炎性基因与环境交互作用及胃癌易感性分析

目的 探讨胃癌患病风险的炎性基因白介素1(IL-1)、肿瘤坏死因子(TNF)及巨噬细胞转移抑制因子(MIF)与环境间交互作用.方法 用多因子降维法(MDR)模型分析基因-环境的交互作用对胃癌易感性影响,结合logistic回归分析进行补充验证.结果 最佳交互作用模型是IL-1B-511、IL-1RN、TNF-A-308和肿瘤家族史的联合作用(P＜0.01),交叉验证一致性10/10,检验样本准确度为0.72;根据模型将研究对象划分为高危、低危人群,胃癌发病风险交互效应的危险度估计OR＝ 13.49,95％CI＝8.62～21.10,且交互作用有统计学意义(P＜0.01);将危险因素按结合数量进行分析,结果显示含有1、2、3个危险因素组在病例和对照中分布差异均有统计学意义(P＜0.05),OR值分别为2.17、11.61、27.19.结论 IL-1B-511、IL-1RN、TNF-A-308和肿瘤家族史的交互作用可能增加胃癌患病风险.     

IL-1B及IL-1RN基因多态性在河南汉族人群中的分布特点

目的了解IL-1B及IL-1RN基因多态性在河南汉族人群中的分布特点及其在不同地区的异同。方法用PCR和限制性内切酶图谱的方法检测河南地区243名人群中IL-1B-31、IL-1B-511及IL-1RN基因多态性,并结合文献进行不同地区间的比较。结果在河南汉族人群中,IL-1B-31等位基因C型发生频率高(0.59),T型为0.41;IL-1B-511等位基因T型较高(0.56),C型为0.44;IL-1RN等位基因频率分别为I型(0.899)、Ⅱ型(0.078)、Ⅲ型(0.002)、Ⅳ型(0.02),Ⅰ型纯合子最为常见(占82%),其次为Ⅰ/Ⅱ型(占12%)。与其他地区相比,基因频率的分布国内和东亚地区较为接近,而和西方国家不同。结论IL-1B-31I、L-1B-511I、L-1RN基因多态性在不同地区人群间的分布存在明显差异。     

IL-1A、IL-1B、IL-6基因多态性与妊娠期巨细胞病毒感染的关联

目的 探讨白细胞介素-1A(IL-1A)和白细胞介素-1B(IL-1B)和白细胞介素-6(IL-6)基因多态性与妊娠期巨细胞病毒(CMV)感染相关性。方法 选择海南医学院第一附属医院2019年1月-2020年8月收治的CMV感染自然流产孕妇80例为研究对象,根据CMV-DNA检测结果将其分为CMV-DNA阳性组(n=26)和CMV-DNA阴性组(n=54)。入院时抽取其外周血采用聚合酶链式扩增反应检测CMV-DNA水平;采用限制性片段长度多态性聚合酶链反应检测IL-1A基因899启动子、IL-1B基因511启动子和IL-6基因572启动子多态性;采用酶联免疫吸附法检测血清中IL-1A、IL-1B和IL-6水平。结果 两组孕妇IL-1A-899、IL-1B-511和IL-6-572基因型分布在理论值与实际值之间比较差异无统计学意义,具有群体代表性;CMV-DNA阳性组与CMV-DNA阴性组IL-1A-899、IL-1B-511位点多态性基因型分布比较差异无统计学意义,CMV-DNA阳性组IL-6-572位点GG基因型、G等位基因频率高于CMV-DNA阴性组(P<0.05);CMV-...     

