基因多态性与化学物致病风险

个体对外源性化学物的反应因其基因DNA序列的多态性而有所不同 ,这些多态性可影响机体对化学物的易感性 ,进而影响到个体发病风险的差异。本文就近年来毒物代谢酶基因和DNA修复基因多态性影响个体发病风险的研究情况做一简要综述     

慢性苯中毒发病风险与XRCC1基因多态性关联的病例对照研究

采集病例组慢性苯中毒(CBP)患者102名、对照组204名人员静脉血,应用PCR探针法和引物延伸SNa Pshot法检测XRCC1 rs25487、rs25489、rs1799782 SNP位点基因型,分析基因多态位点和CBP易感性的关联,以比值比(odds ratio,OR)及其95%可信限(95%confidence interval,95%CI)表示关联强度。结果显示,XRCC1rs25487CT基因型(ORadj=5.146,95%CI=2.441~10.852,χ2=21.098,P0.05)或TT基因型(ORadj=13.985,95%CI=6.440~30.371,χ2=56.316,P0.05)、rs1799782 AA基因型(ORadj=2.012,95%CI=0.926~4.372,χ2=5.100,P0.05)可使CBP发生风险增高,未发现XRCC1 rs25489位点与CBP发生的关联。提示XRCC1 rs25487 CT或TT基因型、rs1799782 AA基因型多态可能作为CPB发病危险性增加的生物学标志之一。     

MMP-7和MMP-9基因多态与子宫内膜异位症发病风险的关联研究

目的探讨MMP-7和MMP-9基因启动子区多态性与中国北方妇女子宫内膜异位症遗传易感性的关系.方法采用聚合酶链反应-限制性片段长度多态性技术,检测143例子宫内膜异位症患者和160名健康妇女对照的MMP-7基因启动子区-181A/G多态位点和MMP-9基因启动子区-1562C/T多态位点的基因型.结果子宫内膜异位症患者MMP-7中G等位基因频率（7.3%）明显高于对照组（2.8%）（χ2=6.59,P=0.01）;子宫内膜异位症患者A/A、A/G、G/G三种基因型频率分别为86.0%、13.3%和0.7%,正常对照组则分别为94.4%、5.6%和0%,两者有显著差异（χ2=6.50,P=0.039）;与A/A基因型相比,携带G等位基因能明显增加子宫内膜异位症的发病风险,经年龄校正的OR值为2.71（95%CI：1.19～6.16）.MMP-9中C和T等位基因频率在病例组和对照组分别为88.8%、11.2%及91.9%、8.1%,两组差异无统计学意义（χ2=1.64,P=0.20）;病例组C/C、C/T和T/T基因型频率分别为78.3%、21%和0.7%,对照组则分别为83.8%、16.2%和0%,两者差异亦无统计学意义（χ2=2.31,P=0.32）.与C/C基因型相比,携带T等位基因未能明显增加子宫内膜异位症的发病风险,经年龄校正的OR值为1.41（95%CI：0.79～2.52）.结论MMP-7基因启动子区-181A/G多态与子宫内膜异位症发病存在关联,携带G等位基因可能增加该病的发病风险;未发现MMP-9基因启动子区-1562C/T多态性则与子宫内膜异位症发病存在关联.     

DNA修复基因XRCC1和XPC多态性与胰腺癌风险关联研究

目的探讨碱基切除修复相关基因XRCC1及核酸切除修复基因XPC基因多态与胰腺癌发病风险的关系。方法采用病例-对照研究(胰腺癌新发病例101人,对照337人)方法,分析XRCC1Arg399Gln、Arg194Trp及XPC第9内含子的AT双核苷酸的插入/缺失(PAT)多态与胰腺癌风险的关系。结果经年龄、性别及吸烟、饮酒状态调整后,携带XRCC1399Arg/Gln及Gln/Gln基因型的个体较399Arg/Arg者发生胰腺癌的风险有所降低,OR值分别为0·83(95%CI,0·52~1·34,P=0·41)和0·64(95%CI,0·21~1·66,P=0·30),但没有达到统计学显著水平。携带PAT+/+基因型者发生胰腺癌的风险为XPC/PAT-/-基因型者的0·30倍(95%CI,0·10~0·76,P=0·02)。结论XPC-PAT多态可能在胰腺癌的发生中起着一定的作用。     

