非酒精性脂肪性肝病的研究进展

非酒精性脂肪性肝病(nonalcoholic fatty liver disease,NAFLD)患病率高,西方国家15%-30%,我国约15%.单纯性脂肪肝(nonalcoholic simple fatty liver,NAFL)病情稳定,脂肪性肝炎(nonalcoholic steatohepatitis,NASH)是病情恶化的拐点,可发展为肝硬化,甚至肝癌.候选基因研究显示,肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)、瘦素、脂联素等基因单核苷酸多态性(single nucleotide polymorphisms,SNP)与其发病易感性相关.近年全基因组扫描发现,染色体22上调节磷脂酶基因的SNP(adiponutrin或PNPLA3)更为重要.表观遗传学研究发现miR-122表达下调参与NAFLD发病机制.病理组织学是诊断的金标准,但实施困难,影像学检查(特别B超)是临床诊断的主要方法,但无法鉴别NASH和NAFL.基础治疗包括纠正不良生活方式、控制饮食、运动、减肥等,是治疗成功的基石.药物是辅助手段,包括减肥药、胰岛素增敏剂、调脂药、保肝抗炎药物等,尚没有循证医学验证的特效药物.     

肿瘤坏死因子-α基因多态性与非酒精性脂肪性肝病的关系

目的研究肿瘤坏死因子-α(TNF-α)基因-308位点及-238位点多态性在非酒精性脂肪性肝病(NAFLD)患者中的分布,及其在胰岛素抵抗(IR)和 NAFLD 发病中的地位。方法运用聚合酶链反应-限制性片段长度多态性检测117例 NAFLD 患者 TNF-α基因—308位点及—238位点多态性,其中伴肥胖者60例,非肥胖者57例,同时测定患者空腹血清胰岛素(FINS)及空腹血糖,通过体内平衡代谢指数(HOMA)评估 IR,并与120名健康者对照。结果 NAFLD 患者与正常对照组 TNF-α基因-238位点基因多态性分布差异有统计学意义(29.9%比15.8%,P<0.05),而—308位点差异无统计学意义(P>0.05)。NAFLD 患者血清 HOMA-IR、TNF-α明显高于对照者[2.50±0.68比1.16±0.68,(10.54±3.19)ng/L 比(4.54±3.10)ng/L,P<0.01]。FINS、HOMA-IR 在 TNF-α基因-238位点基因变异组明显高于正常基因型组(P<0.05),但在—308位点变异组差异无统计学意义(P>0.05)。NAFLD 患者中无论肥胖或非肥胖患者均较正常对照人群在 TNF-α基因-238位点多态性分布及HOMA-IR、TNF-α差异有统计学意义(P<0.05)。肥胖及非肥胖的 NAFLD 患者之间 HOMA-IR、TNF-α差异无统计学意义(P>0.05)。结论 NAFLD 患者 IR 与其体重关系不显著,非肥胖 NAFLD患者同样有 IR 发生。TNFα基因-238位点 G/A 变异与 IR、NAFLD 易感性相关,TNFα基因-308位点 G/A 的突变与 IR 易感性不相关。NAFLD 发病与 IR、TNF-α密切相关。     

非酒精性脂肪性肝病患者肝组织脂联素表达及其意义

目的探讨肝组织脂联素表达在非酒精性脂肪性肝病(NAFLD)发病机制中的作用及地位,为NAFLD的预防及治疗提供新思路。方法 47例NAFLD患者及20例正常对照均测量身高、体重,计算体重指数(BMI);分别应用ELISA方法测定血清脂联素(adiponectin)浓度、血清肿瘤坏死因子-α(TNF-α)浓度;采用稳态模式评估法,计算胰岛素抵抗指数(HOMA-IR);对肝组织进行HE、Masson染色及脂联素免疫组织化学染色,对脂联素表达量进行半定量分析。结果非酒精性脂肪性肝炎(NASH)组肝组织脂联素表达较对照组及单纯性脂肪肝组显著减少,与血清脂联素浓度呈显著正相关,与血清TNF-α浓度、ALT、HOMA-IR及肝组织炎症、纤维化程度呈负相关,而与脂变程度不相关。多元线性逐步回归分析显示,肝组织脂联素表达是肝组织炎症及纤维化发生的保护因素。结论肝组织脂联素表达在NAFLD患者肝组织炎症及纤维化发生发展中起保护性作用。     

