miR-146a和miR-196a2基因多态性对高危型 HPV感染者宫颈癌易感性的影响

目的探讨微小RNA(miR)-146a和miR-196a2基因多态性对高危型人乳头瘤病毒(HPV)感染患者宫颈癌易感性的影响及诊断价值。方法选择2018年1月-2019年12月海南医学院第二附属医院收治的高危型HPV感染宫颈癌患者70例作为宫颈癌(CC)组,选择同期接受治疗的高危型HPV感染宫颈上皮内瘤变(CIN)患者70例作为CIN组,选择同期无宫颈病变但存在高危型HPV感染的体检者50名作为对照组。分别采用DNA测序法和2~(-△△ct)法检测三组miR-146a基因rs2910164位点、miR196a2基因rs11614913位点基因多态性及其mRNA表达水平。采用受试者工作特征曲线(ROC)对其诊断价值进行评价。结果三组研究对象miR-146a基因rs2910164位点GC、CC基因型、miR196a2基因rs11614913位点CC、TT分布差异具有统计学意义(P0.05);三组研究对象整体miR-146a基因rs2910164位点G/C等位基因、miR196a2基因rs11614913位点C/T等位基因分布差异具有统计学意义(P0.05); CC组miR-146a mRNA、miR196a2 mRNA表达水平高于CIN组及对照组,CIN组高于对照组(P0.05); ROC分析结果显示,外周血中miR-146a、miR196a2 mRNA诊断CC的曲线下面积(AUC)均0.7。结论 miR-146a和miR-196a2基因多态性可能是本地区高危型HPV感染女性宫颈癌的易感因素,其mRNA水平对于宫颈癌具有一定的诊断价值。     

miR-146a和miR-196a2前体区遗传多态性与焦炉工人遗传损伤的关系

目的 探讨miR-146a和miR-196a2前体区遗传多态位点rs2910164 G＞C和rs11614913 T＞C与焦炉工遗传损伤的关联性.方法 于2010年9月至10月,选取湖北省武汉市某焦化厂工龄在1年以上,无肿瘤,无吸烟习惯的焦炉作业工人,共575名.收集一般人口学资料并采集外周静脉血和尿液;采用胞质分裂阻滞试验计算外周血淋巴细胞的微核率来评价染色体损伤的程度;采用TaqMan探针对miR-146a前体区rs2910164 G＞C和miR-196a2前体区rs11614913 T＞C多态位点进行分型分析;采用三明治ELISA测定血浆中苯并[a]芘二氢二醇环氧化物-白蛋白(BPDE-白蛋白)加合物的浓度;并进行数据分析,并计算频率比(FR)及其95％ CI值.结果 共纳入575名工人.与携带野生型rs2910164 GG基因型的工人的外周血淋巴细胞微核率(4.02±3.09)相比,携带rs2910164CC基因型工人的微核率(4.38±3.46)增加(FR=1.18,95％CI:1.04～1.34),且有明显的等位基因剂量-效应关系(P趋势=0.025).按研究对象不同特征分层后,发现男性(FR=1.11,95％ CI:1.02～ 1.20)、不饮酒(FR=1.07,95％ CI:1.00 ～1.14)、工龄＜20年(FR=1.12,95％CI:1.03 ～ 1.22)和低BPDE-白蛋白水平组(FR=1.11,95％CI:1.02～1.21)中,rs2910164C等位基因与微核率的增加具有等位基因剂量-效应关系(P趋势分别为0.011、0.044、0.006和0.020).此外,与携带rs11614913TT基因型的工人(3.90±3.32)相比,携带rs11614913 TC基因型工人的外周血淋巴细胞微核率增加(4.27±2.91)(FR=1.12,95％CI:1.02 ～ 1.23).以同时携带rs2910164 GG及rs11614913TT基因型的工人组作为对照,同时携带rs2910164CC与rs11614913 CC基因型个体的外周血淋巴细胞微核率(5.32±4.94)是对照组(3.75±3.01)的1.51(1.21 ～1.89)倍.结论 miR-146a前体区域rs2910164C等位基因及miR-196a2前体区域rs11614913 C等位基因与焦炉工遗传损伤水平增加有关.     

