【摘要】：背景乙型肝炎病毒（Hepatitis B virus, HBV）感染的后果主要受病毒、宿主和環(huán)境三者影響。隨著人們對HBV認(rèn)識逐漸增多，宿主遺傳因素對HBV感染的后果的影響亦日漸受到人們的關(guān)注，其中細(xì)胞因子的基因多態(tài)性成為研究熱點。多項研究已證明細(xì)胞因子的基因多態(tài)性與HBV感染慢性化的關(guān)系密切。白介素4（Interleukin-4,IL-4）在調(diào)節(jié)T淋巴細(xì)胞亞群的動態(tài)平衡中起著關(guān)鍵的作用，而T淋巴細(xì)胞亞群失衡可影響人類對治療性疫苗的應(yīng)答及人類自身免疫性疾病的易感性。此外，IL-4可抑制γ干擾素（Interferon-γ,IFN-γ）和炎癥介質(zhì)的產(chǎn)生，從而防止炎癥對肝臟的損傷。亦有報道稱IL-4基因突變時，可能改變其表達(dá)及其下游信號，從而增加免疫相關(guān)性肝臟疾病的個人易感性。因此其單核苷酸多態(tài)性（singlenucleotide polymorphism, SNP）可能與慢性乙型肝炎(chronic hepatitis B,CHB)的發(fā)病及臨床不同轉(zhuǎn)歸相關(guān)。 目的研究IL-4rs2227284G/T、rs2243283C/G和rs2243288A/G位點SNP與中國漢族人群HBV感染慢性化的關(guān)系。 方法隨機入組501位慢性HBV患者作為病例組，301位急性自限性HBV感染者作為對照組。分別檢測病例組及對照組所有入組人員的IL-4基因rs2227284G/T、rs2243283C/G和rs2243288A/G三個位點的SNP，分析兩組間的等位基因頻率、單體型頻率、基因型是否存在差異；分析以上三個位點的不同遺傳模型是否存在統(tǒng)計學(xué)意義；計算以上三個位點的兩兩位點間的連鎖不平衡系數(shù)(D’)。我們所采用的是多重單堿基延伸SNP分型技術(shù)(Multiplex SNaPshot technique)。 結(jié)果 1．rs2227284位點3種基因型TT、GT、GG在病例組的分布頻率分別為74.3%、24.3%、1.4%,在對照組分別為76.1%、22.3%、1.6%; rs2243283位點3種基因型CG、CC、GG在病例組的分布頻率分別為33.1%、63.3%、3.6%,在對照組分別為30.2%、65.1%、4.7%; rs2243288位點3種基因型GG、GA、AA在病例組的分布頻率分別為65.1%、31.5%、3.4%,在對照組分別為66.4%、30.6%、3.0%。χ2檢驗結(jié)果顯示, IL-4基因以上3個位點各基因型在兩組間分布差異均無統(tǒng)計學(xué)意義（p值分別為：rs2227284，p=0.969; rs2243283, p=0.416; rs2243288p=0.685）。 2．統(tǒng)計分析顯示IL-4基因rs2227284位點的T等位基因在病例組及對照組的頻率分別為86.4%和87.2%；rs2227284位點的G等位基因在病例組及對照組的頻率分別在分別為13.6%和12.8%。rs2243283位點的C等位基因在病例組及對照組的頻率分別為79.8%和80.2%；rs2243283位點的G等位基因在病例組及對照組的頻率分別為20.2%和19.8%。rs2243288位點的G等位基因在病例組及對照組的頻率分別為80.8%和81.7%；rs2243288位點的A等位基因在病例組及對照組的頻率分別為19.2%和18.3%。結(jié)論：經(jīng)卡方檢驗，三個位點rs2227284、 rs2243283和rs2243288的等位基因頻率在病例組與對照組間均無統(tǒng)計學(xué)差異（P值分別為rs2227284，P=0.655，OR(95%CI)=1.071(0.793-1.445)；rs2243283，P=0.849，，OR(95%CI)=0.976(0.758-1.257)； rs2243288， P=0.659，OR(95%CI)=1.060(0.818-1.375)）。 3．病例組與對照組間加性模型、顯性模型和隱性模型三種不同的遺傳模型也顯示無統(tǒng)計學(xué)差異(rs2227284次要等位基因為G，加性模型、顯性模型和隱性模型的p值分別為0.771，0.563，0.766；rs2243283次要等位基因為G，加性模型、顯性模型和隱性模型的p值分別為0.571,0.599,0.071；rs2243288次要等位基因為A，加性模型、顯性模型和隱性模型的p值分別為0.902,0.691,0.555)。 4．結(jié)果顯示IL-4單體型頻率GCA、TCA、TCG及TGG在病例組分別為13.5%、5.4%、60.9%、19.8%；對照組分別為12.8%、5.5%、62.0%、19.7%。分析顯示無明顯的統(tǒng)計學(xué)意義。P值分別為GCA，P=0.670；TCA,P=0.989；TCG，P=0.733；TGG，P=0.950。 結(jié)論中國漢族人群中IL-4基因標(biāo)簽單核苷酸多態(tài)性(tag Single nucleotidepolymorphisms, tagSNPs) rs2227284，rs2243283和rs2243288可能與HBV感染的慢性化無關(guān)。
[Abstract]:BACKGROUND The consequences of hepatitis B virus (HBV) infection are mainly affected by virus, host and environment. With the increasing awareness of HBV, the influence of host genetic factors on the consequences of HBV infection has attracted more and more attention. Cytokine gene polymorphism has become a research hotspot. Interleukin-4 (IL-4) plays a key role in regulating the dynamic balance of T-lymphocyte subsets, and the imbalance of T-lymphocyte subsets can affect human response to therapeutic vaccines and susceptibility to human autoimmune diseases. Interferon-gamma (IFN-gamma) and inflammatory mediators are produced to prevent inflammation from damaging the liver. It has also been reported that mutations in the IL-4 gene may alter its expression and its downstream signals, thereby increasing individual susceptibility to immune-related liver diseases. Thus, its single nucleotide polymorphism (SNP) may be involved. It can be correlated with the incidence and clinical outcomes of chronic hepatitis B (CHB).