脂联素基因多态性和血清脂联素水平与老年人代谢综合征的相关性

目的 探讨血清脂联素水平及脂联素基因单核苷酸多态性(SNP)45T→G和276G→T两个位点与代谢综合征(MS)的关系.方法 采用放免法对195例老年代谢综合征组(MS组)患者和156例对照组(Con组)人群进行血清脂联素水平测定,并用TaqMan探针技术进行脂联素基因SNP45分析,直接测序法进行脂联素基因SNP276分析.结果 MS组的血清脂联素水平较Con组显著降低(P＜0.05);多元逐步回归分析显示:空腹胰岛素是影响MS患者血清脂联素水平的独立相关因素.脂联素基因多态性分析:SNP45在MS组与Con组比较差异有显著性(P＜0.05);等位基因分布频率提示G等位基因在代谢综合征人群多见(P ＜0.05):MS组中携带TG+GG型的患者血清脂联素水平显著低于TT型的患者(P＜0.05):Con组、MS组二组间SNP276基因型分布差异无统计学意义(P＞0.05),等位基因分布频率分析显示无差异性(P＞0.05).结论 低脂联素血症与MS的发生发展有关,SNP45 G/G基因型可能是中国汉族人MS的易感基因.     

脂联素受体基因多态性与非酒精性脂肪性肝病的关系

非酒精性脂肪性肝病(nonalcoholic fatty liver disease,NAFLD)是一种与遗传、生活环境及人体代谢相关的疾病.NAFLD涉及多基因,与肥胖、胰岛素抵抗、脂肪酸代谢、炎性细胞因子相关的基因都可能与NAFLD有关.脂联素(adiponectin)是脂肪细胞分泌的肽类激素,被认为是NAFLD的发生因素之一.脂联素受体(adiponectin receptor,AdipoR)介导脂联素的多种生物学效应,与NAFLD、糖尿病、肥胖等多种疾病密切相关.本研究旨在分析AdipoR2基因+33371多态性与NAFLD及与部分代谢综合征相关指标的关系.     

脂联素与慢性肝病的研究进展

脂联素是主要由脂肪组织分泌的细胞因子,对机体存在广泛保护作用,也是唯一发挥保护作用的脂肪因子,可防止肝脏脂肪的积累。同时,脂联素具有抗炎、抗纤维化特性,可以对抗肿瘤坏死因子-α(TNF-α)及胰岛素抵抗,从而发挥对肝脏的保护作用,越来越多的学者开始研究将脂联素用于慢性肝病的治疗。此文着重就脂联素与常见慢性肝病,包括酒精性脂肪肝、非酒精性脂肪肝(NAFLD)、病毒性肝炎的研究进展作一综述。     

脂联素基因多态性与早发冠心病的相关性研究

目的:探讨早发冠心病(PCAD)与脂联素基因多态性的相关性。方法:采用病例对照研究方法,连续入选早发冠心病患者563例为病例组,412例冠状动脉造影阴性者为对照组。脂联素基因的17个SNP为候选位点,应用质谱分析的方法对单核苷酸多态性(SNP)进行分型。分析各个SNP的等位基因及基因型频率在病例组和对照组之间的差异,应用Logisitic回归方法分析各个SNP在各种遗传模型下与早发冠心病的关联。结果:脂联素基因各SNP位点的基因型和等位基因在病例组和对照组中的分布频率,差异无统计学意义(P>0.05);应用Logisitic回归方法分别在相加、显性和隐性遗传三种遗传模型下进行SNPs位点与早发冠心病的关联分析,校正混杂因素后发现在相加遗传模型下SNP+45T>G(rs2241766)多态性与中国汉族人群PCAD易感性相关(OR=1.416,95%CI:1.006~2.051,P=0.043)。结论:脂联素基因SNP+45T>G(rs2241766)多态性与中国汉族人群PCAD易感性相关。     

细胞因子、胰岛素抵抗与非酒精性脂肪性肝病

非酒精性脂肪性肝病(NAFLD)的发病机制目前尚不清楚,但大量研究表明胰岛素抵抗与之密切相关.随着胰岛素抵抗程度的加重,调控肝脏糖脂代谢的开关--Foxo1、Foxa2的基因活性发生不同程度的改变,导致肝脏糖脂代谢紊乱,引起NAFLD的续贯性发生.此外,与胰岛素抵抗密切相关的瘦素、肿瘤坏死因子-α作为损害性因子,脂联素作为保护性因子亦在NAFLD的发生、发展中起重要作用.     

