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A Study of the Association between the Polymorphisms of Immunity Related Genes and the Susceptibility to Endometriosis in Southern Chinese Han Women

Author: MaoZuo
Tutor: ZongLiLi
School: Southern Medical University,
Course: Obstetrics and Gynaecology
Keywords: endometriosis interleukin-6 tumor necrosis factor-alpha α2-Heremans-Schmidt glycoprotein transforming growthfactor-β1 interleukin-2receptor β single nucleotide polymorphism High Resolution Melting
CLC: R711.71
Type: Master's thesis
Year: 2012
Downloads: 30
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Abstract


BackgroundEndometriosis (Ems), a major contributor to pelvic pain, abnormal menstruation and sub fertility, is a common gynecological disease characterized by implantation of endometrial tissue outside of the uterus. It affects10%to15%of women in their reproductive years with a growing trend in recent years. Moreover, there is still no specific methods of Ems in clinical treatment. The most common symptoms of Ems are dysmenorrhea, chronic pelvic pain and infertility, which affect health both physically and mentally and reduce the quality of life seriously. Although it is a kind of common gynecologic disease, the patho genesis of Ems is still controversial. As early as1921Sampson proposed the theory of menstrual blood reflux and endometrial planting. Many theories have also been developed since then, such as theory of epithelial metaplasia, Mullerian tube remnants, immunity, distant dissemination by lymph and blood vessels, genetics and harmful pathogenic substances. But these theories are still difficult to illuminate clearly the patho genes is of Ems. The theory of the menstrual blood reflux and endometrial planting is dominant among these ideas. However, it is doubtful that it’s well established that menstrual debris is present in the peritoneal cavity of90%of menstruating women, but only10%-15%of them suffer ectopic endometrial implants. In recent years some scholars have pointed a "theory of eutopic endometrium determinism", namely the biological characteristics of eutopic endometrium of Ems patients make it stronger abilities of adhesion, invasion and angiogenesis. This inherent difference is the determinant pathogenesis of Ems. Immunological reaction and local micro-environment are only additional factors or secondary exhibition or condition affecting endometrium. Based on views above, it is generally considered that susceptibility to Ems is a consequence of genetic predisposition. As early as1997, Kennedy had pointed out that "It is likely that Ems is a common multifactorial disease, like diabetes and asthma, caused by an interaction between multiple gene loci and the environment. Such conditions don’t have a clear Mendelian pattern of inheritance." Disease association studies have found that multiple gene loci are associated with genetic susceptibility to Ems. The variation of multiple gene loci likely plays synergistic role in the occurrence and development of Ems. One of the most common genetic variations in human is single nucleotide polymorphism (SNP) that can lead to individual susceptible to disease differently. Gene polymorphism may determine individual susceptibility and risk to Ems by change in the activity of gene transcription or abnormal expression of proteins.Clinically and pathologically, Ems appears to be an inflammatory process, and the growth of endometriotic lesion depends on specific immune micro-environment of the peritoneal fluid. In clinical epidemiology and fundamental studies, it is discovered that Ems is closely related to abnormal immune regulation. At present, most of studies on association between polymorphisms of genes and genetic susceptibility to Ems are focused on immunity factors