广西地区人群IL-6及IL-10单核苷酸多态性与HBV相关肝癌关联研究

目的 探讨广西地区人群IL-6和IL-10基因单核苷酸多态性(SNP)与HBV相关肝癌的关系.方法 采用以医院为基础的病例对照研究方法,以381例肝癌患者为病例组,340例HBsAg携带者及359例健康体检者为对照组.应用荧光定量PCR对IL-6基因-572位点,IL-10基因-819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人群罹患肝癌的风险.结果 IL-6基因-572位点G/C等位基因在病例组、HBsAg携带组及健康对照组中分布差异有统计学意义(P＜0.05),与CC基因型相比,携带GG基因型个体慢性HBV感染危险性增加(OR=2.171,95%CI:1.068-4.415).IL-10基因-819位点T/C等位基因在三组的分布差异有统计学意义(P＜0.05),与CC基因型相比,携带TT基因型健康个体罹患肝癌的危险性增加(OR=2.791,95%CI:1.326～5.874).携带TT基因型的HBsAg携带者罹患肝癌的风险也增加(OR=3.522,95%CI:1.707～7.266).IL-10基因-592位点A/C等位基因在三组中的分布差异无统计学意义(P＞0.05),与CC基因型相比,携带AA基因型健康个体罹患肝癌的危险性降低(OR=0.389,95%CI:0.173-0.875),携带AA基因型的HBsAg携带者肝癌的罹患风险也降低(OR=0.336,95%CI:0.154-0.734).结论 IL-6基因-572位点SNP与广西地区人群慢性HBV感染有关,IL-10基因-819位点TT基因型个体罹患肝癌的风险增加,IL-592位点从基因型个体罹患肝癌的风险降低.

Abstract：

Objective To investigate the association between single nucleotide polymorphisms (SNPs)in cytokine IL-6, IL- 10 genes and HBV-related hepatocellular carcinoma(HCC). Methods A hospital-based case-control study was conducted in 381 cases with HBV-related HCC, 340 HBsAg carriers and 359 non-tumor controls. Genotypes of-572 site of IL-6 gene and-819, -592 sites of IL-10 gene were determined by real-time polymorphism chain reaction. Unconditional logistic regression was used to estimate the odds ratios(ORs)and 95 confidence intervals(C/s). Results For the G/C alleles of -572 loci on IL-6 gene, there were significant differences between the three groups(P＜0.05). Compared with CC genotype, GG genotype increased the risk of HBV infection (OR=2.171,95% Ch 1.068-4.415), but did not seem to be associated with HCC. For the alleles of-819 and -592 site of IL-10 gene, there were significant differences between the three groups(P＜0.05). Compared with CC genotype, TT genotype increased the risks of both HCC(OR=2.791,95%CI:1.326-5.874), and HCC in HBsAg carriers(0R=3.522,95%CI: 1.707-7.266). When compared with CC genotype on -592 site, the AA genotype reduced the risk of both HCC(OR=0.389, 95% CI:0.173-0.875), and HCC in HBsAg carriers(OR=0.336, 95% CI: 0.154-0.734). Conclusion The SNPs in -572 site of IL-6 gone might be associated with the risk of HBV infection. The SNPs in -819 site of IL-10 gene increased the risk of HCC, but -592 site of IL-10 gene decreased the risk of HCC.     

广西地区人群IL-6及IL-10单核苷酸多态性与HBV相关肝癌关联研究

Objective To investigate the association between single nucleotide polymorphisms (SNPs)in cytokine IL-6, IL- 10 genes and HBV-related hepatocellular carcinoma(HCC). Methods A hospital-based case-control study was conducted in 381 cases with HBV-related HCC, 340 HBsAg carriers and 359 non-tumor controls. Genotypes of-572 site of IL-6 gene and-819, -592 sites of IL-10 gene were determined by real-time polymorphism chain reaction. Unconditional logistic regression was used to estimate the odds ratios(ORs)and 95 confidence intervals(C/s). Results For the G/C alleles of -572 loci on IL-6 gene, there were significant differences between the three groups(P＜0.05). Compared with CC genotype, GG genotype increased the risk of HBV infection (OR=2.171,95% Ch 1.068-4.415), but did not seem to be associated with HCC. For the alleles of-819 and -592 site of IL-10 gene, there were significant differences between the three groups(P＜0.05). Compared with CC genotype, TT genotype increased the risks of both HCC(OR=2.791,95%CI:1.326-5.874), and HCC in HBsAg carriers(0R=3.522,95%CI: 1.707-7.266). When compared with CC genotype on -592 site, the AA genotype reduced the risk of both HCC(OR=0.389, 95% CI:0.173-0.875), and HCC in HBsAg carriers(OR=0.336, 95% CI: 0.154-0.734). Conclusion The SNPs in -572 site of IL-6 gone might be associated with the risk of HBV infection. The SNPs in -819 site of IL-10 gene increased the risk of HCC, but -592 site of IL-10 gene decreased the risk of HCC.     

