【作者】 贺小峰；

【导师】 俞守义；

【作者基本信息】 南方医科大学 ， 流行病学与卫生统计学， 2011， 硕士

【摘要】 1.研究背景HIV-1辅助受体CCR5,SDF和CCR2与HIV-1病毒感染和感染后疾病的进展密切相关,目前,国内外已有许多研究关注CCR5Δ32、CCR2-64I、SDF1-3’A基因的多态性与HIV-1感染相关性的文章,但由于人群间疾病的异质性、单个研究样本量不足、研究设计、种族、实验方法等因素的影响,使得CCR5Δ32、CCR2-64I、SDF1-3’A基因的多态性与HIV-1感染相关性的研究存在较大的争议。为了减少研究间的偏倚、提高统计效力,本次研究运用Meta分析的方法对以往的研究结果进行综合定量评价,观察CCR5Δ32、CCR2-64I、SDF-1基因多态性与HIV-1感染的相关性。2.研究目的2.1.探讨人群中CCR5Δ32基因的多态性与HIV-1病毒感染的相关性2.2.探讨人群中SDF1-3’A基因的多态性与HIV-1病毒感染的相关性2.3.探讨人群中CCR2-64I基因的多态性与HIV-1病毒感染的相关性3.研究方法3.1.纳入标准：(1)研究对象：HIV-1病毒感染者和健康对照个体的CCR5Δ32、CCR2-64I、SDF1-3’A基因的多态性；(2)病例对照研究；(3)观察指标：CCR5Δ32、CCR2-64I、SDF1-3’A基因型的分布频数；(5)基因型分布在对照群体中符合Hardy—Weinberg平衡(HWE)；(6)在文章中如果报道了对两个不同人群研究的研究结果,每个人群将视为一个单独的研究报道,纳入Meta分析中；(7)HIV-1感染者均未经过抗HIV-1逆转录病毒治疗,如果经过治疗,则该文献不被纳入。3.2.排除标准：(1)不能提供完整的四格表资料,或通过计算仍无法得到相应的四格表资料(2)研究数据描述不清(3)数据重复报道的取其中的一篇3.3.检索策略：利用PUBMED搜索1990.1-2010.8相关文献,其语言限制为英语和汉语。检索词："CCR5"、"CCR2"、"SDF"、"polymorphism"和“HIV-1”。3.4.数据采集及分析：仔细阅读所纳入的文献,收集并分析相关数据,利用STATA9.0软件进行Meta分析。4.结果4.1.检索结果：最终符合纳入标准的共34个研究。其中符合CCR5Δ32纳入标准的共29个研究,排除一篇对照组不符合HWE规律的文献,共纳入28个研究进行CCR5Δ32的Meta分析；符合CCR2-64I纳入标准的共18个研究,排除两篇对照组不符合HWE规律的文献,共纳入16个研究进行CCR2-64I的Meta分析；符合SDF1-3’A纳入标准的文献18个研究,排除两篇对照组不符合HWE遗传规律的文献,共纳入16个研究进行SDF1-3’A的Meta分析。4.2.纳入研究特征4.2.1 CCR5Δ32:纳入28个研究,总共有6159个样本,HIV-1感染者和健康对照组分别为2718个和3441个。4.2.2 CCR2-64I:纳入16个研究,共4459例,其中HIV-1感染者共2191例,对照组共2268例。4.2.3 SDF1-3’A:纳入16个研究,共4165例,其中HIV-1感染者共1953例,对照组共2212例。4.3.Meta分析结果4.3.1 CCR5Δ32:纯合子YY和杂合子CY(YY+CY)与野生基因型(CC)的比较,合并的总的OR=1.12(95% CI:0.87-1.44,P=0.382)；杂合子(CY)与野生基因型(CC)的比较,合并的OR=1.12(95% CI:0.94-1.32,P=0.193)；纯合子YY与野生基因型(CC)的比较,合并的OR=0.81(95% CI:0.45-1.43, P=0.464).分层分析中,HIV-1感染长期不进展者(LNTP)的Meta分析结果为：纯合子YY和杂合子CY(YY+CY)与野生基因型(CC)的比较,合并的OR=2.09(95% CI=1.42-3.09,P=0.000)；杂合子CY与野生基因型CC的比较,合并的OR=2.12,95% CI=1.44-3.13,P=0.000).4.3.2 CCR2-64I:纯合子YY和杂合子CY(YY+CY)与野生基因型(CC)的比较,合并的总的OR=0.97(95% CI:0.84-1.11.P=0.662)；杂合子(CY)与野生基因型(CC)的比较,合并的OR=0.95(95% CI:0.82-1.09,P=0.453)；纯合子YY与野生基因型(CC)的比较,合并的OR=1.21 (95% CI:0.84-1.74, P=0.296).4.3.3 SDF1.3’A:纯合子YY和杂合子CY(YY+CY)与野生基因型(CC)的比较,合并的总的OR=0.83(95% CI:0.67-1.03,P=0.090)；杂合子(CY)与野生基因型(CC)的比较,合并的OR=0.86(95% CI:0.70-1.06,P=0.151)；纯合子YY与野生基因型(CC)的比较,合并的OR=0.79(95% CI:0.50-1.26, P=0.322).分层分析中白种人的Meta分析结果为：纯合子YY和杂合子CY (YY+CY)与野生基因型(CC)的比较,合并的OR=0.95(95%CI=0.66-1.35,P =0.982);杂合子CY与野生基因型CC的比较,合并的OR=0.87,95%CI=0.60-1.26,P=0.991)；纯合子YY与野生基因型(CC)的比较,合并的OR=1.87(95% CI:0.80-4.38,P=0.152).中国人群的Meta分析结果为：纯合子YY和杂合子CY(YY+CY)与野生基因型(CC)的比较,合并的OR=1.00(95%CI=0.80-1.25, P=0.992)；杂合子CY与野生基因型CC的比较,合并的OR=0.96,95%CI=0.76-1.21,P=0.713)；纯合子YY与野生基因型(CC)的比较,合并的OR=1.12(95%CI:0.85-1.74, P=0.282)。4.4发表偏倚分析：通过Begg秩相关法、Egger直线回归法和Begg’s漏斗图法判断发表偏倚,利用stata9.0软件进行统计分析,结果显示没有统计学意义,说明所纳入的研究没有发表偏倚。5.结论：本次Meta分析结果显示在白种人的HIV-1长期不进展者中CCR5△32的杂合子突变可以降低HIV-1病毒感染的风险,能够起到一种保护作用；CCR2-64I的突变在整个人群中与HIV-1感染不存在相关性；在白种人和中国人群SDF1-3’A基因的突变与HIV-1感染不存在相关性。更多还原

【Abstract】 1 BackgroundMany studies suggested that the chemokines receptors CCR5, CCR2 and CXCR4 ligand SDF1 play an important role in HIV-1 infected and disease progression. Several studies have reported the role of CCR5A32, SDF1-3’A and CCR2-64I gene polymorphism in HIV-1 infection risk, However, due to the heterogeneity of population; sample size of a single study were inadequate and other factors, making relevant research there is a big controversy. In order to help resolve this uncertainly, we have performed a meta-analysis to further clarify the association between CCR5Δ32, SDF1-3’A and CCR2-64I polymorphisms and risk of HIV-1 infection.2 Objectives2.1. To explore the association between CCR5A32 gene polymorphism and susceptibility to HIV-1 infection.2.2. To explore the association between SDF1-3’A gene polymorphism and susceptibility to HIV-1 infection.2.3. To explore the association between CCR2-64I gene polymorphism and susceptibility to HIV-1 infection. 