 145 (51.1) 1.34 (0.93–1.93) 0.121 1.000\nrs2292566 Exon 3 G/a synonymous 57 (29.4) 76 (26.8) 1.14 (0.76–1.71) 0.530 1.000\nGSTP1 rs1695 Exon 5 A/g Ile/Val 29 (14.9) 40 (14.1) 1.07 (0.64–1.80) 0.792 1.000\nrs4891 Exon 7 T/c synonymous 165 (85.1) 239 (84.2) 1.07 (0.65–1.78) 0.790 1.000\nNAT2 rs1799930 Exon 2 G/a Arg/Gln 131 (74.4) 183 (73.2) 1.07 (0.69–1.65) 0.776 1.000\ndbSNP, Single Nucleotide Polymorphism Database; OR, odds ratio; CI, confidence interval\na In the allele column, a nucleotide on the left-hand side of the slash is a more frequent allele in the controls; each allele is represented by the\nnucleotide sequence of the sense strand of each gene\nb Allele frequency is presented as the number, with the percentage in parenthesis; frequencies listed are higher in the patients than in the controls\nTable 4 Genotype frequencies of the human AhR, GSTM1, and GSTT1 genes and the significance of their association with endometriosis\nGene dbSNP accession no. Genotype a Genotype frequency OR (90 % CI) P value Pc value\nPatients (%) Controls (%)\nAhR rs2106728 CC 1 (1.0) 5 (3.5)\n– CT 23 (23.7) 57 (39.9)\n– TT 73 (75.3) 81 (56.6) 2.33 (1.33–4.08) 0.003 0.087\nGSTM1 – Deletion 43 (44.3) 67 (46.9)\n– Present 54 (55.7) 76 (53.1) 1.11 (0.66–1.86) 0.700 1.000\nGSTT1 – Deletion 38 (39.2) 56 (39.2)\n– Present 59 (60.1) 87 (60.1) 1.00 (0.59–1.69) 0.998 1.000\na Each genotype is represented by the nucleotide sequence of the sense strand of each gene\nEnviron Health Prev Med (2012) 17:512–517 515\n123\n\n(D) was calculated and plotted (ESM Fig. 1). We further\nanalyzed the haplotype constitution with six SNPs, namely,\nrs1476080, rs2237297, rs3802082, rs2066853, rs2040623,\nand rs2106728. Three haplotypes were estimated to have a\nfrequency of [0.1 using Haploview. Haplotype 2 (TGA-\nGAT) was more frequently observed in patients, but not\nsignificantly so, with a difference in frequency between the\ncase and the control group of P\nc = 0.072 (Table 5).\nAlthough we evaluated whether all polymorphisms were\nalso associated with any of the four stage of endometriosis,\nwe found that all SNPs were not significantly associated\nwith stages I/II and III/IV of endometriosis. However, the\nfrequencies of the allele and the TT genotype in intron 10\n(rs2106728) of the AhR gene showed a significant associ-\nation with developing the severe stage (stage III/IV) of\nendometriosis without corrections for multiple testing\n(ESM Table 3a, P = 0.012 and 0.008, respectively). To\nassess the relationship between smoking and rs2106728,\nwe examined the allele and genotype frequencies of five\nsmoking patients and five smoking controls, or 29 non-\nsmoking patients and 29 non-smoking controls. Although\nno significant differences were found between the cases\nand controls in the smoking group, the frequencies of the\nallele and the TT genotype for rs2106728 showed a sig-\nnificant association in the non-smoking group without\ncorrections for multiple testing (ESM Table 3b, P = 0.016\nand 0.017, respectively).\nDiscussion\nThe aim of this pilot study, in which 100 cases and 143\ncontrols were enrolled, was to evaluate whether the poly-\nmorphisms and null mutations in the dioxin receptor, the\nregulatory factor, and the phase I/II drug-metabolizing\ngenes AhR, AHRR, ARNT, CYP1A1, CYP2E1, EPHX1,\nGSTM1, GSTP1, GSTT1, and NAT2 are associated with the\nsusceptibility of endometriosis. Our results indicate a fail-\nure to detect a significant association between polymor-\nphisms of dioxin detoxification genes and endometriosis in\nthis small number of subjects. However, the TT genotypes\nin intron 10 (rs2106728) of the AhR gene showed a prom-\ninent—but not significant—association with the risk of\ndeveloping endometriosis (Table 4, P\nc = 0.087), leading us\nto calculate the genetic power in this association study\n(ESM Table 4). The genetic power for significance at\nP = 0.05 is 0.505 and the number of cases required for\n80 % power is 192; moreover, the genetic power at\nP = 0.001 is 0.096 and number of cases required for 80 %\npower is 392. However, if genetic power is increased simply\nby increasing the number of subjects, the effect sizes in the\nrisk loci for complex diseases identified using the associa-\ntion study of genetic polymorphisms with a disease are\ntypically small. The problem could be overcome using a\nclassification by some risk factors, such as serum cytokines\nand growth factors and exposure of patients to dioxins,\nbecause some association of genetic polymorphisms of\nimmunological factors, cytokines and growth factors with\nendometriosis has been reported, in addition to higher levels\nof dioxin in peritoneal fluid [13, 14]. In addition, there have\nbeen two recent genome-wide association studies which\nhave demonstrated strong associations betweenCDKN2BAS\n(antisense non-coding RNA in the cyclin-dependent kinase\ninhibitor 2A locus), Wnt4, and an intergenic region\nupstream of the NFE2L3 and HOXA10 genes and endo-\nmetriosis [15, 16]. The CDKN2BAS and HOXA10 genes are\ninvolved in the regulation of cell growth and Wnt4 plays\na role in the development of the female genital tract.\nAlthough the ethnic populations in these two studies com-\nprised Japanese, Australia and UK populations, the asso-\nciation of Wnt4 with endometriosis in both studies was\nshown. This finding may suggest that the etiology of\nendometriosis is common between populations but that risk\nvariants are often population-specific.\nIn conclusion, we have genotyped five microsatellites,\n23 SNPs and two deletion markers in human dioxin\ndetoxification genes using 100 Japanese patients with\nendometriosis and 143 controls as pilot study. However,\nthere were no statistically significant differences in the\ngenotype or allele frequency distributions between the\ncases and controls. Overall, these results suggest that these\ngenetic variations analyzed in this study do not appear to\ncontribute to the development of endometriosis. However,\nadditional studies on different female populations are\nrequired to further confirm its role in the pathogenesis of\nendometriosis.\nTable 5 Association between AhR gene haplotypes and endometriosis\nHaplotype no. Haplotype Patients (%) Controls (%) P value Pc value\nHap1 TATACT 0.409 0.348 0.169 0.506\nHap2 TGAGAT 0.217 0.139 0.024 0.072\nHap3 GGAGAT 0.151 0.121 0.926 1.000\nHaplotypes with a frequency of \\0.1 were not included in the table. The P\nc value was corrected for three tests\n516 Environ Health Prev Med (2012) 17:512–517\n123\n\nAcknowledgments This study was partly supported by Health\nSciences Research grants from the Ministry of Health, Labor and\nWelfare of Japan. We thank the members of Teaching and Research\nSupport Center, Tokai University for DNA sequencing.\nConflict of interest None.\nReferences\n1. Bulun SE. Endometriosis. N Engl J Med. 2009;360:268–79.\n2. Giudice LC, Kao LC. Endometriosis. Lancet. 2004;364(9447):\n1789–99.\n3. 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