such as interleukin-6(IL-6), tumor necrosis factor-alpha (TNF-α), α2-Heremans-Schmidt glycoprotein (AHSG), transforming growthfactor-β1(TGF-β1)and interleukin-2receptor β (IL-2Rβ). Several literatures, home and abroad, reveal that studies on these polymorphisms of immunity related genes and genetic susceptibility to Ems are focused on-174G/C site of IL-6gene,-308G/Asite of TNF-α gene, Sac I site in the seventh extron of AHSG gene and AHSG2gene,-509T/C site of TGF-β1gene and-627C/T site of IL-2Rβ gene. Genetic backgrounds of different ethnic populations lead to different research results. Overseas there are reports of researches on following5gene loci: IL-6-634C/G (rs1800796), TNF-α-1031T/C (rs1799964), AHSG6826C/T (rs4917), TGF-β1-509T/C (rs1800469) and IL-2Rβ-627C/T (rs228953), and results of these studies suggest that these5gene loci maybe the relevant susceptibility genes to Ems. But in China especially for southern Chinese Han population, there is still no report of research on these5gene loci. Therefore, this study is mainly focused on the associations between the polymorphisms of these5gene loci and their combination of gene polymorphisms and the genetic susceptibility to Ems.ObjectiveThis study is mainly focused on the associations between the polymorphisms of immunity related genes (IL-6-634C/G, TNF-α-1031T/C, AHSG6826C/T, TGF-β1-509T/C and IL-2Rβ-627C/T) and their combination of gene polymorphisms and the genetic susceptibility to Ems in southern Chinese Han women.Objects and Methods1. Objects of study All objects of study were patients who received an abdominal and pelvic surgery in department of Obstetrics and Gynecology of Nanfang Hospital, Zhujiang Hospital and Foshan First People’s Hospital from October2008to April2010. Total of434Ems patients and502non-Ems controls who had received an operation due to tubal ligation, tubalrecanalization, laparoscopic hydrotubation, ovarian simple cyst and teratoma were collected and separated into Ems and control groups respectively. All cases were confirmed by operation and pathology. There is no significant difference between the two groups of subjects with age (t=1.016, P=0.310). All subjects didn’t have family history of Ems, other family history of genetic disease and cancer history. There were no genetic relationship between the object of study, and all of them were informed consent.2. Specimen collection For every subject in the third day after operation,2ml peripheral venous blood is drawn, saved by Sodium Citrate, and stored at-20℃.3. DNA extraction DNA is extracted from peripheral blood following the instructions of E.Z.N.A.E-Z96Blood DNA kit.4. SNP genotyping The SNPs of genes are determined by using a fluorescent quantitative PCR-based HRM method.5. Statistics and analysis methods Gene frequency distributions of each group are calculated by the direct counting method. The statistical datas are processed by SPSS13.0. For distributions of population gene frequency, Chi-square test is used to determine the fitness of Hardy-Weiberg equilibrium. Chi-square test is used to examine the associations between Ems and the polymorphisms of different genotypes respectively. Comparison of allele and genotype frequencies in two groups are examined via Chi-square test (a=0.05). Relative risk is described by the odds ratio (OR) and95%confidence interval (95%CI). A case-control study is performed to evaluate the association of these SNPs with the genetic susceptibility to Ems.Results1. Distribution of age in two groups The average age is35.4±7.9years in the Ems group (21patient’s age data lost), and the average age is34.9±4.5years in the control group. There is no significant difference between the two groups of subjects with age (t=1.016, P=0.310).2. Distributions of gene polymorphisms in two groups