3 Methods3.1 Criteria for InclusionThe inclusion criteria were (1) Study object:CCR5A32, SDF1-3’A and CCR2-64I gene polymorphism and risk of HIV-1; (2) independent case-control or cohort studies; (3) Observed measures:gene frequency of CCR5A32, SDF1-3’A and CCR2-64I; (4) genotype distribution of control population must be in Hardy-Weinberg equilibrium (HWE); (5) If the results were same in several studies, it will be treated as a single study in this meta-analysis; and (6) HIV-1 infected patients were not HIV-1 anti-retro viral treatment, if patients be treated, the literature is not included.3.2 Criteria for exclusionThe inclusion exclusion were (1) no available genotype frequency; (2) no control population; and (3) duplication of a previous study.3.3 Search strategyWe searched MEDLINE (U.S National Library of Medicine) for all genetic association studies on the CCR5A32, SDF1-3’A and CCR2-64I polymorphisms and the susceptibility of HIV-1 published from December 1990 to September 2010 using the PUBMED search engine. The search used the keywords and subject terms "SDF1-3’A," "CCR5A32" "CCR2-64I" "polymorphism," and "HIV-1," and the language was not limited.3.4 Statistical analysisCarefully read the included documentation, collect and analyze relevant data, this meta-analysis was performed with STATA version 9.0 (STATA Corporation, College Station, TX).4 Results4.1. Study characteristics 34 studies met the inclusion criteria.28 studies met the inclusion criteria of CCR5Δ32; 16 studies met the inclusion criteria of CCR2-64I; 16 studies met the inclusion criteria of SDF1-3’A.3710 cases and 4655 controls were enrolled in meta-analysis of CCR5Δ32 gene polymorphism; 2317 cases and 2385 controls were enrolled in meta-analysis of CCR2-64I gene polymorphism; and 1953 cases and 2212 controls were enrolled in meta-analysis of SDF1-3’A gene polymorphism.4.2. Meta-analysis results4.2.1 CCR5A32When the homozygote YY and heterozygote CY (YY+CY) were compared with the wild-type genotype (CC), the pooled ORs for the 19 studies were 1.12 (95% CI: 0.87-1.44, P=0.382), the heterozygote CY were compared with the wild-type genotype (CC), the pooled ORs for the 18 studies were 1.12 (95% CI:0.94-1.32), P=0.193), the homozygote YY were compared with the wild-type genotype (CC), the pooled ORs for the 7 studies were 0.81 (95% CI:0.45-1.43, P=0.464). In the subgroup analysis for subset of cases, statistically significantly decreased risk was found in LNTP cases (dominant model:OR=2.09,95% CI=1.42-3.09, P=0.000; recessive model:OR=2.12,95% CI=1.44-3.13, P=0.000).4.2.2 CCR2-64IWhen the heterozygote (CY) was compared with the wild-type genotype (CC), the pooled ORS for the 16 studies were 0.95 (95%CI:0.82-1.09), P-value of heterogeneity test was 0.87,I-squared was 0.0%, p-value of significant test was 0.45; the heterozygote and homozygote (CC+YY) were compared with the wild-type genotype (CC), the pooled ORS for the 16 studies were 0.97 (95%CI:0.84-1.11), P-value of heterogeneity test was 0.92, I-squared was 0.0%, P-value of significant test was 0.66; the homozygote (YY) was compared with the wild-type genotype (CC), the pooled ORS for the studies were 1.21 (95%CI:0.84-1.74), P-value of heterozygote was 0.63, I-squared was 0.0%, p-value of significant test was 0.30.4.2.3 SDF1-3’AWhen the heterozygote (CY) was compared with the wild-type genotype (CC), the pooled ORS for the 16 studies