遗传性血色病突变基因与糖代谢紊乱的关系研究

目的 检测2例遗传性血色病患者HFE基因突变情况,初步观察HFE基因突变与糖代谢紊乱的关系.方法 采集患者外周血提取基因组DNA,针对常见HFE基因突变区域设计引物进行PCR,测序后分析基因序列;构建野生型和突变型HFE基因表达载体,转染L02细胞检测胰岛素信号通路及下游有关糖代谢关键酶的表达水平.结果 2例患者均为C282Y A/A纯合突变,无H63D/S65C突变;过表达突变型HFE基因的细胞Akt磷酸化水平较弱,6-磷酸果糖激酶-1表达水平下调而磷酸烯醇式丙酮酸羧激酶和葡萄糖-6-磷酸酶表达水平上调.结论 HFE基因C282Y突变可能与患者的糖代谢紊乱有关.     

HFE基因多态性与非酒精性脂肪肝病遗传易感性的Meta分析

目的 采用Meta分析方法综合评价HFE基因多态性与非酒精性脂肪肝病(NAFLD)遗传易感性之间的关系.方法 检索PubMed、EMBASE、中国知网和万方数据库,获取2016年12月之前发表的关于C282Y和H63D多态性与NAFLD的病例-对照研究.以OR及95% CI为效应指标,应用Stata 12.0软件进行Meta分析、敏感性分析及发表偏倚评价.结果 共纳入17项研究,包含2 181例NAFLD病例和7 921例对照.采用随机效应模型和固定效应模型分别对C282Y和H63D进行合并分析.C282Y、H63D杂合基因型的合并OR分别为1.87(95% CI=1.12-3.12)、1.22(95% CI=1.05-1.41);显性模型合并OR值分别为1.95(95% CI=1.14-3.31)、1.24(95% CI=1.07-1.43).而在根据研究人群进行分层分析时发现,C282Y仅在高加索人中表现出与NAFLD发病的统计学关联,亚洲人群中则不存在该多态性;H63D的突变等位基因增加NAFLD发病风险的效应也仅限于高加索人群和混合人群.此外,研究未观察到发表偏倚,且敏感性分析表明结果稳定.结论 HFE基因的C282Y、H63D多态性可增加NAFLD发病风险,但其致病效应主要出现在高加索人群中.     

遗传性血色病进行缺铁治疗后,二价金属离子转运体1(DMT1)增加,而铁调节基因1(IREG1)和HFE基因mRNA表达不增加

背景和目的:有报道指出,遗传性血色病(HH)患者十二指肠上皮细胞的二价金属离子转运体1(DMT1)和铁调节基因1(IREG1)表达上调,目前对此发现仍存在争议。此外,HFE基因(HH患者发生突变的基因)对上述些分子表达的影响也不清楚。本研究检测了这三种分子在HH患者(已行或未行静脉切开放血治疗)、铁缺乏(ID)患者以及正常对照者十二指肠的表达情况。方法:应用实时聚合酶链反应检测3组人群十二指肠组织中DMT1、IREG1和HFEmRNA的含量。HH患者组均为C282Y纯合子;HD患者组血清铁蛋白浓度小于20μg/L,无C282Y突变;对照组血清铁蛋白浓度正常…     

消化道

野香草在胰腺癌化疗与疼痛治疗中的应用潜力；慢性HCV基因型-1感染的肥胖患抗病毒治疗无应答与肝脏SOCS-3的表达上调有关；诱导型一氧化氮合成酶参与肝硬化和腹水患外周血管张力的调节；肝性脑病患大脑“外周型苯二氮革结合位点”的体内成像；利用人群遗传学或患来检测HFE基因C282Y纯合子亲属的铁负载和发病率.     