Objective To study the relationship between IL-4rs2227284G/T, rs2243283C/G and rs2243288A/G loci SNP and chronic HBV infection in Chinese Han population.
Methods 501 patients with chronic HBV were randomly divided into case group and 301 patients with acute self-limited HBV infection as control group. The linkage disequilibrium coefficients (D') between two or two loci of the above three loci were calculated.
Result
1. The distribution frequencies of TT, GT and GG genotypes at rs2227284 locus were 74.3%, 24.3% and 1.4% respectively in case group, 76.1%, 22.3% and 1.6% in control group, 33.1%, 63.3%, 3.6% in case group, 30.2%, 65.1%, 4.7% in control group, and 30.2%, 65.1%, GA, AA genotypes at rs2243288 locus, respectively. _2 test showed that there was no significant difference in the genotypes of the above three loci between the two groups (p value: rs2227284, P = 0.969; rs2243283, P = 0.416; rs2243288 P = 0.685).
2. Statistical analysis showed that the frequencies of T allele at rs2227284 locus of IL-4 gene were 86.4% and 87.2% respectively in case group and control group, the frequencies of G allele at rs2227284 locus were 13.6% and 12.8% respectively in case group and control group. The frequencies of C allele at rs2243283 locus were 79.8% and 8% respectively in case group and control group. The frequencies of G allele at rs2243283 locus were 20.2% and 19.8% in case group and control group, respectively. The frequencies of G allele at rs2243288 locus were 80.8% and 81.7% in case group and control group, and the frequencies of A allele at rs2243288 locus were 19.2% and 18.3% in case group and control group, respectively. The allele frequencies of rs2227284, rs2243283 and rs2243288 were not significantly different between the case group and the control group (P values were rs2227284, P = 0.655, OR (95% CI) = 1.071 (0.793-1.445), rs2243283, P = 0.849, OR (95% CI) = 0.976 (0.758-1.257), rs2243288, P = 0.659, OR (95% CI) = 1.060 (0.818) - 1.375).
3. There were no significant differences among the three genetic models of additive model, dominant model and recessive model between the case group and the control group (the P values of the secondary allele, additive model, dominant model and recessive model were 0.771, 0.563, 0.766 respectively; the secondary allele, additive model, dominant model and recessive model, rs2243283 were G, additive model, dominant model and recessive model, respectively). The P values of the model were 0.571, 0.599 and 0.071, and the secondary alleles of rs2243288 were A, additive model, dominant model and recessive model were 0.902, 0.691 and 0.555 respectively.
4. The results showed that the haplotype frequencies of IL-4 GCA, TCA, TCG and TGG were 13.5%, 5.4%, 60.9%, 19.8% in the case group, 12.8%, 5.5%, 62.0% and 19.7% in the control group, respectively.
Conclusion Tag Single nucleotide polymorphisms (tagSNPs) rs2227284, rs2243283 and rs2243288 may not be associated with the chronicity of HBV infection in Chinese Han population.
【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】：2014
【分類號】：R512.6

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