It shows SNP distributions in IL-6-634C/G, TNF-α-1031T/C, AHSG6826C/T, TGF-β1-509T/C and IL-2RP-627C/T sites in southern Chinese Han women. And the gene frequency distributions of4SNP sites (IL-6-634C/G,TNF-α-1031T/C, AHSG6826C/T and TGF-β1-509T/C) in the control group fit Hardy-Weinberg equilibrium (χ2=0.075, P=0.784; χ2=0.229, P=0.632; χ2=1.875, P=0.171and χ2=2.176, P=0.140, respectively). The control group, as a whole, demonstrates to be a representative sample of population. However the distribution of IL-2Rβ-627C/T site departs from Hardy-Weinberg equilibrium both in the Ems and control groups (χ2=43.579, P=4.071×10-11and χ2=85.824, P=1.967×10-20, respectively).3. Single gene polymorphism and the genetic susceptibility to Ems3.1Distributions ofIL-6-634C/G gene in two groups The C and G of TNF-α-1031T/C allele frequencies among the Ems and control groups were78.6%,21.4%and74.3%,25.7%, respectively. The CC, CG and GG of IL-6-634C/G genotype frequencies among the two groups were63.4%,30.3%,6.3%and55.5%,37.7%,6.8%, respectively. There were statistical significances in IL-6-634C/G alleles and genotypes distributions between the two groups (χ2=4.604, P=0.032and χ2=6.215, P=0.045, respectively). Allele C enhanced the risk of Ems1.057times (95%CI was1.005~1.112) while allele G reduced the risk of Ems0.835time (95%CI was0.707~0.985); Compared with genotype CC, the risk of Ems with genotype CG reduced0.704time (95%CI was0.533~0.931).3.2Distributions ofTNF-α-1031T/C gene in two groups The Tand C of TNF-a-1031T/C allele frequencies among the Ems and control groups were79.2%,20.8%and81.8%,18.2%, respectively. The TT, TC and CC of TNF-α-1031T/C genotype frequencies among the two groups were63.7%,31.0%,5.3%and66.5%,30.5%,3.0%, respectively. There were no statistical significances in TNF-α-1031T/C alleles and genotypes distributions between the two groups (χ2=1.994, P=0.158and χ2=3.365, P=0.186, respectively).3.3Distributions of AHSG6826C/T gene in two groups The C and T of AHSG6826C/T allele frequencies among the Ems and control groups were79.1%,20.9%and74.3%,25.7%, respectively. The CC, CT and TT of AHSG6826C/T genotype frequencies among the two groups were62.0%,34.0%,4.0%and54.1%,40.5%,5.4%, respectively. There were statistical significances in AHSG6826C/T alleles and genotypes distributions between the two groups (χ2=5.701, P=0.017and χ2=6.158, P=0.046, respectively). Allele C enhanced the risk of Ems1.063times (95%CI was1.011~1.118) while allele T reduced the risk of Ems0.817time (95%CI was0.691~0.965); Compared with genotype CC, the risk of Ems with genotype CT reduced0.733time (95%CI was0.559-0.962).3.4Distributions of TGF-β1-509T/C gene in two groups The T and C of TGF-β1-509T/C allele frequencies among the Ems and control groups were58.4%,41.6%and56.1%,43.9%, respectively. The TT, TC and CC of TGF-β1-509T/C genotype frequencies among the two groups were33.8%,49.3%,16.9%and29.9%,52.5%,17.6%, respectively. There were no statistical significances in TGF-β1-509T/C alleles and genotypes distributions between the two groups (χ2=1.033, P=0.309and χ2=1.670, P=0.434, respectively).3.5Distributions of IL-2R(3-627C/T gene in two groups The C and T of IL-2Rβ-627C/T allele frequencies among the Ems and control groups were51.5%,48.5%and52.0%,48.0%, respectively. The CC, CT and TT of IL-2Rβ-627C/T genotype frequencies among the two groups were34.5%,34.0%,31.5%and37.4%,29.2%,33.4%, respectively. There were no statistical significances in IL-2Rβ-627C/T alleles and genotypes distributions between the two groups (χ2=0.046, P=0.831and χ2=2.540, P=0.281, respectively).4. Combination of gene polymorphisms and the genetic susceptibility to Ems4.1Distributions ofTNF-a-1031T/C and IL-6-634C/G combination genotype The TT+CC, TC+CC, CC+CC, TT+CQ TC+CG,CC+CQ TT+GQ TC+GG