利用人群遗传学或患者来检测HFE基因C282Y纯合子亲属的铁负载和发病率

背景与目的:尽管多数遗传性血红蛋白病与H FE基因的C282Y纯合子突变相关,但临床其他外显基因可能会降低该疾病发病率。因此,有临床表现的家系亲属可能通过遗传这些基因而使更多的铁蓄积。为了寻找相关证据,该文比较了两组来自南威尔士索引病例[即通过对献血者进行遗传学筛查确定的无症状C282Y纯合子携带者(n=56)和有临床表现的携带C282Y纯合子的血红蛋白病患者(n=60)]的一级亲属,检查其铁负载和发病率。方法:所有亲属均接受结构化面谈、临床评估及实验室检查,并进行健康相关的生活质量评价(SF-36第2版)。结果:筛查无症状组(180例)符合…     

肝脏铁超载患者肝移植后的生存率:国家血红蛋白沉积症肝移植注册

背景与目的:以往的无对照研究提示肝脏铁超载患者肝移植预后不佳。检查了H FE突变对于肝脏铁超载患者在肝移植后生存率的影响。方法:从12个肝移植中心纳入260例终末期肝病患者和肝脏铁超负荷患者作为研究对象。记录肝脏铁离子浓度(H IC)、肝脏铁离子指数(H II)、H FE突变状态及肝移植生存时间。结果:H FE相关的血红蛋白沉积病(H H)定义为C282Y纯合突变(n=14,7.2%)或C282Y/H63D杂合突变(n=11,5.6%),12.8%患者确认有以上突变。与简单杂合子(C282Y/wt或H63D/wt)或野生型患者相比,患有H H患者肝移植术后的生存率明显降低(1年、3年和…     

河南汉族人群亚甲基四氢叶酸还原酶基因多态性检测

目的:探讨河南地区汉族人N5,10-亚甲基四氢叶酸还原酶(MTHFR)基因C677T和A1298C位点的遗传多态性.方法:应用PCR-限制性片段长度多态性(RFIP)和TaqMan-MGB探针PCR方法调查河南地区495个汉族人的基因型分布,并同文献比较.结果:677T等位基因频率为45%,TT纯合子频率为27%;1298C等位基因频率为11%.CC纯合子频率为1%;双杂合子CT/AC频率为12%,2个位点的遗传多态性与文献报道不同.结论:MTHFR基因多态性的分布具有种群和地域差异.     

基因研究证实铁与心血管疾病危险有关

血色素沉着症是一种遗传性疾病,此病患者的肝脏、心脏和胰腺吸收了过多的铁。只有那些HFE(HLA-H)编码蛋白中Cys282Tyr突变的纯合子病人才产生明显的症状。近期有两个独立的研究小组报告,此种突变的杂合子病人可能处在心血管疾病危险增加的状态中。     

浙江地区汉族人TAFI基因编码序列C1040T基因多态性的研究

目的研究浙江地区汉族人凝血酶活化的纤溶抑制物基因编码区中与其血浆水平相关的C1040T基因多态性的特点。方法应用PCR技术结合SpeI酶切分析,研究了126名浙江地区汉族人凝血酶活化的纤溶抑制物基因编码区C1040T基因的多态性。结果浙江地区汉族人等位基因C1040与等位基因T1040的频率分别为0.798和0.202;基因型1040C/C纯合子、1040C/T杂合子及1040T/T纯合子的频率分别为0.667、0.262和0.071。结论浙江地区汉族人凝血酶活化的纤溶抑制物C1040T基因多态性的分布与其他人种有显著性差异。     

广东汉族人细胞色素C242T p22phox基因多态性观察

目的调查广东汉族人是否存在细胞色素C242T p22phox基因多态性。方法应用聚合酶链反应-限制性长度多态性法(PCR-RFLP)检测122名广东籍汉族人C242T p22phox基因多态性。结果CC基因型频率为0.877,CT TT基因型频率为0.123,C等位基因频率为0.934,T等位基因频率为0.066。结论广东汉族人存在C242T p22phox基因多态性,该基因多态性存在种族差异。     

Prevalence of C282Y and H63D mutations in the hemochromatosis (HFE) gene in the United States