幽门螺杆菌与白细胞介素-1基因交互作用

目的 探讨幽门螺杆菌（Hp）感染与白细胞介素-1基因家族中白细胞介索-1B（IL-1B）-31与IL-1B-511（IL-1B）位点单核苷酸多态性（SNP）、IL-1RN可变数目串连重复序列（VNTR）及二者交互作用与十二指肠溃疡病（DU）发病风险的关系。方法 用病例对照研究方法，调查94例对照和54例DU患者，ELISA方法检测患者IgG抗体，PCR扩增目的基因，电泳检测IL-1RN可变数目串连重复序列，限制性片段多态性分析（RFLP）检测IL-1B-31、IL-1B-511单核苷酸多态性。结果 Hp感染、IL-1B-511C／C型增加DU的患病危险，OR分别为8．26（95％CI=3．02～22．59），3．05（95％CI=1．23～7．57）。Hp感染和IL-1B-31T／T、IL-1B-511C／C、非Ⅰ型IL-1RN之间有交互作用存在，交互作用项OR分别为16．75（95％CI=3．64～77．04），41．42（95％CI=8．96～191，40），4．93（95％CI=1．35～17．99），交互作用系数（γ）分别为1．22，1．7，0．84。结论 IL-1B-31T／T、IL-1B-511C／C能增加Hp感染对十二指肠溃疡病患病的危险作用，而非Ⅰ型IL-1RN则减弱Hp的危险作用。这种交互作用的存在有助于解释Hp感染临床结局的复杂性。     

TNF-α、IL-1β和IL-10启动子区基因多态性与肺癌发病易感性的关系研究

[目的]研究肿瘤坏死因子α（TNF-α）、白介素1β（IL-1β）和白介素10（IL-10）基因启动子区单核苷酸多态性（single nueleofide polymorphism,SNP）与肺癌易感性的关系。[方法]采用病例-对照研究,使用real-timePCR法对132例健康人和106例肺癌病人的TNF-α-308、IL-1β-511和IL-10-10823个SNP位点进行基因分型。[结果]TNF-α-308、IL-1β-511和IL-10-1082多态性位点的基因型频率和等位基因频率在病例组和对照组中的分布差异没有统计学意义。根据吸烟史的分层分析发现,TNF-α-308 AA＋AG基因型频率分布差异在无吸烟史亚组中有统计学意义（P=0．049）,比值比（OR）为4．881,95％可信区间（95％CI）为1．007—23．646 IL-1β-511CC基因型频率在无吸烟史亚组中分布有差异（P=0．022）,OR值为4．091（95％CI为1．222～13．690）。在女性人群中,IL-1β-511CC基因型频率分布差异有统计学意义（P=0．014）,OR值为8．067（95％CI为1．538—42．318）。[结论]就本研究范围的中国大陆人群中,尚未发现TNF-α-308、IL-1β-511和IL-10-1082的SNP位点与肺癌发生有相关性;而在无吸烟史的人群中,TNF-α-308 AA＋AG基因型和IL-1β-511CC基因型可能是发生肺癌的相关因素;IL-1β-511CC基因型可能是女性肺癌的高发病因素之一。     

IL-1B基因多态性在十二指肠溃疡发病中的作用

目的探讨幽门螺杆菌(Hp)感染与IL-1B-511位点单核苷酸多态性(SNP)在十二指肠溃疡(DU)发病中的作用。方法用病例-对照研究方法,调查某院54例DU患者及94例同院同期非DU患者(对照),用ELISA方法检测其血清Hp IgG抗体,PCR扩增IL-1B-511,限制片段长度多态性分析(RFLP)检测其SNP。结果DU组Hp阳性率为90.74%(49/54),而对照组则为54.26%(51/94),病例组高于对照组,OR为8.26(95%CI为3.02~22.59)。DU组IL-1B-511基因T/T、C/T和C/C基因型频率分别为31.48%,35.19%,33.33%;而在对照组则分别为38.30%,46.81%,14.89%,IL-1B-511 C/C型能增加DU的患病危险,OR为3.05(95%CI为1.23~7.57),但按有无Hp感染进行分层后,则IL-1B-511 C/C只在有Hp感染时才有作用,OR为4.60(95%CI为1.40~15.12)。结论Hp感染时IL-1B-511 C/C能增加十二指肠溃疡病的患病风险,机体的遗传基因与Hp共同影响Hp感染者的临床结局。     