瘦素及瘦素受体基因多态性与中国南方汉族人群冠心病的关联研究

目的探讨瘦素基因rs2167270、rs4731426和瘦素受体基因rs12405556单核苷酸多态性与中国南方汉族人群冠心病(Coronary Artery Disease,CAD)的遗传易感性的关系。方法应用SNPscan TM多重SNP分型试剂盒对中国南方汉族人的1 044例冠心病患者和1 349例健康对照样本进行SNP分型;等位基因关联分析采用卡方检验;基因型关联分析采用单因素和多因素非条件Logistic回归分析方法。结果等位基因和基因型关联分析未发现rs2167270、rs4731426和rs12405556与冠心病有关联(P=0.242~0.978);进一步按性别、是否患高血压、是否患2型糖尿病这3个混淆因素分层后,仍未发现3个SNP在各亚组与冠心病有关联(P=0.0938~0.997)。此外,也未发现这3个SNP与冠心病合并高血压/2型糖尿病存在显著关联(P=0.258~0.994)。结论本研究未发现瘦素基因rs2167270、rs4731426及瘦素受体基因rs12405556单核苷酸多态性与中国南方汉族人群的冠心病有关联。     

基因单核苷酸多态性与宫颈癌关系研究进展

宫颈癌在发展中国家有很高的发病率及死亡率,宫颈癌仍然是女性第二高发肿瘤,其发病率仅次于乳腺癌,死亡率仅次于胃癌。越来越多的研究表明,宫颈癌是人乳头瘤病毒(HPV)感染引起的^[1], HPV感染可以认为是宫颈癌发生发展的重要环境因素, 但只有一少部分持续感染HPV的患者, 这表明 HPV感染并不足以导致肿瘤的发生, 其中激素、性伴 侣个数、怀孕的年龄以及遗传背景等在宫颈癌的发病中可能 起重要作用^[2]。     

REG1a基因单核苷酸多态性与胃癌遗传易感性研究

目的寻找中国汉族人群REG1a基因单核苷酸多态性位点,探讨其基因多态性与胃癌(Gastric Cancer)的关系。方法应用PCR产物测序的方法在中国人群中检测散发性胃癌组(n=183)及对照组(n=204)REG1a基因的单核苷酸多态性(single nucleotide polymorphisms,SNPs)。结果REG1a基因第929位(T/C)、第1790位(C/G)、第2751位(A/T)发现3个新的SNP位点,其中第929位和第1790位2个位点基因型在胃癌与健康人群的差异具有统计学意义(P<0.05)。结论对特定人群进行测序可有效筛查出候选SNP位点,初步发现REG1a基因的2处单核苷酸多态性与胃癌的发生、淋巴转移和远处转移有一定关系,为后续利用单核苷酸多态性标志进行胃癌风险预测奠定了研究基础。     

Sp110基因多态性与重庆汉族肺结核遗传易感性关联性研究

目的研究Sp110基因SNP位点多态性与重庆市汉族人群肺结核发病的关系。方法采用病例-对照研究设计,问卷调查收集肺结核相关危险因素;多种方法检测rs1135791C/T、rs722555A/G、5′-UTRrs11679983A/G、rs28930679C/T、rs9061A/G、rs1063154G/T、rs1047254A/G、rs3948464C/T位点SNP多态性,用SAS软件进行显著性检验,用MDR软件分析与肺结核易患性相关的SNP位点的交互作用。结果 (1)Sp110基因rs1135791CT基因型、rs722555GG基因型、rs11679983GG基因型、rs3948464CC基因型在病例组的频率明显高于对照组;(2)Logistic回归分析rs1135791C/T、rs722555A/G、rs11679983A/G、rs3948464C/T基因型,吸烟史、家庭中有结核病人、人均居住面积及BMI与重庆地区汉族肺结核的易患性有关;(3)Sp110基因rs722555A/G与rs1135791C/T、rs11679983A/G、rs3948464C/T3个位点有交互作用。结论 rs1135791C/T、rs722555A/G、rs11679983A/G、rs3948464C/T可能是重庆市汉族人群肺结核易患的危险因素。     