广西地区人群IL-6及IL-10单核苷酸多态性与HBV相关肝癌关联研究

Objective To investigate the association between single nucleotide polymorphisms (SNPs)in cytokine IL-6, IL- 10 genes and HBV-related hepatocellular carcinoma(HCC). Methods A hospital-based case-control study was conducted in 381 cases with HBV-related HCC, 340 HBsAg carriers and 359 non-tumor controls. Genotypes of-572 site of IL-6 gene and-819, -592 sites of IL-10 gene were determined by real-time polymorphism chain reaction. Unconditional logistic regression was used to estimate the odds ratios(ORs)and 95 confidence intervals(C/s). Results For the G/C alleles of -572 loci on IL-6 gene, there were significant differences between the three groups(P＜0.05). Compared with CC genotype, GG genotype increased the risk of HBV infection (OR=2.171,95% Ch 1.068-4.415), but did not seem to be associated with HCC. For the alleles of-819 and -592 site of IL-10 gene, there were significant differences between the three groups(P＜0.05). Compared with CC genotype, TT genotype increased the risks of both HCC(OR=2.791,95%CI:1.326-5.874), and HCC in HBsAg carriers(0R=3.522,95%CI: 1.707-7.266). When compared with CC genotype on -592 site, the AA genotype reduced the risk of both HCC(OR=0.389, 95% CI:0.173-0.875), and HCC in HBsAg carriers(OR=0.336, 95% CI: 0.154-0.734). Conclusion The SNPs in -572 site of IL-6 gone might be associated with the risk of HBV infection. The SNPs in -819 site of IL-10 gene increased the risk of HCC, but -592 site of IL-10 gene decreased the risk of HCC.     

外周血miR-146基因多态性与乙型肝炎病毒感染患者肝硬化的易感性

目的探讨外周血微小RNA(miR)-146基因多态性与乙型肝炎病毒感染患者肝硬化的易感性及其水平与病情严重程度的关系。方法选择杭州市西溪医院肝病科2018年5月-2020年6月收治的乙型肝炎肝硬化患者100例纳入研究组,选择同期医院收治的乙型肝炎非肝硬化患者60例作为对照组。采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)技术检测两组miR-146a基因rs2910164位点基因型及表达水平,比较不同基因型患者乙型肝炎病毒载量、血清谷丙转氨酶(ALT)、谷草转氨酶(AST)及总胆固醇(TC)水平。结果研究组miR-146a基因rs2910164位点CC基因型、C等位基因频率均高于对照组(P0.05); 100例慢性乙型肝炎肝硬化患者根据病情程度分为Child-pugh(A、B、C)三组,Child-pugh C组CC基因型频率高于Child-pugh A组及Child-pugh B组(χ~2=18.291、11.431,P均0.001); miR-146a基因rs2910164位点CC基因型患者miR-146 mRNA、AST、ALT、TC水平高于TT/TC患者(P0.05),HBV-DNA水平比较差异无统计学意义。结论 miR-146a基因rs2910164位点多态性与HBV感染者发生肝硬化风险相关,miR-146 mRNA水平对肝硬化程度判断具有一定的价值。     