脂联素与非酒精性脂肪肝病

脂联素(adiponectin,ADP)作为一种新发现的脂肪激素,主要是由脂肪细胞分泌的,在肥胖者、糖尿病及非酒精性脂肪性肝病(nonalcoholic fatty liver disease,NAFLD)患者中血清ADP水平低于正常.ADP有胰岛素增敏作用,与胰岛素抵抗相关;能够使肝脏肿瘤坏死因子(tumor necrosis factor-alpha,TNF-α)分泌下降,减少肝中脂肪堆积和炎症介质作用,对ADP的研究将为探讨NAFLD的发病机制及治疗方案提供新的线索.     

脂联素水平及基因多态性与代谢综合征的关系

目的:探讨脂联素(APN)水平及其单核苷酸基因多态性(SNP) +45T/G和+276G/T两个位点与代谢综合征(MS)的关系.方法:238例研究对象分为对照组和MS组,采用实验-对照研究方法,应用酶联免疫吸附法(ELISA)及聚合酶链反应-限制性片段长度多态性(PCR-RFLP)技术,对血浆APN浓度及其2个位点基因多态性进行检测.结果:与对照组比较,MS组APN水平降低(P＜0.05);MS组SNP+276T等位基因分布明显升高,多因素逐步Logistic回归分析显示SNP+276基因多态性为MS危险因素.结论:MS患者APN水平下降,携带SNP+276T等位基因者患MS的风险增加.     

Effect of peroxisome proliferator‐activated receptors‐γ and co‐activator‐1α genetic polymorphisms on plasma adiponectin levels and susceptibility of non‐alcoholic fatty liver disease in Chinese people

Background/Aims: Peroxisome proliferator‐activated receptors‐γ (PPAR‐γ) and its co‐activator‐1α (PGC‐1α) are involved in the regulation of lipid and glucose metabolisms. This study aimed to investigate the genetic polymorphisms of PPAR‐γ and PGC‐1α in Chinese people and their influence on plasma adiponectin levels and non‐alcoholic fatty liver disease (NAFLD) susceptibility. Methods: Ninety‐six patients with NAFLD and 96 healthy controls were included. The single nucleotide polymorphisms (SNPs) of C161T PPAR‐γand Gly482Ser PGC‐1α genes were analysed by polymerase chain reaction and restriction fragment length polymorphism. Result: The CC, CT and TT genotypic distributions of the NAFLD group were significantly different from those of controls (55.2, 39.6, 5.2 vs. 74.0, 25.0, 1.0%; P=0.015). The allelic frequencies of C and T were also different between the two groups (P=0.004). As for the PGC‐1α gene, there was no difference of the genotypic and allelic frequencies between the two groups (P>0.05). In NAFLD patients, the plasma adiponectin concentrations were lower in the PPAR‐γ CT/TT genotypes compared with those in the CC genotype group (3.0±0.6 vs. 4.3±0.9, P=0.02). Multivariate logistic regression analysis showed that CT/TT genotypes of PPAR‐γ, TG, waist hip ratio, hypoadiponectinaemia and homoeostasis model assessment (HOMA)‐IR were the risk factors for NAFLD. Conclusion: SNPs in the PPAR‐γ, but not PGC‐1α, gene are associated with NAFLD susceptibility possibly through the adiponectin pathway.     

Influence of polygenetic polymorphisms on the susceptibility to non‐alcoholic fatty liver disease of Chinese people

Background and Aim: The aim of this study was to investigate the influence of polygenetic polymorphisms, which play a role in the pathogenesis of metabolic syndrome, on the susceptibility to non‐alcoholic fatty liver disease (NAFLD) of Chinese people. Methods: The subjects were selected from an epidemiological survey in the Guangdong province of southern China. In each polymorphism study, 50–117 subjects who met the diagnostic criteria of NAFLD and had typical clinical and ultrasonographic findings were placed into the case group. Using a nested case–control design, the same numbers of matched people without NAFLD were included as controls. Single nucleotide polymorphisms (SNP) at nine positions in seven candidate genes were tested. These SNP were found to be associated with the pathogenesis of metabolic syndrome. Genetic analyses were performed using genomic DNA extracted from peripheral blood leukocytes. Polymerase chain reaction–restriction fragment length polymorphism was applied to detect SNP. Results: Most candidate genes' SNP were associated with susceptibility to NAFLD. Some showed positive relationships (increased risk): tumor necrosis factor‐α‐238, adiponectin‐45, leptin‐2548, peroxisome proliferator‐activated receptors‐161 and phosphatidyletha‐nolamine N‐methyltransferase‐175. Other SNP demonstrated a negative association (decreased risk): adiponectin‐276 and hepatic lipase‐514. Only two were not associated: tumor necrosis factor‐α‐380 and peroxisome proliferator‐activated receptors‐γ co‐activator‐1α‐482. Conclusion: Most candidate genes' SNP examined in metabolic syndrome patients were associated with susceptibility to NAFLD.     