白介素10基因多态性与肝细胞癌关系

目的 探讨细胞因子白介素10(IL-10)基因启动子区单核苷酸多态性和环境因素的交互作用与肝细胞癌(HCC)遗传易感性关系。方法 采用以医院为基础的病例对照研究方法,选择589例HCC患者为病例组,同期在相同医院住院的597例无肿瘤患者为对照组;应用TaqMan MGB实时荧光定量PCR技术对IL-10基因-819位点和-592位点进行基因分型,采用非条件Logistic回归模型分析比较携带不同基因型者罹患HCC风险,以及基因多态性和环境因素的交互作用。结果 IL-10-819位点CC、CT、TT基因型在2组中分布差异无统计学意义(P>0.05),3种基因型与HCC患病风险无统计学关联(P>0.05);IL-10基因-592位点CC、AC、AA基因型在2组中分布差异无统计学意义(P>0.05),3种基因型与HCC患病风险无统计学关联(P>0.05);交互作用分析结果表明,IL-10基因-819和-592位点单核苷酸多态性与吸烟、饮酒、食鱼生及乙型肝炎表面抗原(HBsAg)阳性等环境因素在HCC发生中存在交互作用。结论 IL-10基因多态性在HCC发生过程中,可能无独立的危险作用,但与吸烟、饮酒、食鱼生及HBsAg阳性等环境因素的交互作用能增加HCC的患病风险。     

毒物代谢酶基因多态性与胃癌易感性

简要综述毒物代谢酶一相酶细胞色素P4502E1（CYP4502E1）、二相酶谷胱甘肽S－转硫酶M1、T1GSTM1、GSTT1）、N－乙酰化转移酶（NAT）的基因多态性与胃癌的遗传易感性的国内外研究进展。     

Assignment of a Chinese xeroderma pigmentosum patient from Taiwan to complementation group C

A 2 years and 7 months-old Chinese boy with severe skin symptoms was diagnosed as xeroderma pigmentosum (XP) at Chang Gung Memorial Hospital in Taipei, Taiwan. Skin fibroblasts derived from the patient (patient identification number, XP1CTA) were used for genetic complementation analysis by the conventional cell-fusion technique followed by measurement of ultraviolet light (UV)-induced unscheduled DNA synthesis (UDS). The level of UDS in XP1CTA cells measured by autoradiography was about 20% of that in normal cells. When XP1CTA cells were fused with cells of a representative strain from each of the complementation groups A, D, E, F, G, and H, binuclear cells showed UDS levels in the range of normal cells, demonstrating a clear complementation between XP1CTA strain and either one of these strains. XP1CTA cells failed to complement with all the five reference strains belonging to group C. From these results, the XP1CTA was unambiguously assigned to complementation group C. Sensitivity of XP1CTA cells to UV, as measured by colony-forming ability, also fell within a range of variation in UV sensitivities of these group C XP cell strains.     

维生素D受体基因多态性与卵巢癌遗传易感性研究

目的 探讨中国人群维生素D受体基因FokⅠ和ApaⅠ位点单核苷酸多态性与卵巢癌易感性的关系.方法 采用Taqman-MGB方法检测FokⅠ和ApaⅠ位点各基因型频率在129例卵巢癌患者和298例对照者中的分布.结果 在调整年龄,绝经情况和BMI后,与CC基因型相比,FokⅠ位点的CT可以显著增加个体卵巢癌的患病风险(ORadj.ed=1.96,95％ CI:1.21 ～3.17);在未绝经女性中,与FokⅠ CC基因型相比,携带CT/TT可增加患卵巢癌的风险(ORadiusied=4.19,95％ CI:1.75 ～ 10.05);与TT单倍型相比,携带CT单倍型的个体可降低卵巢癌发病风险(ORadjustd=0.68,95％ CI:0.47～0.97).结论 维生素D受体基因多态性改变可能与中国人群卵巢癌遗传易感性有关.     