Toll样受体2及Toll样受体9基因多态性与胃癌易感性的关系

目的 探讨Toll样受体2(Toll-like receptor 2,TLR2)及TLR9基因多态性与胃癌易感性的关系.方法 以山东省临朐县胃癌高发现场人群为基础,选取248例胃癌患者,采用年龄、性别匹配的方法在同一地区按分层随机抽样方法选取496例浅表性胃炎或轻度萎缩性胃炎患者为对照,用聚合酶链式反应-限制性片段长度多态性方法检测TLR2基因rs3804099位点及TLR9基因rs187084位点基因型.采用多因素logistic回归模型并调整年龄、性别、幽门螺杆菌感染及吸烟因素后,计算OR值(95%CI).结果 TLR2基因rs3804099位点TT、TC、CC基因型频率在病例组分别为53.2%(132/248)、39.9%(99/248)、6.9%(17/248),在对照组分别为43.5%(216/496)、46.6%(231/496)、9.9%(49/496),各基因型频率在两组间分布的差异有统计学意义(χ2=6.665,P=0.036).多因素logistic回归显示,以TT基因型为参照,携带TC+CC基因型者发生胃癌的风险明显降低(OR=0.68,95%CI:0.50～0.93).联合效应分析显示,以携带rs3804099位点TC+CC基因型且未感染幽门螺杆菌者为参照,携带TT基因型并感染幽门螺杆菌者发生胃癌的风险明显增加(OR=3.42,95%CI:2.16～5.42).TLR9 基因rs187084位点TT、TC、CC基因型频率在病例组分别为35.9%(89/248)、50.0%(124/248)、14.1%(35/248),在对照组分别为33.3%(165/496)、49.0%(243/496)、17.7%(88/496),各基因型频率在两组间分布的差异无统计学意义(χ2=1.684,P=0.431).结论 TLR2 基因rs3804099位点多态与胃癌发病风险密切相关.

Abstract：

Objective To explore the relationship between the polymorphisms of Toll-like receptor 2(TLR2) and TLR9 and the susceptibility to gastric cancer.Methods A population-based case-control study was conducted at Linqu county,Shandong province,China,including a total of 248 cases of gastric cancer.Another total of 496 age and sex-matched controls were randomly selected from the same cohorts.TLR2 rs3804099 and TLR9 rs187084 were detected by polymerase chain reaction-restriction fragment length polymorphism method.Odds ratios(ORs) and 95% confidence interval(CI) were computed from logistic regression models after adjusting for age,sex,Helicobacter pylori(H.pylori) infection and smoking status.Results The frequencies of TT,TC and CC genotype on TLR2 rs3804099 in control group were 43.5%(216/496),46.6%(231/496) and 9.9%(49/496),respectively; whereas those in case group were 53.2%(132/248),39.9%(99/248) and 6.9%(17/248),respectively.Significant differences in the frequencies of TLR2 rs3804099 were found between case and control groups(χ2=6.665,P=0.036).It was found that compared with the TT genotype,TC+CC genotype carriers obviously less susceptible to gastric cancer(OR=0.68,95%CI:0.50-0.93).Joint effects analysis indicated that the TLR2 rs3804099 TT genotype carriers and H.pylori infectors had higher susceptility to gastric cancer(OR=3.42,95%CI:2.16-5.42),compared with TC+CC genotype carriers and non-H.pylori infection group.The frequencies of TT,TC and CC genotype on TLR9 rs187084 in control group were 33.3%(165/496),49.0%(243/496) and 17.7%(88/496),respectively; whereas those in case group were 35.9%(89/248),50.0%(124/248) and 14.1%(35/248),respectively.No significant association with gastric cancer was observed for TLR9 rs187084 polymorphism(χ2=1.684,P=0.431).Conclusion Our findings indicate that TLR2 rs3804099 is closely associated with susceptibility to gastric cancer.     