精神分裂症与亲核素β基因多态性关系

目的 探讨亲核索β(KPNBs)中KPNB1和KPNB2基因与精神分裂症的关系.方法 采用聚合酶链式反应一限制性片段长度多态性(PCR-RFLP)方法,收集中国吉林省汉族精神分裂症患者及其健康父母双亲组成的233个核心家系成员,分别检测位于KPNB1和KPNB2基因上的2个单核苷酸多态性(SNPs)rs11871606和rs266443.利用拟合优度x2检验分析等位基因和基因型分布频率是否符合哈迪-温伯格定律(Hardy-Weinberg Law),应用遗传统计学软件(UNPHASED)进行2个SNPs的传递不平衡检验(TDT)以及双位点联合作用分析.结果 患者组与其父母组比较,KPNB1基因rs11871606及KPNB2基因rs266443等位基因和基因型频率的分布差异均无统计学意义(P>0.05),符合Hardy-Weinberg平衡定律;TDT结果提示,KPNB1基因rs11871606及KPNB2基因rs266443与精神分裂症无连锁及关联.双位点联合作用分析结果显示,rs11871606与rs266443两位点未显示联合作用(P>0.05).结论 KPNB1基因rs11871606位点及KPNB2基因rs266443位点多态性可能与精神分裂症无关,但不能排除KPNB1基因及KPNB2基因其他SNPs与精神分裂症相关联.     

军团菌感染与2个细胞因子基因多态性关系

目的探索肿瘤坏死因子-α(TNF-α)-308位点、白介素-1β(IL-1β)-511位点基因多态性与军团菌感染的关系。方法将32例军团菌感染者作为病例组,随机抽取100例军团菌检测阴性的肺部感染者为患者对照组,同期收集70例健康体检者为健康人对照组,采用聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)技术检测3组TNF-α基因-308位点、IL-1β基因-511位点的单核苷酸多态性。结果病例组TNF-α-308基因型GG、GA、AA分别占75%、25%、0%,患者对照组GG、GA、AA基因型分别占87%、13%、0%,健康人对照组GG、GA、AA基因型分别占68.6%、31.4%、0%;病例组与患者对照组比较、病例组与健康人对照组比较,TNF-α-308位点基因型和等位基因频率差异无统计学意义(χ2=0.437、0.362,P=0.509、0.548;χ2=2.609、2.384,P=0.106、0.123);病例组IL-1β-511基因型CC、CT、TT分别占:0%、53.1%、46.9%,患者对照组CC、CT、TT基因型分别占3.4%、48.3%、48.3%,健康人对照组CC、CT、TT基因型分别占10%、51.4%、38.6%,3组比较,IL-1β-511位点基因型和等位基因频率差异无统计学意义(χ2=4.466,P=0.334;χ2=2.420,P=0.298)。结论 TNF-α-308位点、IL-1β-511位点的基因多态性与军团菌感染无关,TNF-α基因和IL-1β基因不是军团菌感染的易感基因。     

IL-1RN内含子2和外显子2基因多态性的分布特点及其与血脂的相关关系

目的 探讨武汉地区汉族健康人群白细胞介素-1受体拮抗剂基因(IL-1RN)第2号内含子中可变数串联重复序列(VNTR)多态性和第2号外显子 8006位点单核苷酸多态性(SNP)的分布特点及其与血脂的相关关系。方法 采用聚合酶链反应(PCR)和PCR-限制性片段长度多态性(RFLP)的分析方法,检测了251名武汉地区汉族健康者IL-1RN(VNTR)和IL-1RN( 8006)多态性,同时检测其血脂、IL-1和IL-1Ra水平。结果 IL-1RN(VNTR)的等位基因以Ⅰ型最为常见,其次为Ⅱ型,Ⅳ型较为罕见;IL-1RN( 8006)的等位基因以T型最为常见,其次为C型;IL-1RN(VNTR)的等位基因Ⅱ总是伴随着IL-1RN( 8006)的等位基因C而出现;这两种多态性的分布在男女间差异不显著,且与血脂、IL-1和IL-1Ra水平间不存在相关关系(P>0.05)。结论 武汉地区汉族健康人群IL-1RN内含子2和外显子2中均存在基因多态性,其等位基因间存在连锁不平衡;这两种多态性与血脂、IL-1和IL-1Ra水平间不存在相关关系。     

IL-8基因1633C/T多态性与迟发性阿尔茨海默病关系研究

目的 探讨白细胞介素-8(IL-8)基因1633 C/T多态性与新疆汉族迟发性阿尔茨海默病(LOAD)遗传易感性的关系,为迟发性阿尔茨海默病(LOAD)遗传病因研究提供参考依据.方法 采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法检测80例LOAD患者与80例正常人的IL-8基因1633 C/T多态性的分布情况;采用直接计数法计算等位基因及基因型频率,对基因型进行Hardy-Weinberg平衡估计,其他统计分析用SPSS 13.0软件完成,基因型频率及等位基因频率比较采用x2检验.结果 在IL-8基因1633C/T中LOAD组CC基因型频率为20.0％、CT基因型频率为41.2％、TT基因型频率为38.8％,对照组CC、CT、TT基因型频率分别为11.3％,40.0％,48.7％,两组比较差异无统计学意义(P＞0.05).结论 IL-8基因1633 C/T多态性可能与迟发性阿尔茨海默病易感性不相关.     