DNA切除修复基因XPD751位点多态性与食管癌发病风险的Meta分析

目的 探讨DNA切除修复基因XPD751位点多态性与食管癌的发病风险关系.方法 检索中外数据库,获得有关XPD751位点多态性与食管癌发病风险的病例对照研究资料进行Meta分析,并按组织学类型进行分层分析,得到合并OR值(95%CI).结果 共纳入文献11篇,研究12项,累计食管癌病例2558例,对照5122例,与野生基因型Lys/Lys相比,Lys/Gln、Gln/Gln和(Lys/Gln+Gln/Gln)合并的OR值(95%CI)分别为1.19(1.05,1.34)、1.22(0.86,1.74)、1.20(1.01,1.42).分层分析显示,累计食管鳞癌病例1417例,对照2312例,携带Lys/Gln、(Lys/Gln+Gln/Gln)的个体患食管鳞癌的风险分别是Lys/Lys的1.22倍(95%CI:1.02,1.46)、1.24倍(95%C1:1.01,1.47);累计食管腺癌病例935例,对照2604例,未发现XPD751位点多态性与食管腺癌发病风险的统计学相关性.结论 XPD751位点杂合基因型Lys/Gln和(Lys/Gln+Gln/Gln)是食管癌发病的危险因素.XPD751位点杂合基因型Lys/Gln和(Lys/Gln+Gin/Gin)与食管鳞痛的发病风险相关,未发现XPD751位点多态性与食管腺癌的发病风险有关.     

Topical and systemic chemotherapy with 5-fluouracil in facial carcinoma secondary to xeroderma pigmentosum

OBJECTIVE: to evaluate the feasibility, tolerance/toxicity and therapeutic efficacy of 5-fluorouracil (5-FU) by topical application and systemic use, in facial carcinoma associated with XP. METHODS AND PATIENTS: This is a prospective study of 10 patients with a median age of 22.9 years and a sex ratio of 4. Tumour lesions were facial mainly in the jugal and temporal region (36%). Chemotherapy indication was discussed in multidisciplinary committee, the topical 5-fluorouracil was applied locally twice a day, whereas the systemic treatment consisted of FUFOL protocol (every 4 weeks a combinaison of a short perfusion of 340 mg/m2 5-FU and preceded by an infusion of 20mg/m2 of folic acid, day 1 to 5); or C-FU protocol, combining continuous infusion of 5-FU (1 g/m2) 5 days associated with cisplatin (100 mg/m2, day 1) every 3 weeks. RESULTS: The median topical treatment duration was of 12 months in 10 patients. We noted a full tumoral regression in 10% of cases. Concerning systemic treatment, the median number of FUFOL cycles was 4 (2 to 6) and we observed a complete response in 6 patients (60%), partial in 2 cases (20%). Treatment was well tolerated in most cases except for the cutaneous irritation on 5-FU application zone and a 4 grade cisplatin otoxicity. CONCLUSION: Systemic or topical chemotherapy represents an interesting palliative option for facial carcinoma associated with XP, avoiding reiterated surgery and its cosmetic consequences.     