miR-196a2和miR-149单核苷酸多态性与缺血性脑卒中的相关性分析

目的分析miR-196a2 rs11614913和miR-149 rs2292832单核苷酸多态性与缺血性脑卒中的相关性。方法选取378例缺血性脑卒中患者为病例组,378名经性别和年龄匹配且未患缺血性脑卒中的正常体检者为对照组,收集两组一般体检资料并采用Taqman-PCR和DNA直接测序技术检测两组miR-196a2 rs11614913和miR-149 rs2292832位点基因型和等位基因频率,采用Gen AIEx 6.5软件进行哈代-温伯尔遗传平衡定律分析,采用条件Logistic回归分析上述位点与缺血性脑卒中发病风险的关系。结果病例组患有糖尿病、高血压、体质指数≥24 kg/m2及血脂代谢异常患者比例均高于对照组(P0.01)。miR-196a2 rs11614913位点等位基因C、基因型TC和CC与缺血性脑卒中均无统计学关联(P0.05),miR-149 rs2292832与缺血性脑卒中在等位基因模型(C vs.T:P=0.026,OR=1.269,95%CI=1.031~1.569)、共显模型(CC vs.TT:P=0.011,OR=1.812,95%CI=1.150~2.850)和隐性模型(CC vs.TC+TT:P=0.008,OR=1.739,95%CI=1.142~2.647)与缺血性脑卒中相关。结论 miR-149 rs2292832位点与缺血性脑卒中相关,提示此位点可能参与缺血性脑卒中的发病过程,是遗传风险易感位点。     

急性乙型肝炎临床特征和病毒标志物动态变化分析

Objective To explore the dynamic change of viral marker and clinical features in acute hepatitis B (AHB)and distinguish AHB from chronic hepatitis B(CHB) in acute onset. Methods Viral marker, HBV DNA in serum and clinical features were analyzed in 105 patients with AHB (AHB group) and 102 patients with CHB in acute onset (CHB group) between 2005 and 2009. Results There was no statistical difference in the mean levels of ALT, TBil, HBsAg, HBeAg and HBV DNA between AHB and CHB group on admission. However, the titer of auti-HBc-IgM in AHB group was(26.34 ±3.74)S/CO, which was obviously higher than that in CHB group, which was( 14.46 ± 3.10)S/CO, there was a statistical difference between the two groups( P < 0.05). After 2 weeks treatment, the levels of ALT and TBil in AHB patients decreased (1540.50±225.54)IU/L and (103.60± 46.48) μmol/L respectively, the decreased levels in AHB group were high compared to CHB group; the levels of HBsAg, HBeAg and HBV DNA in AHB group decreased (2558.46 ±644.26) IU/mL, (420.20± 63.20) S/CO and (4.53± 1.42) log10copies/mL respectively, and the levels decreased obviously compared to CHB group (P < 0.05). The decreased level of anti-HBc-IgM in AHB group was no statistical difference to CHB group after 2 weeks treatment (P > 0.05). 19.04% of the AHB patients were HBV DNA negative seroconversion before they were hospitalized. The level of HBsAg and HBeAg in AHB group declined quickly. Separately, 90.47% and 94.24% of the AHB patients had HBsAg and HBeAg seroconversion at the end of follow-up in AHB group. The level of ALT in AHB decreased quickly but its normalization was slower than the clearance of HBV. Conclusions There is no difference in viral marker, HBV DNA and clinical features between AHB and CHB in acute onset patients on admission, but the recovery of liver function in AHB is obviously after treatment. Anti-HBc-IgM (≥20 S/CO), dynamic change and seroconversion viral marker, ALT ≥20×ULN and recovery can be used to differentiate AHB from CHB in acute onset.     

Association between microRNA196a2 rs11614913 genotypes and the risk of non-small cell lung cancer in Korean population

Objectives

The microRNA (miRNA) miR-196a2 may play an important role in lung cancer development and survival by altering binding activity of target mRNA. In this study, we evaluated their associations with the susceptibility of non-small cell lung cancers (NSCLC) by case-control study in a Korean population.

Methods

We performed genotyping analyses for miR-196a2 rs11614913 T/C at miRNA regions in a case-control study using blood samples of 406 NSCLC patient and 428 cancer-free control groups.

Results

The total C allele frequencies for miR-196a2 were 48.8% for the patients and 45.6% for the controls; and the genotype frequencies of TT, TC, and CC were 23.7%, 55.2%, and 21.1% for the patients and 31.1%, 46.35%, and 22.4% for the controls (p<0.05). Participants who possesses TC/CC genotypes showed high risk for NSCLC compared to those possessed TT genotypes (OR, 1.42; 95% CI, 1.03 to 1.96). The association was persisted in 60 and older age group, male, smokers, those without family history for cancer. However, no significant association of CC genotypes in recessive genetic model was observed.

