本文選題：系統(tǒng)性紅斑狼瘡 + 瘦素基因��； 參考：《安徽醫(yī)科大學(xué)》2017年碩士論文

【摘要】：研究背景系統(tǒng)性紅斑狼瘡(Systemic lupus erythematosus,SLE)是一種以產(chǎn)生大量自身抗體、累及多系統(tǒng)臟器、出現(xiàn)免疫復(fù)合物沉積為主要特征的結(jié)締組織疾病,同時也是一種系統(tǒng)性的自身免疫性疾病。該疾病不僅會影響血管壁、皮膚等組織,同時還會造成關(guān)節(jié)、腎臟、血液系統(tǒng)及神經(jīng)系統(tǒng)的改變。目前認(rèn)為在不同地區(qū)和不同種族間SLE的發(fā)病率存在一定的差異,且男女性別間SLE發(fā)病率也存在較大差異。SLE患者中90%以上為女性,發(fā)病年齡多集中在25~45歲,目前我國女性SLE發(fā)病率約為110/10萬,嚴(yán)重地影響了育齡期女性的身心健康。SLE的病因和發(fā)病機制至今尚未明確,可能是受遺傳因素和環(huán)境因素的雙重影響。瘦素是一種由瘦素基因(leptin gene,LEP)編碼產(chǎn)生的蛋白質(zhì),參與體內(nèi)多種免疫炎癥過程。瘦素可以通過與瘦素受體結(jié)合形成二聚體,激活JAK2/SATA3和mTOR信號通路從而影響免疫系統(tǒng)功能;瘦素也可以促進T細(xì)胞增殖,抑制T細(xì)胞凋亡,誘導(dǎo)白細(xì)胞介素1(interleukin 1,IL-1)、IL-6、腫瘤壞死因子α(tumor necrosis factorα,TNF-α)等多種細(xì)胞因子的表達,同時促進輔助T細(xì)胞向Th1細(xì)胞轉(zhuǎn)變,從而參與免疫調(diào)節(jié)過程。近期研究認(rèn)為瘦素基因、瘦素受體基因(leptin receptor gene,LEPR)多態(tài)性及瘦素的表達水平與SLE、類風(fēng)濕關(guān)節(jié)炎(rheumatoid arthritis,RA)等多種自身免疫性疾病的發(fā)生、發(fā)展存在關(guān)聯(lián)。目前,關(guān)于SLE患者體內(nèi)瘦素表達水平變化與疾病之間的關(guān)聯(lián)研究結(jié)果尚有爭議,且在中國漢族人群中開展的瘦素和瘦素受體基因多態(tài)性與SLE遺傳易感性的關(guān)聯(lián)研究非常有限。目的探討LEP和LEPR基因單核苷酸多態(tài)性(single nucleotide polymorphism,SNP)與中國漢族人群SLE患者遺傳易感性間的關(guān)聯(lián),分析LEP、LEPR基因相關(guān)snp與sle患者主要臨床表現(xiàn)之間的關(guān)聯(lián),并比較lep、lepr基因相關(guān)snp與sle患者血清瘦素表達水平的聯(lián)系。方法本課題采用病例對照研究方法,選取sle患者633例,來源于安徽醫(yī)科大學(xué)附屬省立醫(yī)院、安徽醫(yī)科大學(xué)第一附屬醫(yī)院和安慶市立醫(yī)院三家醫(yī)院風(fēng)濕免疫科的門診或住院患者,病例診斷依據(jù)美國風(fēng)濕病學(xué)會1997年修訂的sle分類標(biāo)準(zhǔn)。選取健康對照559例,來源于安徽醫(yī)科大學(xué)第一附屬醫(yī)院健康體檢中心健康體檢者。采用多重高溫連接酶檢測反應(yīng)技術(shù)(improvedmultipleligasedetectionreaction,imldr)進行基因分型檢測,對lep基因4個位點(rs11761556,rs12706832,rs2071045,rs2167270)以及l(fā)epr基因9個位點(rs10749754,rs1137100,rs1137101,rs13306519,rs1805094,rs1805096,rs3790434,rs3806318,rs7518632)的單核苷酸多態(tài)性進行分析。采用酶聯(lián)免疫吸附試驗(enzymelinkedimmunosorbentassay,elisa)測定sle患者血清瘦素表達水平。結(jié)果瘦素及瘦素受體基因的13個多態(tài)性位點的基因型頻率及等位基因頻率在sle患者與健康對照之間的差異均無統(tǒng)計學(xué)意義(均有p0.05),調(diào)整性別和年齡后發(fā)現(xiàn)leprrs1137100位點基因型頻率分布在兩組間的差異存在統(tǒng)計學(xué)意義(ggvs.aa:χ2=3.904,p=0.048,or=1.948,95%ci:1.005-3.776)。同時,進一步分析了顯性模型、隱性模型和相加模型等遺傳模型在病例組與對照組之間的分布,兩者之間的分布差異也均無統(tǒng)計學(xué)意義(均有p0.05)。調(diào)整性別和年齡后發(fā)現(xiàn)leprrs1137100位點的隱性模型及相加模型在兩組間的差異分布存在統(tǒng)計學(xué)意義(ga+ggvs.aa:χ2=4.365,p=0.037,or=0.496,95%ci:0.257-0.958;ggvs.aa:χ2=3.871,p=0.049,or=0.514,95%ci:0.265-0.997)。對基因多態(tài)性與臨床表現(xiàn)之間的關(guān)聯(lián)分析發(fā)現(xiàn),lep基因rs2071045位點在伴有心包炎的sle患者中,其tt基因型頻率及t等位基因頻率高于未伴有心包炎的sle患者(χ2=8.811,p=0.012;χ2=6.432,p=0.011)。rs11761556位點等位基因頻率與sle患者是否伴隨顴部紅斑之間存在統(tǒng)計學(xué)關(guān)聯(lián)(χ2=4.067,p=0.044)。lepr基因rs3806318位點基因型及等位基因頻率分布與sle患者是否伴有光敏感之間具有統(tǒng)計學(xué)關(guān)聯(lián),sle同時伴有光敏感者其gg和ga基因型頻率以及G等位基因頻率高于SLE未伴有光敏感者(χ2=8.693,P=0.013;χ2=6.948,P=0.008)。同時,該位點基因型頻率還與SLE患者中關(guān)節(jié)炎的發(fā)生存在統(tǒng)計學(xué)關(guān)聯(lián)(χ2=6.204,P=0.045)。另外,在SLE合并光敏感的患者中,rs1137100位點AA和GA基因型頻率及A等位基因頻率高于未合并光敏感的患者(χ2=6.272,P=0.043;χ2=5.609,P=0.018)。單倍型分析發(fā)現(xiàn),LEPR基因的9個位點構(gòu)建的單倍型中,SLE病例組ACGCAGCAA單倍型頻率低于對照組(χ2=9.038,P=0.003,OR=0.745,95%CI:0.615-0.903);而ATGCAGCAA單倍型結(jié)構(gòu)在SLE病例組中的頻率高于健康對照組(χ2=4.327,P=0.038,OR=1.390,95%CI:1.018-1.897)。SLE患者的瘦素血清表達水平與13個位點單核苷酸多態(tài)性之間均無統(tǒng)計學(xué)關(guān)聯(lián)(均有P0.05)。結(jié)論瘦素和瘦素受體基因的13個位點SNP與SLE遺傳易感性無統(tǒng)計學(xué)關(guān)聯(lián),但調(diào)整性別、年齡后發(fā)現(xiàn)LEPR rs1137100位點基因型頻率在兩組中分布存在差異,且SLE患者不同瘦素和瘦素受體基因型下的的血清瘦素表達水平差異無統(tǒng)計學(xué)意義,但部分位點SNP可能與該疾病的某些臨床表型有關(guān)。