广东省成人代谢综合征与非酒精性脂肪肝患病的关系

目的 研究广东省普通人群成人代谢综合征（metabolic syndrome，MS）与非酒精性脂肪肝（nonalcoholic fatty liver disease，NAFLD）患病的关系。方法 用多阶段分层随机整群抽样方法，调查广东省成人代谢综合征和NAFLD患病情况。代谢综合征的诊断根据美国胆固醇教育计划第三次报告标准及世界卫生组织亚洲太平洋地区肥胖标准。结果 3164成人中代谢综合征345例（10．9％），NAFLD 525例（16．5％）。多因素Logistic回归分析显示高血压、肥胖、高腰臀比、粗腰围、高甘油三酯血症和血糖升高是NAFLD的危险因素。结论 广东省成人NAFLD患病率较高，发病与代谢综合征关系密切。     

Genetic influences in nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is a metabolic liver disease with widely variable phenotypes extending from simple steatosis, through nonalcoholic steatohepatitis (NASH) to cirrhosis and hepatocellular carcinoma. Inevitably, this reflects the interplay of well-recognized environmental factors and disease associations such as obesity and insulin resistance with host genetic factors, which are polygenic or complex in nature. Most of the observed phenotypic variability will probably be explained by variations in single nucleotide polymorphism frequency, although knowledge of the effect of most polymorphisms on biologic function is currently limited. Several observational studies of kindred with NASH suggest a genetic contribution. Most data characterizing genetic variation in different NAFLD phenotypes is derived from case-control association studies involving putative candidate genes. These candidate genes have been selected largely based upon the "two-hit hypothesis" of the pathogenesis of NAFLD, although other hypothesis-independent approaches can also be informative in gene selection. Thus far, candidate gene association studies have had significant limitations such as small cohort sizes and poor reproducibility. Rapid technologic developments are increasing the capability of detecting genetic variation. Identification of the genetic contribution to NAFLD will inform theories of disease pathogenesis and progression and ultimately improve management.     

非酒精性脂肪性肝病合并胆结石患者代谢相关基因表达的研究

目的 探讨非酒精性脂肪性肝病合并胆结石患者外周血单个核细胞代谢相关基因的表达情况.方法选择体重指数(BMI)≥27的肥胖人群,分为三组,单纯肥胖组(n=10),非酒精性脂肪性肝病组(NAFLD组,n=7)和NAFLD伴胆结石组(n=16),另设两组对照,BMI<25的正常人(n=10)和单纯胆结石组(n=16).检测比较各组调节脂肪酸合成转录因子甾醇调节因子结合蛋白-lc(SREBP-lc)、调节脂肪酸氧化的过氧化酶体增殖物激活受体α(PPARα)和瘦素长型受体(Leptin Rb)在外周血单个核细胞的表达.结果 三种基因PPARα、SREBP-lc和Leptin Rb的mRNA在五组人群的外周血单个核细胞中均有不同程度表达,其中Leptin Rb的表达在单纯肥胖组和NAFLD伴胆结石组、单纯胆结石组和NAFLD伴胆结石组、NAFLD组和NAFLD伴胆结石组、单纯肥胖组和正常对照组同差异有统计学意义(P值分别=0.037、0.050、0.044和0.038).NAFLD伴胆结石组Leptin Rb的mRNA表达最低.结论NAFLD合并胆结石患者外周血单个核细胞Leptin Rb mRNA呈低表达;胆结石可能增加胰岛素抵抗的程度,促进NAFLD进展.     

PEMT基因G175A和rs12325817位点多态性与非酒精性脂肪肝的关系

目的:研究磷脂酰乙醇胺N甲基转移酶基因(PEMT)G175A和rs12325817位点多态性与非酒精性脂肪性肝病(NAFLD)的关系.方法:运用聚合酶链反应一限制性片段长度多态性检测156例NAFLD患者和188名健康对照PEMT基因G175A和rs464396基因型,等位基因频率分布,分析NAFLD患者与对照组临床各...     

Interferon-gamma receptor-1 gene promoter polymorphisms and susceptibility to leprosy in children of a single family

The autosomal recessive disorder, because of a single mutation in interferon-γ receptor-1(IFNGR1) at position -56, was found to be associated with susceptibility to leprosy in children of the same family. The existence of such heterozygous carriers might explain the crucial role of IFNGR1 in the host defense against intracellular pathogens such as Mycobacterium leprae. The single nucleotide polymorphisms (SNPs) in major candidate genes, i.e., natural resistance-associated macrophage protein 1 (NRAMP1), vitamin D receptor (VDR), tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), interleukin-12-receptor 1 (IL-12R1), were not found to be associated with this disease.     