Conclusions

In conclusion, this case-control study provides evidence that miR-196a2 rs11614913 C/T polymorphisms are associated with a significantly increased risk of NSCLC in a dominant model, indicating that common genetic polymorphisms in miR-196a2 rs11614913 are associated with NSCLC. The association of miR196a2 rs11614913 polymorphisms and NSCLC risk require confirmation through additional larger studies.     

survivin基因易感性及其单倍型与原发性肝细胞癌关系

目的探讨汉族人群中存活素(survivin)基因rs8073069及rs1042489位点与原发性肝细胞癌(HCC)的相关性,为采取干预措施提供参考依据。方法采用病例对照研究方法对在江苏省海门市10个社区收集的176例汉族HCC病例和随机匹配的196名健康汉族人群进行一般情况问卷调查以及survivin基因rs8073069和rs1042489位点基因分型。结果 rs8073069位点CC、CG、GG基因型和C、G 2个等位基因在HCC病例组的频率分别为8.52%、35.22%、56.25%2、6.14%7、3.86%,在对照组的频率分别为6.12%3、9.80%、54.08%、26.02%7、3.98%,不同遗传模式下rs8073069位点基因型和等位基因分布在HCC病例组与对照组间分布差异均无统计学意义(P>0.05);rs1042489位点CC、CT、TT基因型和C、T 2个等位基因在HCC病例组的频率分别为17.61%、55.68%、26.70%、45.45%、54.55%,在对照组的频率频率为13.78%、52.04%、34.18%、39.80%、60.20%,不同遗传模式下rs1042489位点基因型及等位基因在HCC病例组与对照组间分布差异均无统计学意义(P>0.05);多因素Logistic回归分析结果表明,在相加遗传模式下,HBsAg+和有乙肝史是HCC的危险因素r,s8073069G-rs1042489T单倍型是HCC的保护因素;不同遗传模式下环境因素与单倍型交互作用分析结果表明,显性、隐性和相加遗传模式均未发现单倍型与环境因素的交互作用(P>0.05)。结论汉族人群survivin基因rs8073069和rs10424892位点多态性与HCC的易感性无关;rs8073069G-rs1042489T单倍型是HCC的保护单倍型。     

let-7启动子区基因多态性与肝细胞肝癌遗传易感性的关联

目的 探讨let-7启动子区域基因多态与中国人群肝细胞肝癌(HCC)易感性的关联.方法 采用病例-对照研究设计,以经确诊的1300例乙型肝炎病毒(HBV)阳性HCC患者作为病例组,选取1344例HBV持续性感染患者作为对照组.收集研究对象血液标本5ml,提取基因组DNA.以let-7启动子区rs10877887和rs13293512为研究位点,应用TaqMan探针方法进行多态性检测,并用logistic回归计算OR(95％CI)值,比较不同基因型与HCC患病风险的关系.结果 rs10877887位点3种基因型TT、CT及CC在病例组分布频率分别为43.0％ (542/1261)、44.7％ (564/1261)及12.3％( 155/1261);在对照组中分别为44.0％( 581/1319)、44.4％( 585/1319)及11.6％ (153/1319).rsl3293512位点3种基因型TT、CT及CC在病例组分布频率分别为32.0％( 406/1270)、48.1％(611/1270)及19.9％ (253/1270),在对照组中分别为33.1％ (427/1291)、49.4％( 638/1291)及17.5％ (226/1291).多因素logistic回归分析显示,携带rs10877887位点至少1个突变等位基因C的个体与携带TT基因型的个体相比,HCC患病风险差异无统计学意义(CC+ CT对TT:调整OR=1.05,95％ CI:0.90～ 1.23);与携带TT基因型个体比较,携带rs13293512位点至少1个突变等位基因C的个体HCC患病风险差异无统计学意义(CC+ CT对TT:调整OR=1.06,95％ CI:0.89～ 1.25).两位点联合分析显示:携带0、1、2及3～4个突变等位基因C的患者在病例组分别占13.3％( 164/1235)、36.2％ (447/1235)、33.0％ (408/1235)及17.5％ (216/1235),在对照组中分别占14.2％ (181/1269)、37.0％ (469/1269)、33.1％ (420/1269)及15.7％ (199/1269).携带1、2及3～4个突变等位基因C个体的HCC患病风险分别是不携带突变等位基因个体的1.05(0.81～1.34)、1.07(0.83～1.38)、1.22(0.91 ～ 1.62)倍,呈一致趋势,但无统计学意义(Wald x2=1.79,P=0.181).结论 let-7启动子区域rs10877887和rs13293512位点多态改变可能不是中国人群HCC易感性标志.     