CONTEXT: Population-based estimates of the prevalence of disease-associated mutations, such as hemochromatosis (HFE) gene mutations, are needed to determine the usefulness of genetic screening. OBJECTIVE: To estimate the prevalence of the HFE mutations C282Y and H63D in the US population. DESIGN: Cross-sectional population-based study of samples in the DNA bank from phase 2 of the Third National Health and Nutrition Examination Survey conducted from 1992 to 1994. SETTING AND PARTICIPANTS: Genotyped samples of cells from a total of 5171 participants, cross-classified by sex, age, and race/ethnicity in the analysis. MAIN OUTCOME MEASURES: Estimates of the prevalence of C282Y and H63D mutations. RESULTS: The prevalence of C282Y homozygosity is estimated to be 0.26% (95% confidence interval [CI], 0.12%-0.49%); 1.89% (95% CI, 1.48%-2.43%) for H63D homozygosity; and 1.97% (95% CI, 1.54%-2.49%) for compound heterozygosity. The prevalence estimates for C282Y heterozygosity (C282Y/wild type) are 9.54% among non-Hispanic whites, 2.33% among non-Hispanic blacks, and 2.75% among Mexican-Americans. The prevalence estimates of the C282Y mutation in the US population are 5.4% (95% CI, 4.7%-6.2%) and 13.5% (95% CI, 12.5%-14.8%) for the H63D mutation. CONCLUSIONS: Estimates of prevalence of HFE mutations are within the expected range for non-Hispanic whites and blacks but the estimated prevalence of the C282Y mutation among Mexican-Americans is less than expected. Mutation data now need to be linked to clinically relevant indices, such as transferrin saturation level.     

Curaçao patients with coronary artery disease have a higher prevalence of the HFE C282Y mutation

Epidemiological studies indicate a positive relation between iron status and coronary artery disease (CAD) risk The HFE C282Y allele is associated with increased iron status and higher CAD risk. We investigated whether HFE C282Ymight be a CAD risk factor in Cura?ao in a case-control study design. The patient group comprised 42 men and 10 women. Fifty-four men and 30 women without history of CAD served as age and gender matched controls. HFE C282Y genotypes were established using sequence-specific priming polymerase chain reaction. None of the investigated subjects were homozygous for HFE C282Y, whereas 5/52 (9.6%) CAD patients and 1/84 controls (1.2%) were heterozygous for HFE C282Y (p = 0.03). The HFE C282Y mutation was 8.8 fold (95% CI 1.001, 77.8; p = 0.049) more prevalent in CAD patients than in controls. The HFE C282Y allele frequency in Cura?ao is higher than that of African populations, but comparable with that of Jamaica. We conclude that Cura?ao CAD patients have somewhat higher frequency of HFE C282Y heterozygosity than controls, and that the HFE C282Y allele frequency in the Cura?ao population is higher than might be expected in persons of African descent. The consequences of HFE C282Y heterozygosity as CAD risk factor are as yet uncertain, since there is no proof that iron lowering reduces CAD risk.     

HFE-codon 63/282 (H63D/C282Y) gene variants in Mexican Mestizos are not risk factors for leukemia

BACKGROUND: In some Caucasian populations it has been found that the C282Y hemochromatosis (HFE) gene mutation is a risk factor for the development of leukemia and other malignancies. METHODS: In a group of 50 Mexican mestizo patients and 153 normal controls, the HFE gene mutations H63D and C282Y were studied by means of ARMS-PCR. RESULTS: In the group of patients with leukemia we found a heterozygote for the C282Y mutation, seven heterozygotes for the H63D mutation, a double heterozygote for the H63D / C282Y mutation and 41 normal homozygotes. These data are not different from those observed in normal controls, where the allele frequencies were 0.062 and 0.013 for the H63D and C282Y HFE gene mutations, respectively. CONCLUSIONS: These HFE gene mutations are not risk factors for the development of leukemia in Mexican mestizos.     

