摘要
第一部分PDCD1基因PD1.3A/G多态性与系性红斑狼疮关联研究的Meta-分析
背景系统性红斑狼疮(systemiclupuserythematosus,SLE,OMIM 152700)是一种复杂的自身免疫性遗传疾病,已有的研究结果提示该病与遗传、环境、免疫系统紊乱和性激素等多种因素的综合作用有关,其中遗传因素可能是SLE发病的根本原因。通过运用全基因组扫描策略,迄今被OMIM收录的易感区域有SLEB1—12。其中,位于SLEB2的PDCD1基因PD1.3A/G多态性与系统性红斑狼疮的关联研究有很多,但结果不完全一致,甚至截然相反。
目的评价PDCD1基因PD1.3A/G多态性与系统性红斑狼疮关联研究的合并证据、评价该多态与系统性红斑狼疮关联的效应大小并探索影响该效应的主要因素。
方法在PubMed上系统检索截至到2008年5月的关于PDCD1基因PD1.3A/G多态性与系统性红斑狼疮关联研究的文献。浏览获得的文献、按事先制定的标准剔除不合格的研究并提取所纳入研究的关键信息。通过敏感性分析评估异质性、探索其根源,然后按研究人群的不同来源并根据异质性检测结果选择固定或随机效应模型进行分层Meta-分析以计算合并的危险比(OR)。用漏斗图和Egger检验检测出版偏倚,同时计算合并研究的统计效能。
结果通过筛选所检索到的文献,来自8篇文献的20个研究符合本分析的纳入标准,进入了我们的研究。在这20个研究中有15个来自欧洲高加索人群,包含1 837个病例和3 001个正常对照。分层Meta-分析结果显示:在欧洲非西班牙人群中PD1.3A与系统性红斑狼疮的易感性存在显著关联(OR=1.290,95%CI=1.098-1.516;z=3.10,P=0.002),而在欧洲西班牙人群中PD1.3G与系统性红斑狼疮的易感性存在显著关联(OR=1.414,95%CI=I.075-1.862;z=2.48,P=0.013)。这两个关联分析的统计效能都超过80%。另外,在本Meta-分析所纳入的研究中不存在显著的发表偏倚。
结论在欧洲非西班牙人群中PDCD1基因PD1.3A与系统性红斑狼疮的易感性存在显著关联,而在欧洲西班牙人群中与系统性红斑狼疮易感性存在显著关联的是PD1.3G;PDCD1基因可能是系统性红斑狼疮的易感基因。
第二部分维生素D受体基因BsmI、TaqI、ApaI和FokI多态性与银屑病易感性关联研究的Meta-分析
背景1,25-双羟维生素D_3[1,25(OH)2D_3]及其类似物对银屑病具有治疗作用。通过与维生素D受体(Vitamin D receptor,VDR)结合,1,25-双羟维生素D_3可以抑制培养的人角质形成细胞增殖和分化,同时也可通过多种途径调节机体的免疫系统。迄今,对VDR基因多态性与银屑病关联分析的研究大部分集中在BsmI、TaqI、ApaI和FokI四个位点,但来自不同团队的研究结果不尽一致、甚至完全相反。
目的为克服单个研究的局限性,我们采用Meta-分析的方法对VDR基因BsmI、TaqI、ApaI和FokI多态性与银屑病易感性的关系进行综合评价。
方法系统检索所有2008年10月前在PubMed上发表的有关VDR基因BsmI、TaqI、ApaI和FokI多态性与银屑病关联分析的文献,然后按一定的标准选择合格的研究并从每个纳入研究中提取相关信息。对于任何一个FokI、ApaI、BsmI或TaqI多态位点,我们都进行基于等位基因、显性遗传模式和隐性遗传模式关联研究的Meta-分析。而对于每一种模式下的分析,我们除了在总的人群中进行分析外,还按不同种族在亚人群(高加索人群、东亚人群)中进行分析,也就是分层分析,以探索可能存在的种族特异性效应。通过固定或随机效应模型计算合并的危险比(Odds ratio,OR)。通过敏感性分析确定异质性并探索其来源。用漏斗图和Egger检验检测出版偏倚。
结果对检索到的23篇相关文献按我们的纳入标准进行筛选,最终有9个研究符合我们的标准进入本Meta-分析。对于ApaI位点,基于等位基因及显性遗传模式关联研究的Meta-分析结果显示:在高加索人群中,等位基因a是银屑病发病的危险因素[分别为OR_(固定效应模型)=1.463(1.017-2.103),OR_(固定效应模型)=1.934(1.105-3.386)];在总的研究中,来自韩国的一个研究是异质性的主要来源,当排除该研究后,同样表现了这一趋势[分别为OR_(固定效应模型)=1.400(1.088-1.800),OR_(固定效应模型)=1.853(1.181-2.908)]。对于TaqI位点,基于等位基因关联研究的Meta-分析显示:在高加索人群中,等位基因t是银屑病发病的危险因素[OR_(固定效应模型)=1.344(1.033-1.749)]。而对于BsmI和FokI位点,无论在总人群、东亚人群还是高加索人群中,基于等位基因、显性遗传模式和隐性遗传模式关联研究的Meta-分析均显示不存在显著性关联。另外,本Meta-分析中任一位点关联研究的文献均不存在显著的发表偏倚。
结论维生素D受体基因ApaI、TaqI多态位点是银屑病的易感位点,而BsmI、FokI多态位点则与银屑病不存在显著的关联;维生素D受体基因可能是银屑病的易感基因。
PartⅠAssociation between the PD1.3A/G polymorphism of the PDCD1 gene and Systemic Lupus Erythematosus:a meta-analysis
Backgrounds Systemic lupus erythematosus(systemiclupuserythematosus,SLE, OMIM 152700) is a complex autoimmune disease,with contributions anticipated from genetic factors,environment,immune system disorders,sex hormones and other factors,and the genetic factors may be the root cause of the incidence of SLE. Through the use of whole-genome scan strategy,SLEB1-12 were identified as the susceptible loci.It is known that programmed cell death 1(PDCD1) gene locates in SLEB2.So far,the association of PDCD1 polymorphism(PD1.3A/G) with SLE has been widely investigated,but there are no unambiguous conclusions.