Genetic variants in IL33 and IL1RL1 genes confer susceptibility to HBV-related liver cirrhosis in Chinese Han population

IntroductionPrevious studies indicate that the IL-33/ST2 pathway is involved in hepatitis B virus (HBV) -related liver diseases. This study aimed to determine the relationship between genetic variants in IL-33/ST2 pathway with susceptibility to liver cirrhosis.Materials and methodsA total of 2632 Han Chinese samples met the inclusion and exclusion criteria, including 840 negative controls (NeC), 691 chronic hepatitis B (CHB), 680 HBV-related liver cirrhosis (LC) and 421 HBV-related hepatocellular carcinoma (HCC) (without LC) patients. Four polymorphisms (IL33-rs4742170, rs1048274, rs10975519 and IL1RL1-rs1041973) were selected and genotyping was performed. All statistical analyses were performed by SPSS21.0, mainly using the Hardy-Weinberg equilibrium test, Pearson chi-square, unconditional Logistic regression and haplotype analysis.ResultsAfter adjusting for age, sex, smoking and drinking, significant associations were observed between IL33-rs4742170, rs1048274 and rs10975519 polymorphisms with LC risk. NeC with IL33-rs4742170 CC genotype was 1.80 times more likely to develop LC compared with TT genotype, while NeC with rs10975519(TC + CC) genotype was 1.32 times more likely to develop LC when compared with the TT genotype. CHB cases with rs4742170(CC + TC) genotype had 1.30 times higher susceptibility to develop LC compared with the TT genotype. The IL33-rs1048274G allele occurred more frequently in the LC group compared with the HCC group in codominant model (AG/AA: P = 0.001, OR = 1.66, 95%CI = 1.22–2.25; GG/AA: P = 0.018, OR = 1.54, 95%CI = 1.08–2.20). The IL33 haplotype CG conformed by rs10975519C and rs1048274G was more frequent in the LC group than in the NeC group and CHB group. Moreover, the IL33 haplotype CCG conformed by rs4742170C, rs10975519C and rs1048274G was found to be more frequent in the LC group than the HCC group. However, there was no association between IL1RL1-rs1041973 and LC risk.ConclusionOur findings demonstrate the association between genetic variants in IL33 with susceptibility to liver cirrhosis. IL33-rs4742170C, rs1048274G and rs10975519C could serve as biomarkers of LC.     

叉形头转录因子O亚型相关基因位点多态性与肝细胞癌关系

目的探讨叉形头转录因子O亚家族（forkhead box-containing protein O subfamily,FOXO）基因多态性与肝细胞癌（hepatocellular carcinoma,HCC）遗传易感性的关系。方法采用以医院为基础的病例对照研究方法,选取1 049例HCC患者作为病例组,1 052例无肿瘤患者作为对照组,对照组按年龄、性别、民族与病例组频数匹配。采用高通量TaqMan MGB实时荧光定量聚合酶链式反应（real-time fluorescent guantitative polymerase chain reaction,RT-PCR）技术对FOXO1的rs17592236位点、FOXO3的rs4946936位点和FOXO4的rs4503258位点进行基因分型。应用Logistic回归模型分析上述位点单核苷酸多态性（single nucleotide polymorphism,SNP）与HCC发病风险的关系,并研究基因多态性与环境因素的交互作用。结果 rs17592236、rs4946936和rs4503258位点基因型在病例组和对照组中分布差异均无统计学意义（均有P〉0.05）。多因素Logistic回归分析发现,rs17592236位点CT/TT基因型可能降低HCC发病风险[P=0.010,OR（95%CI）=0.699（0.526~0.927）]。分层分析结果显示rs17592236位点SNP与HCC发病风险存在统计学关联。交互作用分析显示,rs17592236、rs4946936、rs4503258位点多态性与吸烟、饮酒、HBV感染、肝癌家族史4种环境因素均存在交互作用,rs17592236与rs4503258位点SNPs之间存在基因-基因交互作用[P=0.003,OR（95%CI）=0.755（0.628~0.908）]。结论携带FOXO1的rs17592236位点突变等位基因T可能降低HCC发病风险。rs17592236、rs4946936、rs4503258与环境危险因素的交互作用可能与HCC发生有关。     