Prevalence of common HFE and SERPINA1 mutations in patients with hepatocellular carcinoma in a Moroccan population

BACKGROUND: Hereditary hemochromatosis and SERPINA1 mutation were reported to affect liver functions. Our objective was to estimate the prevalence of HFE and SERPINA1 (formerly known as alpha1-antitrypsin, AAT) mutations and assess their influence on hepatocellular carcinoma development. METHODS: This study included 222 controls and 96 cases with hepatocellular carcinoma. PCR-RFLP was used to characterize S and Z alleles in SERPINA1, as well as C282Y/H63D alleles of HFE. RESULTS: In healthy subjects and hepatocellular carcinoma patients as well, no homozygotes for the C282Y mutation were found. In controls, heterozygosity and homozygosity for the H63D mutation were 27 and 0.9%, respectively. Among patients, homozygosity for the H63D mutation was 3.1%, whereas heterozygosity for C282Y and H63D was 2.1 and 35.4%, respectively. Interestingly, albeit it does not reach significance (p=0.062), H63D was more prevalent in hepatocellular carcinoma patients than in controls (38.5 vs. 27.9%, respectively). The association was stronger when considering only male patients with hepatocellular carcinoma (47.1 vs. 23.6, p=0.001). Allele frequencies of S and Z in controls were 0.45% (95% CI=0.2-1.07) and 0.22% (95% CI=0.2-0.6), respectively, and 1 for S and 0% for Z in HCC. No significant difference was found between cases and controls. CONCLUSIONS: We provide a novel appraisal of HFE and SERPINA1 mutations prevalence in the Moroccan population. Results are consistent with the worldwide spread of the H63D and S mutation and the north European restriction of the C282Y and Z. Our results show that H63D carriage is increased among hepatocellular carcinoma patients, suggesting that it may confer an increased susceptibility to hepatocellular carcinoma even in a heterozygous state. On the contrary, HFE C282Y and SERPINA1 mutations do not contribute to hepatocellular carcinoma development.     

Analysis of HFE-codon 63/282 (H63D/C282Y) gene variants in mexican mestizos. Blood donors and patients with hereditary hemochromatosis

BACKGROUND: The prevalence of hereditary hemochromatosis (HH) (H63D/C282Y) gene variants in Mexico is unknown. METHODS: Using amplification refractory mutation system polymerase chain reaction, an analysis of HFE-codon 63/282 (H63D/C282Y) gene variants was performed in a group of 153 Mexican mestizo blood donors and six individuals with familial iron overload. RESULTS: In normal blood donors, three heterozygotes for the C282Y mutation (2.0%) were found, whereas 18 heterozygotes and one homozygote for the H63D mutation (11.8% and 0.6%, respectively) were identified; there was one compound heterozygote for the C282Y/H63D mutation. These data resulted in allele frequencies of 0.013 (+/-0. 2%, alpha = 0.05) and 0.062 (+/-0.9%, alpha = 0.05), respectively, for these two mutations, results similar to those found in whites. In the six patients with the HH phenotype, two were found to be heterozygous for C282Y and one heterozygous for H63D; three individuals with HH had no gene mutations. Two heterozygous HH individuals were found to have iron overload associated with other conditions: one heterozygous for C282Y infected with HIV, and another heterozygous for H63D with heterozygous beta-thalassemia. CONCLUSIONS: The prevalence of C282Y and H63D HFE gene mutations in Mexican mestizos is similar to that found in other populations. In addition, other gene mutations responsible for HH in the Mexican mestizo population should be investigated, because, in three of six individuals with the HH phenotype, neither of the two mutations was recorded.     

Coinheritance of hereditary spherocytosis and reversibility of cirrhosis in a young female patient with hereditary hemochromatosis

Here we report a 33-years-old woman with hereditary spherocytosis and hemochromatosis due to homozygosity for the C282Y mutation of the HFE gene. The coinheritance of both conditions led to severe iron overload and liver cirrhosis at young age. The patient was treated by repeated phlebotomy, and reversibility of cirrhosis was documented by transient elastography. This report discusses the pathophysiology of iron accumulation in patients with hemolytic anemia combined with HFE C282Y homozygosity. The case indicates that patients with hematological disorders characterized by increased erythropoetic activity should be screened for HFE mutations.     