Genetic polymorphisms related to interleukin-1 beta production and disease risk

PURPOSE: Interleukin (IL)-1A C-889T, IL-1B C-511T, IL-1B C-31T, IL-1B C3954T, and IL-1RN 86-bp VNTR (variable number of tandem repeats) are polymorphisms potentially influencing IL-1 beta production. This review summarizes 1) the biological roles of IL-1 beta, 2) allele frequencies of the polymorphisms, and 3) the reported associations between these polymorphisms and disease risk. METHODS: Papers were obtained from PubMed with keywords "IL-1, polymorphism", as well as from the references in each paper. The most relevant papers were then selected. In this review, a narrative approach was adopted. RESULTS: IL-1 beta is a multifunctional proinflammatory cytokine, whose signal is transduced through IL-1 receptor I (IL-1RI) on the cell surface. Binding levels are influenced by the IL-1 receptor antagonist (IL-1Ra), IL-1RII (decoy receptor with no signal transduction), soluble IL-1RI, and soluble IL-1RII. IL-1B encoding IL-1 beta is located on chromosome 2q14, along with IL-1A encoding IL-1 alpha and IL-1RN encoding IL-1Ra. The minor alleles, IL-1A-889T, IL-1B 3954T, and IL-1RN 2R, are rarer in Japanese than in Caucasians, while IL-1B-511T and IL-1B-31C are more frequent. These polymorphisms have been reported to have potential associations with the risk of diseases, such as stomach cancer, breast cancer, inflammatory bowel, Alzheimer's, and osteoporosis. DISCUSSION: Although there are many inconsistent findings on associations with the polymorphisms, IL-1B C-511T and the tightly linked T-31C may be useful for predicting the risk of diseases with an inflammation basis among Japanese.     

IL-1B-511 Allele T and IL-1RN-L/L Play a Pathological Role in Helicobacter Pylori (H. Pylori) Disease Outcome in the African Population

Background

Many of the pathogenic effects of Helicobacter pylori infection are related to chronic active inflammation, which is controlled and maintained by the complex interplay of pro-inflammatory and anti-inflammatory mediators. Pro-inflammatory genetic polymorphisms tend to increase the risk of development of gastric cancer. In Africa, the data are scarce regarding the effects of these polymorphisms on gastric pathology. The objective of this study is therefore to investigate the pro-inflammatory genetic polymorphisms and their role in H. pylori-related gastric disorders in a select African population.

Methods

This cross-sectional prospective study recruited six hundred and ninety six adult subjects with a history of uninvestigated dyspepsia. The H. pylori status was determined by tissue Giemsa staining, Rapid Urease Test (RUT), H. pylori stool antigen test (HpSAT), and PCR using the 16s-rRNA gene. The polymorphisms in IL-1B (511 C/T), TNF-A (_308 G/A) and IL-1RN were assessed by the PCR-restricted fragment length polymorphism (RFLP).

Results

H. pylori was significantly associated with gastric pathologies investigated (P = 0.0000). Heterozygous allele TC of IL-1 β -511 was significantly associated with H. pylori infection (p = 0.003815). Similarly, allele IL-1 RN*2/2 and allele IL-1 RN-L/L were associated with H. pylori infection (p = 0.0025 and p = 0.0203). Allele T of IL-1 β -511 and IL-1 RN-L/L are more frequent in H. pylori associated gastric pathologies in this series.

Conclusion

Allele T of IL-1 β -511 and long allele IL-1 RN-L/L play a role in H. pylori disease in this population.     