原发性肝癌的遗传流行病学研究

目的　研究原发性肝癌的遗传模式 ,探讨本病的遗传与环境的交互作用。方法　采用Penrose法、简单分离分析和Falconer法对乙型肝炎表面抗原 (HBsAg)阳性队列中的 10 0例原发性肝癌家系资料进行遗传流行病学研究。先证者样本来自同地区 9万名 8年随访队列人群 ,分析遗传模式并将队列中家系样本发病情况分别与队列人群和一般人群的发病情况进行比较 ,计算遗传度。结果　先证者家系一级亲属肝癌发生率为 4 .0 % ,高于一般人群发生率 (0 .4 4 % ) ,也高于队列人群的肝癌发生率 (1.0 3% )。HBsAg阳性在先证者家系中存在聚集 ,且HBsAg阳性与肝癌的发生有强相关(OR =8.4 4 ,95 %CI :3.37～ 2 0 .0 6 ,P <0 .0 0 1) ;应用Penrose法计算 ,同胞肝癌发生率 一般人群肝癌发生率 (s q)接近 1 q1 2 ;简单分离分析提示不符合单因子遗传模式 ;与一般人群遗传度相比 (5 9%±7% ) ,队列人群遗传度h2 =4 2 %± 6 % ,P <0 .0 5。在控制了HBsAg后 ,一般人群遗传度下降为4 7%± 7% ,队列人群遗传度下降为 2 9%± 8%。结论　肝癌不符合单基因遗传模式 ,为一多因子疾病 ,受遗传与环境的综合影响。     

Impacts of human leukocyte antigen DQ genetic polymorphisms and their interactions with hepatitis B virus mutations on the risks of viral persistence,liver cirrhosis,and hepatocellular carcinoma

Human leukocyte antigen (HLA)-DQ genetic polymorphisms have been associated with chronic hepatitis B virus (HBV) outcomes. We aimed to determine impacts of HLA-DQ polymorphisms and their interactions with HBV mutations on the risks of liver cirrhosis (LC) and hepatocellular carcinoma (HCC). rs2856718 (A > G) and rs9275319 (A > G) were genotyped in 1342 healthy controls, 327 HBV surface antigen (HBsAg) seroclearance subjects, 611 asymptomatic HBsAg carriers (ASCs), 1144 chronic hepatitis B (CHB) patients, 734 LC patients, and 1531 HCC patients using quantitative PCR. HBV mutations were detected by direct sequencing. Logistic regression analyses were utilized to assess the factors and/or multiplicative interactions significantly associated with liver diseases. rs9275319 variant genotypes were inversely associated with HBV persistence compared to HBV natural clearance subjects. rs2856718 variant genotypes significantly increased LC risk compared to ASCs plus CHB patients (GG vs. AA: odds ratio [OR], 1.52, 95% confidence interval [CI], 1.17–1.97 and AG + GG vs. AA: OR, 1.27; 95% CI, 1.04–1.54) and decreased HCC risk compared to HCC-free HBV-infected subjects (AG vs. AA: OR, 0.76; 95% CI, 0.65–0.89 and AG + GG vs. AA: OR, 0.78, 95% CI, 0.68–0.90). rs2856718 variant genotypes were significantly associated with an increased frequency of HBV A1726C mutation, a LC-risk, HCC-protective mutation, in genotype C. A rs9275319 variant genotype (GG) was significantly associated with an increased frequency of preS1 start codon mutation, an HCC-risk mutation, in genotype C. The interaction of rs2856718 AG + GG genotype with T1753V, a HCC-risk mutation, significantly reduced LC risk, with an OR of 0.26 (95% CI, 0.09–0.78); whereas the interaction of rs2856718 AG genotype with C1673T, a LC-risk mutation, significantly increased HCC risk, with an OR of 2.80 (95% CI, 1.02–7.66) in genotype C HBV-infected subjects. Conclusively, the HLA-DQ polymorphisms affect the risks of LC and HCC differently in chronic HBV-infected subjects, possibly via interacting with the HBV mutations.