and CC+GG combination genotype frequencies among the two groups were39.4%,19.4%,4.6%,20.6%,8.8%,0.9%,3.5%,2.3%,0.5%and36.7%,17.4%,1.4%,26.1%,10.4%,1.2%,3.8%,2.6%,0.4%, respectively. There were no statistical significances in the combination genotype distributions between the two groups (χ2=13.153, P=0.107). As compared with carriers of TT+CC combination genotype, the Ems risk of carriers of other combination genotypes were no statistical significances (all P’>0.05).4.2Distributions of AHSG6826C/T and IL-6-634C/G combination genotype The CC+CC, CT+CC, TT+CC, CC+CQ CT+CQ TT+CQ CC+GG,CT+GG and TT+GG combination genotype frequencies among the two groups were40.3%,20.6%,2.5%,17.8%,11.1%,1.4%,3.9%,2.3%,0.0%and29.7%,22.4%,3.4%,20.4%,15.2%,2.0%,4.0%,2.8%,0.0%, respectively. There were no statistical significances in the combination genotype distributions between the two groups (χ2=12.987, P=0.072). As compared with carriers of CC+CC combination genotype, the Ems risk of carriers of CT+CG combination genotype reduced0.537time (95%CI was0.352~0.820, P’=0.028), and the Ems risk of carriers of other combination genotypes were no statistical significances (all P’>0.05).4.3Distributions of TGF-β1-509T/C and IL-6-634C/G combination genotype The TT+CC, TC+CC, CC+CC, TT+CG,TC+CG,CC+CG,TT+GG,TC+GG and CC+GG combination genotype frequencies among the two groups were20.4%,33.6%,9.7%,11.6%,13.0%,5.6%,1.9%,2.8%,1.6%and17.2%,28.5%,9.8%, 10.2%,20.8%,6.6%,2.4%,3.2%,1.2%, respectively. There were no statistical significances in the combination genotype distributions between the two groups (χ2=13.118, P=0.108). As compared with carriers of TT+CC combination genotype, the Ems risk of carriers of TC+CG combination genotype reduced0.526time (95%CI was0.339~0.817, P’=0.032), and the Ems risk of carriers of other combination genotypes were no statistical significances (all P’>0.05).4.4Distributions ofIL-2Rβ-627C/T and IL-6-634C/G combination genotype The CC+CC, CT+CC, TT+CC, CC+CG,CT+CG, TT+CG,CC+GG,CT+GG and TT+GG combination genotype frequencies among the two groups were20.7%,21.7%,20.7%,10.7%,10.7%,9.1%,3.0%,1.6%,1.6%and19.9%,16.7%,18.9%,14.7%,10.5%,12.9%,2.8%,2.0%,1.6%, respectively. There were no statistical significances in the combination genotype distributions between the two groups (χ2=9.489, P=0.303). As compared with carriers of CC+CC combination genotype, the Ems risk of carriers of other combination genotypes were no statistical significances (all P’>0.05).4.5Distributions of AHSG6826C/T and TNF-a-1031T/C combination genotype The CC+TT, CT+TT, TT+TT, CC+TC, CT+TC, TT+TC, CC+CC, CT+CC and TT+CC combination genotype frequencies among the two groups were38.2%,22.7%,2.8%,20.1%,9.7%,1.2%,3.7%,1.6%,0.0%and35.7%,26.9%,4.0%,16.6%,12.8%,1.0%,1.8%,0.8%,0.2%, respectively. There were no statistical significances in the combination genotype distributions between the two groups (χ2=12.762, P=0.120). As compared with carriers of CC+TT combination genotype, the Ems risk of carriers of other combination genotypes were no statistical significances (all P’>0.05).4.6Distributions of TGF-β1-509T/C and TNF-α-1031T/C combination genotype The TT+TT, TC+TT, CC+TT, TT+TC, TC+TC, CC+TC, TT+CC, TC+CC and CC+CC combination genotype frequencies among the two groups were23.8%,31.0%,8.8%,8.1%,15.0%,7.9%,1.9%,3.2%,0.2%and19.6%,34.5%,12.4%,10.0%,15.8%,4.6%,0.2%,2.2%,0.6%, respectively. There were statistical significances in the combination genotype distributions between the two groups (χ2=18.814, P=0.012). As compared with carriers of TT+TT combination genotype, the Ems risk of carriers of other combination genotypes were no statistical significances (all P’>0.05).4.7Distributions of IL-2Rβ-627C/T and TNF-a-1031T/C combination genotype The CC+TT, CT+TT, TT+TT, CC+TC, CT+TC, TT+TC, CC+CC, CT+CC