SNP selection and multidimensional scaling to quantify population structure

In the new era of large‐scale collaborative Genome Wide Association Studies (GWAS), population stratification has become a critical issue that must be addressed. In order to build upon the methods developed to control the confounding effect of a structured population, it is extremely important to visualize and quantify that effect. In this work, we develop methodology for single nucleotide polymorphism (SNP) selection and subsequent population stratification visualization based on deviation from Hardy‐Weinberg equilibrium in conjunction with non‐metric multidimensional scaling (MDS); a distance‐based multivariate technique. Through simulation, it is shown that SNP selection based on Hardy‐Weinberg disequilibrium (HWD) is robust against confounding linkage disequilibrium patterns that have been problematic in past studies and methods as well as producing a differentiated SNP set. Non‐metric MDS is shown to be a multivariate visualization tool preferable to principal components in conjunction with HWD SNP selection through theoretical and empirical study from HapMap samples. The proposed selection tool offers a simple and effective way to select appropriate substructure‐informative markers for use in exploring the effect that population stratification may have in association studies. Genet. Epidemiol. 33:488–496, 2009. © 2009 Wiley‐Liss, Inc.     

梅州地区TLR4基因连锁不平衡与缺血性脑卒中相关性研究

目的 检测梅州地区缺血性脑卒中患者和健康对照人群TLR4基因的（rs10759932、rs11536879、rs11536891、rs1927914）的基因多态性，经连锁不平衡分析其与缺血性脑卒中的相关性。方法 收集2018年1月1日 - 2018年7月31日住院治疗的突发缺血性脑卒中患者作为病例组，同期在体检中心收集健康人群作为对照组。应用Massarray SNP 分型技术检测两组患者TLR4基因的4个位点基因型，进行Hardy - Weinberg（H - W）平衡检测。采用不同模型分析上述位点不同基因型与脑梗死发病风险的相关性，并通过连锁不平衡分析其与缺血性脑卒中的相关性。结果 病例组纳入病例186名，对照组纳入健康人194名；4种SNP位点均符合H - W 平衡。rs1927914位点G/G基因型在对照组出现频率远远高于病例组（χ2 = 9.267，P＜0.05）。rs10759932位点T/T基因型在女性对照组中出现的频率显著高于男性[OR = 0.38 (0.18 - 0.81)，P＜0.05]。4个SNP位点之间均存在连锁不平衡，TGCG基因型组合在缺血性卒中男性患者出现的频率显著高于女性[OR = 3.54 (1.17 - 10.69)，P＜0.05]。结论 梅州地区rs1927914位点A＞G为保护性基因突变，可以降低缺血性脑卒中发生。4个位点的连锁不平衡与缺血性脑卒中发生存在部分性别差异，TGCG组合为男性人群的危险基因，脑卒中发生率显著升高。     

Power estimation of multiple SNP association test of case-control study and application

At the current stage, a large number of single nucleotide polymorphisms (SNPs) have been deployed in searching for genes underlying complex diseases. A powerful method is desirable for efficient analysis of SNP data. Recently, a novel method for multiple SNP association test using a combination of allelic association (AA) and Hardy-Weinberg disequilibrium (HWD) has been proposed. However, the power of this test has not been systematically examined. In this study, we conducted a simulation study to further evaluate the statistical power of the new procedure, as well as of the influence of the HWD on its performance. The simulation examined the scenarios of multiple disease SNPs among a candidate pool, assuming different parameters including allele frequencies and risk ratios, dominant, additive, and recessive genetic models, and the existence of gene-gene interactions and linkage disequilibrium (LD). We also evaluated the performance of this test in capturing real disease associated SNPs, when a significant global P value is detected. Our results suggest that this new procedure is more powerful than conventional single-point analyses with correction of multiple testing. However, inclusion of HWD reduces the power under most circumstances. We applied the novel association test procedure to a case-control study of preterm delivery (PTD), examining the effects of 96 candidate gene SNPs concurrently, and detected a global P value of 0.0250 by using Cochran-Armitage chi(2)s as "starting" statistics in the procedure. In the following single point analysis, SNPs on IL1RN, IL1R2, ESR1, Factor 5, and OPRM1 genes were identified as possible risk factors in PTD.     

Quantitative trait locus detection using combined linkage/disequilibrium analysis

We describe an extension of the variance component linkage method that augments identity-by-descent information from relatives with identity-by-state information from unrelated individuals, exploiting disequilibrium to facilitate fine mapping of quantitative trait loci. An advantage of the combined linkage/disequilibrium test is that it detects association only in the presence of linkage and is not biased by population stratification.