[Abstract]:Background systemic lupus erythematosus (Systemic lupus erythematosus) is a kind of connective tissue disease characterized by the production of a large number of autoantibodies, involving multiple system organs and the deposition of immune complex. It is also a systemic autoimmune disease. The disease not only affects the blood vessel wall, skin and other tissues, but also the disease. There are also changes in the joint, kidney, blood system and nervous system. At present, there is a certain difference in the incidence of SLE between different regions and different races, and the incidence of SLE among men and women is also significantly different. More than 90% of the.SLE patients are women, the age of onset is at the age of 25~45, and the incidence of SLE in Chinese women is about 11. 0/10 million, seriously affecting the physical and mental health of women of childbearing age, the etiology and pathogenesis of.SLE is not yet clear. It may be affected by both genetic and environmental factors. Leptin is a protein encoded by the leptin gene (LEP) and participates in a variety of immune inflammatory processes in the body. Leptin can be affected by leptin. Body combination forms two polymer and activates JAK2/SATA3 and mTOR signaling pathways that affect the function of the immune system, and leptin can also promote the proliferation of T cells, inhibit the apoptosis of T cells, induce the expression of interleukin 1 (interleukin 1, IL-1), IL-6, tumor necrosis factor alpha (tumor necrosis factor A, TNF- alpha) and so on, and promote the auxiliary T thin. In recent studies, the expression of leptin gene, leptin receptor gene (leptin receptor gene, LEPR) and the expression level of leptin are associated with the development of many autoimmune diseases such as SLE, rheumatoid arthritis (rheumatoid arthritis, RA) and other autoimmune diseases. There is a relationship between the development of the leptin gene and leptin receptor gene (rheumatoid arthritis, RA) and other autoimmune diseases. Currently, it is related to the body of SLE patients. The correlation between leptin expression level and disease is controversial, and the association of leptin and leptin receptor gene polymorphism with SLE genetic susceptibility in Chinese Han population is very limited. The purpose of this study is to explore the single nucleotide polymorphisms of LEP and LEPR genes (single nucleotide polymorphism, SNP) and Chinese Han people Association of genetic susceptibility to group SLE patients, analysis of the association between LEP, LEPR gene related SNP and the main clinical manifestations of SLE patients, and compare the relationship between LEP, LEPR gene related SNP and the level of serum leptin expression in SLE patients. Methods a case control study was used to select 633 cases of SLE patients, from the affiliated province of Medical University Of Anhui. The hospital, the First Affiliated Hospital of Medical University Of Anhui and the three hospitals of the Department of Rheumatology in the Department of Rheumatology, three hospitals and hospitalized patients, were diagnosed according to the SLE classification standard revised by the American rheumatology society in 1997. 