脂联素基因SNP276多态性与儿童青少年肥胖的相关性研究

目的研究脂联素（APM1）基因SNP276 G/T多态性与儿童青少年单纯性肥胖及其代谢指标的相关性。方法以2004至2006年于复旦大学附属儿科医院内分泌门诊就诊的单纯性肥胖或超重儿童青少年分别作为肥胖组和超重组;选择某中学正常体重学生作为正常对照组。分别测量身高和体重,计算体重指数（BMI）。测定血清空腹葡萄糖（FPG）、空腹胰岛素（FIns）、三酰甘油（TG）和总胆固醇（TC）水平。计算胰岛素抵抗指数（HOMA-IR）和胰岛素敏感指数（QUICKI）。抽提外周血基因组DNA,采用Taqman-MGB探针技术检测APM1基因SNP276 G/T多态性,分析不同基因型与代谢指标和BMI间的关联性。结果肥胖组纳入227例,超重组纳入231例,正常对照组纳入216名。①肥胖＋超重组的BMI、FPG、FIns、TG和HOMA-IR均显著高于正常对照组。②基因分布频率符合Hardy-Weinberg平衡。③肥胖组、超重组和正常对照组的G等位基因频率分别为71.4%、72.5%和69.7%,GG基因型频率分别为50.2%、52.4%和45.8%,GT基因型频率分别为42.3%、40.3%和47.7%;各组差异均无统计学意义（P均〉0.05）。④SNP276 GG、GT和TT基因型的BMI、FPG、FIns、TG、TC、HOMA-IR和QUICKI差异均无统计学意义（P=0.49～0.99）。⑤肥胖＋超重组IFG儿童青少年中GG＋GT型有70例,TT型4例;正常对照组IFG儿童青少年中GG＋GT型有10例,TT型0例;两组差异无统计学意义（P=0.45）。结论APM1基因SNP276 G/T多态性与青少年儿童单纯性肥胖及其代谢指标间无显著关联性,提示该SNP位点可能存在种族特异性。     

Relation of a common variant of the adiponectin gene to serum adiponectin concentration and metabolic traits in an aged Japanese population

Adiponectin is an adipocyte-derived protein that is down-regulated in obesity-linked disorders. Variants of the adiponectin gene (ADIPOQ) have been shown to affect adiponectin level. We have now examined the relation of polymorphisms of ADIPOQ to adiponectin concentration and to metabolic disorders in the Kita-Nagoya Genomic Epidemiology study, a population-based study of elderly Japanese. The genomic region including ADIPOQ was genotyped for 30 single nucleotide polymorphisms in 500 subjects of a screening population with the use of a fluorescence- or colorimetry-based allele-specific DNA primer-probe assay system. Four polymorphisms were then selected for genotyping in an additional 2797 subjects. Serum adiponectin level was negatively associated with metabolic abnormalities after adjustment for age and sex. The minor alleles of the rs1656930, Ile164Thr, and rs9882205 polymorphisms were associated with a low serum adiponectin level. Whereas the minor alleles of rs1656930 and rs9882205 were common (minor allele frequency of 6.2 and 38.5%, respectively), that of Ile164Thr was rare (0.9%). The minor allele of rs1656930 was positively associated with systolic blood pressure and the prevalence of hypertension. The association of rs1656930 with adiponectin level was replicated in an independent population. A subject with the 164Thr/Thr genotype had an extremely low serum adiponectin level (0.6 μg/ml) and the phenotype of metabolic syndrome. Our results suggest that a common variant of ADIPOQ, the minor allele of rs1656930, is associated with hypoadiponectinemia and hypertension. Screening for a common genetic background underlying low adiponectin levels might provide important information for assessment and management of metabolic disorders.     

Allele-specific gene expression patterns in primary leukemic cells reveal regulation of gene expression by CpG site methylation

To identify genes that are regulated by cis-acting functional elements in acute lymphoblastic leukemia (ALL) we determined the allele-specific expression (ASE) levels of 2, 529 genes by genotyping a genome-wide panel of single nucleotide polymorphisms in RNA and DNA from bone marrow and blood samples of 197 children with ALL. Using a reproducible, quantitative genotyping method and stringent criteria for scoring ASE, we found that 16% of the analyzed genes display ASE in multiple ALL cell samples. For most of the genes, the level of ASE varied largely between the samples, from 1.4-fold overexpression of one allele to apparent monoallelic expression. For genes exhibiting ASE, 55% displayed bidirectional ASE in which overexpression of either of the two SNP alleles occurred. For bidirectional ASE we also observed overall higher levels of ASE and correlation with the methylation level of these sites. Our results demonstrate that CpG site methylation is one of the factors that regulates gene expression in ALL cells.     