中国汉族人群结核易感基因多态性与耐药结核病相关性研究

目的 了解结核易感基因SLC11A1基因、VDR基因、MBL基因以及IFNG基因多态性在中国汉族人群敏感和耐药结核病患者中的分布,探讨其与耐药结核病发生的相关性.方法 使用焦磷酸测序法、Real-time探针法、SNaPshot法测定229例敏感肺结核(敏感组)和230例耐药肺结核(耐药组)患者的VDR基因、SLC11A1基因、MBL基因、IFNG基因的单核苷酸多态性(SNP).结果 VDR基因多态性位点在敏感组和耐药组间差异均无统计学意义(P＞0.05).SLC11A1基因的INT4位点基因型和等位基因频率在敏感组和耐药组间差异有统计学意义(P值分别为0.031、0.046);INT4位点在隐性遗传模型假定下,敏感组和耐药组间差异具有统计学意义(OR=5.756,95%CI:1.261～26.269,P=0.011),结合该位点各种组合下的OR值间的数量关系,确定该位点的遗传模型符合隐性遗传模型.MBL基因Q/P位点基因型和等位基因频率在敏感组和耐药组间差异有统计学意义(P值分别为0.029、0.033);在隐性遗传模型假定下,MBL基因Q/P位点基因型和等位基因频率在不同组别间差异有统计学意义(OR=9.290,95%CI:1.167～73.949,P=0.011).IFNG基因的多态性位点在敏感组和耐药组之间的分布无统计学意义.结论 SLC11A1基因的INT4位点和MBL基因Q/P位点可能与中国汉族人群耐药结核病的发生具有一定的相关性.

Abstract：

Objective To investigate the distribution of polymorphisms of SLC11A1 gene,VDR gene,MBL gene and IFNG gene with susceptibility to tuberculosis (TB) in Chinese Han population suffering from drug-sensitive TB and drug-resistant TB so as to identify the correlation between gene polymorphisms and the development of drug-resistant TB.Methods Single nucleotide polymorphisms (SNP) of VDR gene,SLC11A1 gene,MBL gene,IFNG gene were typed and analyzed by pyrosequencing,Real-time Probe and SNaPshot among 229 patients with drug-sensitive TB and 230 patients with drug-resistant TB.Results The polymorphic foci of VDR gene from the drug-sensitive TB group and the drug-resistant TB group showed no significant difference (P＞0.05).The genotype of INT4 site and allelic frequency of SLC11A1 gene for drug-sensitive TB group were significantly different from those for drug-resistant TB group(P=0.031,0.046).If recessive inheritance was assumed,the genotypes of INT4 site from the two groups were significantly different (0R=5.756,95% CI:1.261-26.269,P=0.011).Considering the relationship between OR values under various combination,our findings confirmed that the genetic mode of INT4 site was in accordance with recessive inheritance.The genotypes of Q/P site and allelic frequencies of MBL gene from drug-sensitive and drug-resistant groups were significantly different (P=0.029,0.033).The difference still existed under the hypothesis of recessive inheritance (OR=9.290,95% CI:1.167-73.949,P=0.011).The polymorphic foci of IFNG gene from the two groups showed no significant difference.Conclusion INT4 sites on SLC11A1 gene and Q/P site on MBL gene were probably associated with the development of drug-resistant TB in Chinese Han population.Further study on this issue would be helpful in locating the population at high risk of drug-resistant TB and exploring the effective intervention to decrease the incidence of this disease.     

Sex-specific association of estrogen receptor 2 polymorphisms with hepatitis C virus infection outcomes in a high-risk Chinese Han population

Hepatitis C virus (HCV) has different clinical and biological characteristics in women versus men, which suggests the potential involvement of estrogen. Estrogen signaling is mediated by the estrogen receptor, and genetic variations in the estrogen receptor gene might affect the pathology of HCV infection. We performed logistic regression analysis to explore the associations between rs1256049, rs4986938 and rs944459 polymorphisms of the estrogen receptor 2 gene (ESR2) and HCV infection outcomes. The variant A allele of rs4986938 was associated with an increased HCV infection susceptibility in the males (additive model: adjusted OR = 1.493, P = 0.010) and a significantly reduced risk of HCV infection in the female subgroup (GA vs. GG: adjusted OR = 0.710, P = 0.012; dominant model: adjusted OR = 0.686, P = 0.004; additive model: adjusted OR = 0.703, P = 0.002). In addition, females carrying the rs4986938 AA genotype appeared to clear HCV spontaneously more readily (adjusted OR = 0.237, P = 0.011), and additive model analyses showed that each additional allele contributed a decreased risk of approximately 34% for HCV chronicity (adjusted OR = 0.659, P = 0.006). Furthermore, a significant multiplicative interaction between the combined rs1256049 and rs4986938 genotypes was found to decrease HCV infection risk (adjusted OR = 0.583, P = 3.000 × 10⁻⁴). The area under the curve, based on the model and including age, gender, HCV genotypes and the three SNPs, was significantly related to the clearance of HCV (P = 0.003). We provide here the first report that rs4986938 in the ESR2 gene played a potential sex-specific role in the etiology of HCV infection in a high-risk Chinese Han population, suggesting that ESR2 is a candidate susceptibility gene for HCV infection and viral clearance.     