were 0.86 (95%CI:0.70-1.06), P-value of heterogeneity test was 0.02, I-squared was 46.5%, P-value of significant test was 0.15; the heterozygote and homozygote (CC+YY) were compared with the wild-type genotype (CC), the pooled ORS for the 16 studies were 0.83 (95%CI:0.67-1.03), P-value of heterogeneity test was 0.003, I-squared was 56.1%, P-value of significant test was 0.09; the homozygote (YY) was compared with the wild-type genotype (CC), the pooled ORS for the studies were 0.79 (95%CI:0.50-1.26), P-value of heterogeneity test was 0.007, I-squared was 41.0%, P-value of significant test was 0.32. In the subgroup analysis for ethnicity, when the heterozygote (CY) was compared with the wild-type genotype (CC) in Caucasian population, the pooled ORS were 0.87(95%CI:0.60-1.26), P-value of heterogeneity test was 0.46 I-squared was 0.0%, P-value of significant test was 0.99; the heterozygote and homozygote (CC+YY) were compared with the wild-type genotype (CC), the pooled ORS were 0.95 (95%CI:0.66-1.35), P-value of heterogeneity test was 0.98, I-squared was 0.0%, P-value of significant test was 0.98; the homozygote (YY) was compared with the wild-type genotype (CC), the pooled ORS for the studies were 1.87 (0.80-4.38), P-value of heterogeneity test was 0.60, I-squared was 0.0%, P-value of significant test was 0.15. there is a big heterozygote in Asian population, we further stratified analysis for Asian population, In the subgroup analysis for China population, when the heterozygote (CY) was compared with the wild-type genotype (CC), the pooled ORS were 0.96 (95%CI:0.76-1.21), P-value of heterogeneity test was 0.56, I-squared was 0.0%, P-value of significant test was 0.71; the heterozygote and homozygote (CC+YY) were compared with the wild-type genotype (CC), the pooled ORS were 1.00 (95%CI:0.80-1.25), P-value of heterogeneity test was 0.48,I-squared was 0.0%, P-value of significant test was 0.99, the homozygote (YY) was compared with the wild-type genotype (CC), the pooled ORS for the studies were 1.12(0.85-1.74), P-value of heterogeneity test was 0.55, I-squared was 0.0%, p-value of significant test was 0.28.4.3 Publication biasThe egger’s regression test and Begg’s adjusted rank correlation test indicate no evidence of publication bias in CCR5A32 meta-analysis (dominant model:P=0.922 and 0.484; recessive model:P=0.932 and 0.544); the egger’s regression test and Begg’s adjusted rank correlation test also suggested the absence of publication bias in SDF1-3’A meta-analysis (P=0.404 and 0.344 for dominant model, P=0.444 and 0.558 for additive model, P=0.404 and 0.344 for recessive model); the egger’s regression test and Begg’s adjusted rank correlation test also suggested the absence of publication bias in CCR2-64I meta-analysis (P=0.334 and 1.000 for dominant model, P=0.363 and 0.502 for additive model, P=0.431 and 0.964 for recessive model). The shapes of the funnel plot indicate that it did not any evidence of obvious asymmetry in these models. The results indicated that the results of this meta-analysis are relatively stable and that publication bias can not affect the results of our meta-analysis.5 ConclusionsThis meta-analysis indicated that the heterozygote of CCR5delta32 may decrease risk in the Caucasian of HIV-1-infected long-term non-progressors (LNTP); this meta-analysis indicated that the mutation of CCR2-64I can not decrease the risk of HIV-1-infected in the whole population; and this meta-analysis indicated that the mutation of SDF1-3’A can not decrease the risk of HIV-1-infected in Caucasian and China population.更多还原