Objectives To assess the combined evidence for the association between PD1.3A/G polymorphism and SLE,and to summarize the effect size of the polymorphism associated with susceptibility to SLE.
Methods We surveyed studies on the PD1.3A/G polymorphism and SLE using comprehensive PubMed search up to May 2008.The retrieved literatures were screened according to the criteria and the eligible papers were entered into our study. Subsequently,the key data were extracted from each included study.Through sensitivity analysis,heterogeneity in the meta-analysis was assessed,and the source of which was also explored.A fixed-or random-effect model was choosed in the stratified meta-analysis based upon the heterogeneity analysis to calculate the combined odds ratio(OR),while publication bias was examined by funnel plot and Egger's test.We also computed the power for a given number of samples.
Results A total of 20 datasets from 8 studies that met our inclusion criteria were included,15 of which were come from Europe and comprised of a total of 1 837 cases and 3 001 controls.Stratified meta-analysis demonstrated a significant association between PD1.3A and SLE among non-Spanish European descents(OR=1.290,95% CI=1.098-1.516;z=3.10,P=0.002),while a negative association was observed in Spanish population(OR=0.707,95%CI=0.537-0.930;z=2.48,P=0.013),that is, PG1.3G is the risk allele in the latter population(OR=1.414,95%CI=1.075-1.862; z=2.48,P=0.013).Both results have sufficient power to support these findings,and no publication bias presented in the studies analyzed.
Conclusions This meta-analysis demonstrates a significant association between PDCD1 gene PD1.3A and SLE among non-Spanish European descents,while PD1.3G correlates with SLE susceptibility in Spanish population.PDCD1 gene may be a candidate gene of Systemic Lupus Erythematosus.
PartⅡBsmI,TaqI,ApaI and FokI polymorphisms in the vitamin D receptor(VDR) gene and the risk of psoriasis:a meta-analysis
Backgrounds 1,25-dihydroxyvitamin D_3[1,25(OH)_2D_3]and its analogs are effective for the treatment of psoriasis.Through the vitamin D receptor(VDR), 1,25(OH)_2D_3 inhibits proliferation and induces terminal differentiation of cultured human keratinocytes,and also modulate the immune system in a variety of ways.So far,most of the genetic studies that have investigated the association between psoriasis and VDR gene were performed in 4 polymorphisms:ApaI,BsmI,FokI and TaqI,but the results were much controversial or non-conclusive.
Objectives To overcome the limitations of individual studies,a meta-analysis was conducted to assess the association between ApaI,BsmI,FokI and TaqI polymorphisms and psoriasis susceptibility.
Methods All genetic association studies that investigated the association of the BsmI,TaqI,ApaI and FokI polymorphisms in the VDR gene with the development of psoriasis published before Oct 2008 were searched.All retrieved papers were selected according to the inclusion criteria and the eligibility ones were entered into our meta-analysis.For each included study,the informations,such as first author,year of publication,country where the trial was conducted,sample origin,numbers of cases and controls,and distributions of allele and genotype in both case and control groups, were extracted.For each of the 4 polymorphisms,we explored the significance of the associations for the allele contrast as well as the recessive and dominant models,and for each genetic contrast,in addition to the analysis among overall samples,subgroup analysis according to ethnicity was also considered for Caucasian and East Asian populations in order to estimate the possible ethnic-specific effect.The pooled odds ratio(OR) was calculated using a fixed- or a random-effects model.Heterogeneity was identified by sensitivity analysis and publication bias was examined by funnel plot and Egger's test.
Results A total of 9 studies that met our inclusion criteria were included.For the ApaI polymorphism,both the allele contrast a vs.A and dominant models for allele a produced significant results in Caucasians[OR_(fixed-effect model)=1.463(1.017-2.103), OR_(fixed-effect model)=1.934(1.105-3.386),respectively],and also in overall samples [OR_(fixed-effect model)=1.400(1.088-1.800),OR_(fixed-effect model)=1.853(1.181-2.908), respectively]after removing Park et al's study which accounted for the heterogeneities.Regarding TaqI polymorphism,allele contrast t vs.T produced significant result in Caucasians[OR_(fixed-effect model)=1.344(1.033-1.749)].As for the BsmI and FokI polymorphisms,allele contrast,recessive and dominant models produced non-significant results in either Caucasians,East Asians or overall samples.
Conclusions It seems from our meta-analysis that ApaI,TaqI polymorphisms, rather than BsmI,FokI polymorphisms in VDR gene,correlate with psoriasis.VDR gene might be a susceptibility gene of psoriasis.
引文
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