长链非编码RNA多态性和女性常见肿瘤易感性的研究进展

目的 近年研究发现长链非编码RNA(lncRNA)存在广泛单核苷酸多态性(SNPs),可影响个体对癌症的遗传易感性。本文对lncRNA SNPs与四种女性常见肿瘤发病风险的关系作一综述。方法 以“长链非编码RNA、多态性、乳腺癌、宫颈癌、卵巢癌、子宫内膜癌”为关键词,检索近五年中英文文献,对lncRNA 多态性与女性常见肿瘤发病风险相关性进行综述。结果 通过回顾性分析,发现多个lncRNA SNPs可影响乳腺癌、宫颈癌、卵巢癌、子宫内膜癌的遗传易感性。结论 lncRNA多态性影响女性常见肿瘤发病风险,可为女性常见肿瘤高危人群筛选提供依据。     

Association of toll-like receptors with susceptibility to tuberculosis suggests sex-specific effects of TLR8 polymorphisms

Background: Toll-like receptors (TLRs) are involved in the recognition of conserved microbial structures, leading to activation of an inflammatory response and formation of an adaptive immune response. Methods: Twenty-three polymorphisms in five TLR genes were genotyped in 729 tuberculosis cases and 487 healthy controls in a population-based case-control association study in a South African population. Results: We detected sex-specific associations for TLR8 polymorphisms, with rs3761624 (OR = 1.54, p < 0.001), rs3764879 (OR = 1.41, p = 0.011) and rs3764880 (OR = 1.42, p = 0.011) associated in females and rs3764879 (OR = 0.72, p = 0.013) and rs3764880 (OR = 0.75, p = 0.036) associated in males. Epistatic interactions between the TLR genes were investigated and the TLR1_rs4833095 polymorphism was shown to interact with TLR2_rs3804100 and (GT)_n microsatellite (p = 0.002) and alter susceptibility to TB. We also studied the role of TLRs in disease caused by different Mycobacterium tuberculosis genotypes in 257 tuberculosis cases, and identified associations between specific TLR polymorphisms and disease caused by specific strains. Conclusion: This study provides further evidence that the TLRs play an important role in the outcome of tuberculosis disease, and suggests a partial explanation for the male bias in tuberculosis ratios.     

GSTM1和GSTT1基因多态性与噪声性听力损失易感性的关系

目的探讨GSTM1和GSTT1基因多态性与噪声性听力损失易感性的关系。方法采用病例对照研究方法和多重聚合酶链反应(PCR)技术检测听损组123(118)例和对照组123(114)例的GSTM1和GSTT1基因缺失型频率,以2检验检测听损组和对照组基因型频率的差异。结果GSTM1基因在听损组和正常组的缺失率分别为69.1%和56.1%,差异具有统计学意义(P<0.05)。GSTM1(-)基因型携带者发生噪声性听力损失的危险性是携带GSTM1( )基因型者的1.75倍。GSTT1基因在听损组和正常组的缺失率为50.8%和57.9%,差异没有统计学意义(P>0.05)。联合分析表明,携带GSTM1(-)和GSTT1(-)基因型者发生噪声性听力损失的危险性虽稍高于携带GSTM1( )和GSTT1( )基因型者(OR=1.11,2=0.16,P>0.05),但差异无统计学意义,由此认为GSTM1和GSTT1基因之间可能不存在联合作用。结论GSTM1基因缺失可能是发生噪声性听力损失的易感因素之一。