Alpha1-antitrypsin gene polymorphism related to respiratory system disease

Summary Restriction fragment length polymorphism (RFLP) in the alpha₁-antitrypsin gene region was studied in relation to chronic obstructive airway disease (COAD) and pneumoconiosis. Genomic DNA of 122 studied subjects was digested with Hind III restriction endonuclease and hybridized with the alpha₁-antitrypsin gene probe. In eight patients with COAD an unusual 10-kb restriction fragment was found hybridizing with the probe. Three of 70 patients were homozygotes for this variant allele and 5 were heterozygotes, showing the presence of two fragments, 2.7 kb and 10 kb. The presence of 10-kb restriction fragment seems to be related to the early development of COAD in studied subjects and therefore might be used as a genetic marker of the disease.Abbreviations bp base pair - COAD chronic obstructive airway disease - kb kilobase - RFLP restriction fragment length polymorphism     

中老年人群脂联素基因多态性与脑白质病变的关系

目的 探讨在中老年人群中脂联素基因多态性与脑白质病变(WML)之间的关系。方法 纳入2012年6月—2013年1月第三军医大学大坪医院神经内科811例中老年(≥50岁)住院患者的临床资料、血液学指标等进行横断面研究。根据头颅MRI检查结果及Fazekas评分标准诊断WML并分组:诊断为WML者419例纳入观察组,非WML者392例纳入对照组。采用连接酶链反应对患者基因进行分型。应用多因素logistic回归分析脂联素基因多态性与WML关系。结果 与对照组比,观察组平均年龄更大,冠心病、既往卒中史、高血压和糖尿病的比例更高,血浆TC、高密度脂蛋白胆固醇(HDL-C)和载脂蛋白A-Ⅰ浓度较低,空腹血糖浓度较高(P值均<0.05)。rs7649121的AA、AT、TT基因型、等位基因A、T频率在两组间的分布差异有统计学意义(P<0.01)。调整了年龄、性别、既往卒中史、冠心病、高血压、糖尿病和HDL-C后,相对AA基因型,AT基因型和TT基因型仍是WML的独立危险因素;在显性模型中,AT/TT基因型患WML的风险是AA基因型的1.73倍。结论在中国中老年人群中首次发现,脂联素基因的rs7649121位点与WML有关,T等位基因是WML发生的易感基因。     

基因多态性与疾病相关性的遗传分析中某些值得注意的问题

本文对基因多态性与疾病相关性的遗传分析(包括连锁分析和群体关联分析)中某些值得注意的问题进行了讨论,提出了一些解决途径和建议。     

The human GIMAP5 gene has a common polyadenylation polymorphism increasing risk to systemic lupus erythematosus

Background

Several members of the GIMAP gene family have been suggested as being involved in different aspects of the immune system in different species. Recently, a mutation in the GIMAP5 gene was shown to cause lymphopenia in a rat model of autoimmune insulin‐dependent diabetes. Thus it was hypothesised that genetic variation in GIMAP5 may be involved in susceptibility to other autoimmune disorders where lymphopenia is a key feature, such as systemic lupus erythematosus (SLE).

Material and methods

To investigate this, seven single nucleotide polymorphisms in GIMAP5 were analysed in five independent sets of family‐based SLE collections, containing more than 2000 samples.

Result

A significant increase in SLE risk associated with the most common GIMAP5 haplotype was found (OR 1.26, 95% CI 1.02 to 1.54, p = 0.0033). In families with probands diagnosed with trombocytopenia, the risk was increased (OR 2.11, 95% CI 1.09 to 4.09, p = 0.0153). The risk haplotype bears a polymorphic polyadenylation signal which alters the 3′ part of GIMAP5 mRNA by producing an inefficient polyadenylation signal. This results in higher proportion of non‐terminated mRNA for homozygous individuals (p<0.005), a mechanism shown to be causal in thalassaemias. To further assess the functional effect of the polymorphic polyadenylation signal in the risk haplotype, monocytes were treated with several cytokines affecting apoptosis. All the apoptotic cytokines induced GIMAP5 expression in two monocyte cell lines (1.5–6 times, p<0.0001 for all tests).

Conclusion

Taken together, the data suggest the role of GIMAP5 in the pathogenesis of SLE.     

Reward dependence is related to norepinephrine transporter T-182C gene polymorphism in a Korean population

It is well established that approximately 50% of the variance in personality traits is genetic. The goal of this study was to investigate a relationship between personality traits and the T-182C polymorphism in the norepinephrine transporter gene. The participants included 115 healthy adults with no history of psychiatric disorders and other physical illness during the past 6 months. All participants were tested with the Temperament and Character Inventory and genotyped norepinephrine transporter gene polymorphism. Differences on the Temperament and Character Inventory dimensions among three groups were examined with one-way analysis of variance. Our study suggests that the norepinephrine transporter T-182C gene polymorphism is associated with reward dependence in Koreans, but the small number of study participants and their sex and age heterogeneity limits generalization of our results. Further studies are necessary with a larger number of homogeneous participants to confirm whether the norepinephrine transporter gene is related to personality traits.     

肥胖患者性别差异的基因表达谱数据分析

目的 采用生物信息学手段对男女肥胖患者与正常人群的差异基因进行分析,研究肥胖个体脂肪细胞基因表达在性别上的差异.方法 从公共数据库基因表达数据库(Gene Expression Omnibus,GEO)中下载肥胖相关数据集,采用Qlucore Omics Explorer(QOE)、DAIVID在线分析,并利用蛋白质相互作用数据库分子作用数据库(MINT)进行蛋白质作用网络分析.结果 在女性患者中,99条基因表达上调,79条下调,男性患者中有39条高表达基因,23条下调基因.GO分析显示女性肥胖患者的差异基因所涉及GO类别较男性患者多,两组蛋白质作用网络核心节点差异较大,FYN与PDIA3分别是男性女性蛋白质作用网络中重要节点.结论 肥胖发生机制存在性别差异,针对节点FYN与PDIA3的后续研究可能对肥胖的发生机制及相应并发症的研究起到重要作用.