and TT+CC combination genotype frequencies among the two groups were21.0%,22.4%,20.3%,12.8%,8.4%,9.8%,0.7%,3.3%,1.4%and24.0%,19.0%,23.8%,11.3%,9.9%,9.1%,2.2%,0.2%,0.6%, respectively. There were statistical significances in the combination genotype distributions between the two groups (χ2=22.939, P=0.001). As compared with carriers of CC+TT combination genotype, the Ems risk of carriers of CT+CC combination genotype enhanced18.511times (95%CI was2.390-143.383, P’=0.000), and the Ems risk of carriers of other combination genotypes were no statistical significances (all P’>0.05).4.8Distributions of TGF-β1-509T/C and AHSG6826C/T combination genotype The TT+CC, TC+CC, CC+CC, TT+CT, TC+CT, CC+CT, TT+TT, TC+TT and CC+TT combination genotype frequencies among the two groups were19.4%,31.5%,1.1%,13.9%,16.0%,4.2%,0.5%,1.9%,1.6%and15.8%,30.9%,7.4%,13.4%,18.2%,8.8%,0.6%,3.4%,1.4%, respectively. There were statistical significances in the combination genotype distributions between the two groups (χ2=15.708, P=0.042). As compared with carriers of TT+CC combination genotype, the Ems risk of carriers of CC+CT combination genotype reduced0.385time (95%CI was0.205~0.721, P’=0.016), and the Ems risk of carriers of other combination genotypes were no statistical significances (all P’>0.05).4.9Distributions of TGF-β1-509T/C and IL-2Rβ-627C/T combination genotype The TT+CC, TC+CC, CC+CC, TT+CT, TC+CT, CC+CT, TT+TT, TC+TT and CC+TT combination genotype frequencies among the two groups were12.8%,16.3%,5.4%,10.5%,17.5%,6.1%,10.5%,15.4%,5.6%and12.1%,18.1%,7.2%,9.5%,15.1%,4.6%,8.5%,19.1%,5.8%, respectively. There were no statistical significances in the combination genotype distributions between the two groups (χ2=6.650, P=0.575). As compared with carriers of TT+CC combination genotype, the Ems risk of carriers of other combination genotypes were no statistical significances (all P’>0.05).4.10Distributions of IL-2Rβ-627C/T and AHSG6826C/T combination genotype The CC+CC, CT+CC, TT+CC, CC+CT, CT+CT, TT+CT, CC+TT, CT+TT and TT+TT combination genotype frequencies among the two groups were19.6%,22.1%,20.5%,13.3%,10.5%,10.0%,1.6%,1.4%,0.9%and18.8%,14.7%,20.4%,16.5%,12.7%,11.5%,2.2%,1.6%,1.6%, respectively. There were no statistical significances in the combination genotype distributions between the two groups (χ2=11.404, P=0.180). As compared with carriers of CC+CC combination genotype, the Ems risk of carriers of other combination genotypes were no statistical significances (all P’>0.05).Conclusion1. The study suggests there are significant associations between genetic susceptibility to Ems and the polymorphisms of IL-6-634C/G and AHSG6826C/T separately, whereas there aren’t significant associations between genetic susceptibility to Ems and the polymorphisms of TNF-α-1031T/C, TGF-β1-509T/C and IL-2Rβ-627C/T seperately in southern Chinese Han women.2. The results indicate that there are significant associations between genetic susceptibility to Ems and the combination polymorphisins ofTGF-β1-509T/C&TNF-α-1031T/C,IL-2Rp-627C/T&TNF-α-1031T/C,TGF-β1-509T/C&AHSG6826C/T,AHSG6826C/T&IL-6-634C/G and TGF-β1-509T/C&IL-6-634C/G, whereas there aren’t significant associations between genetic susceptibility to Ems and the combinationpolymorphisms of TNF-α-1031T/C&IL-6-634C/G, IL-2Rβ一627C/T&IL-6-634C/G,AHSG6826C/T&TNF-α-1031T/C, TGF/β1-509T/C&IL-2Rβ一627C/T and IL-2Rβ-627C/T&AHSG6826C/T in southern Chinese Han women.3. The risk of developing Ems may increase for individual of combined genotypes. Because Ems is a genetic disease which is multiple gene loci associated.

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CLC: > Medicine, health > Obstetrics and Gynaecology > Gynecology > Other diseases of the female genital > Endometriosis
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