Behavioral risk exposure and host genetics of susceptibility to HIV-1 infection

BACKGROUND: Some individuals are readily infected with low human immunodeficiency virus type 1 (HIV-1) exposure, whereas others appear less susceptible, suggesting that host genetics plays a role in the viral entry pathway. The matched case-control study design with measured risk exposures provides an avenue for discovering genes involved in susceptibility to infection. METHODS: We conducted a nested case-control study of African Americans (266 HIV-1 seroconverter cases and 532 seronegative controls from the AIDS Link to Intravenous Experience cohort), to examine the association between 50 single-nucleotide polymorphisms (SNPs) in 9 candidate genes (CCR5, CCR2, RANTES, MIP1A, MCP2, IL10, IFNG, MCSF, and IL2) and susceptibility to HIV-1 infection. To account for differential exposure propensities, risk behavior self-reported during semiannual visits was used to estimate a standardized cumulative risk exposure (SCRE). Individual SNPs were evaluated using conditional logistic-regression models, and the inferred haplotypes were assessed in the haplotype trend regression analyses after adjusting for age and SCRE. RESULTS: Four SNPs (CCR2-V64I, CCR5-2459, MIP1A+954, and IL2+3896) and specific haplotypes in the IL2 and CCR2/CCR5 regions were significantly associated with HIV-1 infection susceptibility in different genetic models. CONCLUSIONS: Our results suggest that genetic variants in associated host genes may play an important role in susceptibility to HIV-1 infection.     

The genetic backgrounds in nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease worldwide. Nonalcoholic steatohepatitis (NASH), a severe form of NAFLD, can lead to hepatocellular carcinoma (HCC) and hepatic failure. The development and progression of NAFLD are determined by environmental and genetic factors. The effect of genetic factors has been demonstrated by familial studies, twin studies and several cross-sectional studies. In the past 10 years, genome-wide association studies have revealed several single nucleotide polymorphisms (SNPs) associated with the pathology of NAFLD. Among them, the Patatin-like phospholipase domain-containing 3 (PNPLA3) gene variant I148M showed a strong relationship with the development and progression of NAFLD, NASH, and NAFLD-related HCC. The transmembrane 6 superfamily member 2 (TM6SF2) gene variant E167 K was also associated with NAFLD, and it has a relationship with cardiovascular disease. Furthermore, several genes have been proposed as candidate genes to be associated with NAFLD based on case–control studies. We conducted a comprehensive literature search and review on the genetic background of NAFLD.     

Three ulcerative colitis susceptibility loci are associated with primary sclerosing cholangitis and indicate a role for IL2, REL, and CARD9

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by inflammation and fibrosis of the bile ducts. Both environmental and genetic factors contribute to its pathogenesis. To further clarify its genetic background, we investigated susceptibility loci recently identified for ulcerative colitis (UC) in a large cohort of 1,186 PSC patients and 1,748 controls. Single nucleotide polymorphisms (SNPs) tagging 13 UC susceptibility loci were initially genotyped in 854 PSC patients and 1,491 controls from Benelux (331 cases, 735 controls), Germany (265 cases, 368 controls), and Scandinavia (258 cases, 388 controls). Subsequently, a joint analysis was performed with an independent second Scandinavian cohort (332 cases, 257 controls). SNPs at chromosomes 2p16 (P-value 4.12 × 10(-4) ), 4q27 (P-value 4.10 × 10(-5) ), and 9q34 (P-value 8.41 × 10(-4) ) were associated with PSC in the joint analysis after correcting for multiple testing. In PSC patients without inflammatory bowel disease (IBD), SNPs at 4q27 and 9q34 were nominally associated (P < 0.05). We applied additional in silico analyses to identify likely candidate genes at PSC susceptibility loci. To identify nonrandom, evidence-based links we used GRAIL (Gene Relationships Across Implicated Loci) analysis showing interconnectivity between genes in six out of in total nine PSC-associated regions. Expression quantitative trait analysis from 1,469 Dutch and UK individuals demonstrated that five out of nine SNPs had an effect on cis-gene expression. These analyses prioritized IL2, CARD9, and REL as novel candidates. CONCLUSION: We have identified three UC susceptibility loci to be associated with PSC, harboring the putative candidate genes REL, IL2, and CARD9. These results add to the scarce knowledge on the genetic background of PSC and imply an important role for both innate and adaptive immunological factors.