Haemochromatosis gene frequency in a control and diabetic Irish population

Background  Hereditary haemochromatosis is inherited in an autosomal recessive manner. Two major mutations have been identified and the condition is emerging as one of the most common recessive mutations among subjects of Northern European descendants. Aim  This study investigated the prevalence of C282Y, H63D and S65C (three mutations of clinical significance for haemochromatosis), in a diabetic and control population from the North West of Ireland. Methods  DNA was extracted from whole blood samples of 249 known diabetics and 249 controls and assayed for the three genetic variants (C282Y, H63D and S65C). Results  The incidence for C282Y homozygosity is higher in the control population (1 in 83) when compared to the diabetic group (1 in 249). However, this is not statistically significant. S65C heterozygosity occurs with an incidence of 1 in 32 in control individuals and 1 in 124 in the diabetic population. The prevalence of the H63D mutation was similar in both populations. Conclusion  For the three haemochromatosis mutations, there was no significant difference between the control group and the diabetic populations.     

HFE genetic variability and risk of alcoholic liver disease: A meta-analysis

Studies examining the association of hemochromatosis (HFE) gene polymorphisms and susceptibility to alcoholic liver disease (ALD) yielded inconsistent results. Thus, we performed a metaanalysis to investigate whether the variations in HFE gene increase the risk of ALD. The studies published up to Feb. 2014 were identified by searching PubMed/MEDLINE, ISI Web of Science, EMBASE and China National Knowledge Infrastructure databases, which was complemented by screening the references of the retrieved studies. For all genotypes and alleles, the odds ratios (ORs) with 95% confidence intervals (CIs) according to the heterogeneity were pooled using fixed-effect model. Sixteen studies with 1933 cases and 9874 controls were included for this meta-analysis. C282Y/C282Y, C282Y/wild type, H63D/wild type and C282Y/H63D were found not to be associated with susceptibility to ALD, but increased risk of H63D/H63D (OR: 1.52, 95% CI: 1.05–2.22, P=0.029) was observed for ALD when compared to total control. Comparison of ALD patients with alcoholics without liver damage revealed a significant association of D allele, as well as a marginal association of H63D/wild type with ALD, while H63D/H63D was not significantly associated with ALD although increased value of OR was obtained. The presence of Y allele and other genotypes yielded insignificant findings when ALD patients were compared with alcoholics without liver damage. No evident publication bias or significant heterogeneity among studies was detected in this meta-analysis. In conclusion, our metaanalysis showed a marginal higher prevalence of H63D variant in ALD but did not support an increased risk of C282Y mutation.     

Directions for clinical practice improvement in HFE gene mutation testing

OBJECTIVE: To audit the clinical indications for HFE gene mutation testing in a consecutive series of requests. DESIGN: Retrospective audit of reasons prompting 187 HFE test requests received between June 2003 and June 2005, by examination of the request form, hospital notes (when available) and, when required, information from the referring doctor. SETTING: A tertiary care public teaching hospital laboratory, Perth, Western Australia. MAIN OUTCOME MEASURES: Reasons prompting requests for HFE genotype testing and compliance with accepted clinical indications (biochemical evidence of iron overload on repeated samples, or a first-degree relative with either haemochromatosis or a C282Y mutation). RESULTS: Insufficient clinical details in requests prevented the inclusion of interpretive comments in HFE genotype reports in 70 of 187 cases (37%). Re-evaluation after collation of the missing details for all but seven requests revealed that 103 of the 180 auditable requests (57%) had been prompted for reasons other than biochemical evidence of iron accumulation or family history. CONCLUSIONS: A substantial proportion of HFE genotype test requests are made for inappropriate reasons. Clinical practice could be improved by educating doctors on the practical utility of this genetic test and by laboratories taking steps to secure the clinical information needed to include appropriate interpretive comments in their reports.