559 healthy controls were selected from the health checkup in the health check-up center of the First Affiliated Hospital of Medical University Of Anhui. Improvedmultipleligasedetectionreaction (imldr) was used to detect the genotyping of the 4 loci of the LEP gene (rs11761556, rs12706832, rs2071045, rs2167270) and the 9 loci of the LEPR gene. The single nucleotide polymorphisms were analyzed. The serum leptin expression level in SLE patients was measured by enzymelinkedimmunosorbentassay (ELISA). The genotype frequencies and allele frequencies of 13 polymorphic loci of leptin and leptin receptor genes were not statistically significant between SLE patients and healthy controls. Meaning (all P0.05), after adjusting sex and age, it was found that the difference in the frequency distribution of leprrs1137100 loci in the two groups was statistically significant (ggvs.aa: x 2=3.904, p=0.048, or=1.948,95%ci:1.005-3.776). Meanwhile, the genetic models of dominant, recessive and additive models were further analyzed between the case group and the control group. There was no statistical significance (all P0.05) in the distribution difference between the two groups. The difference distribution between the two groups was statistically significant (ga+ggvs.aa: x 2=4.365, p=0.037, or=0.496,95%ci:0.257-0.958, ggvs.aa: Chi 2=3.871, p=0.049, or=0.514,95%ci) after adjusting the sex and age of the leprrs1137100 site. 0.265-0.997. Analysis of the association between gene polymorphism and clinical manifestations found that the frequency of the TT genotype frequency and T allele frequencies of the LEP gene rs2071045 locus in the SLE patients with pericarditis were higher than those of the SLE patients without pericarditis (x 2=8.811, p=0.012; Chi 2=6.432, p=0.011) allele frequencies with those of the patients. There was a statistical correlation between the zygomatic erythema (x 2=4.067, p=0.044).Lepr gene rs3806318 genotype and the allele frequency distribution with the light sensitivity of SLE patients. The frequencies of GG and GA genotype and G allele frequencies of SLE and G alleles were higher than those of SLE without photosensitivity ( X 2=8.693, P=0.013; X 2=6.948, P=0.008). At the same time, the genotype frequency of this loci was also associated with the occurrence of arthritis in SLE patients (x 2=6.204, P=0.045). In addition, the frequency of AA and GA genotypes and A alleles at rs1137100 loci were higher in patients with SLE with light sensitivity than those without light sensitivity. 2=5.609, P=0.018). The haplotype analysis found that in the haplotype of the 9 loci of LEPR gene, the frequency of ACGCAGCAA haplotype in SLE case group was lower than that of the control group (x 2=9.038, P=0.003, OR=0.745,95%CI:0.615-0.903), and the frequency of ATGCAGCAA haplotype in SLE case group was higher than that of the healthy control group (x 2=4.327, P=0.038, etc.) 897) there was no statistical correlation between the serum level of leptin in.SLE patients and the single nucleotide polymorphisms of the 13 loci (all P0.05). Conclusion the 13 loci of leptin and leptin receptor gene SNP were not associated with the genetic susceptibility to SLE, but the genotype frequencies of the LEPR rs1137100 loci were found to be distributed in the two groups after the adjustment of sex. There is no significant difference in the level of serum leptin expression in SLE patients with leptin and leptin receptor genotypes, but some of the site SNP may be related to some clinical phenotypes of the disease.
【學(xué)位授予單位】：安徽醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R593.241

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