不宁腿综合征遗传学研究进展

不宁腿综合征(Restless legs syndrome, RLS)遗传学研究近年来获得了许多重要的进展, 极大地丰富了对于这种疾病分子机制的认识。RLS是一种常见的复杂疾病, 几个遗传流行病学和双生子研究对RLS遗传组分进行了剖析, 说明RLS是一个遗传性很强的性状, 其遗传力约为50%。采用基于模型的连锁分析方法或者是不依赖于模型的连锁分析方法目前已定位了5个重要的RLS疾病连锁位点: 12q13-23, 14q13-21, 9p24-22, 2q33和20p13, 为定位克隆RLS致病基因或者易感基因提供了连锁图谱。最新基于高通量的SNPs分型平台开展的全基因组分析确立3个与RLS显著关联的区域: 6p21.2, 2p14和15q23。文章结合作者近年来从事不宁腿综合征遗传学的研究工作, 对该领域的重要成果进行了汇总和评述。     

喉癌的比较基因组杂交研究

寻找与喉癌发生进展的相关基因,应用比较基因组杂交技术分析了18例喉癌患者。结果显示,每例喉癌细胞染色体均有不同程度的变化,包括染色体全部或部分的扩增或丢失。平均每例有12．9处异常区域,丢失多于扩增,分别为每例7．2处和5．7处。主要为3q(78％,)、5p(61％)、11q(56％)、1q(50％,)、8p(44％)、8q(39％)和15q(39％)的扩增;3p(70％)、5q(78％)、90(67%)、13q(50％)、1p(44％)和14q(39％)的丢失。有多条染色体区带上出现特异的扩增或丢失,特别是1p13-21(8／18)、3p21-23(14／18)、5p21-22(14／18)、9p12-pter(10／18)和13q21-31(8／18)的拷贝数增加明显,而1q11-2l(11／18)、3q15-21(12／18)、8p22-24(6／18)、11q12-13(8／18)、15q21-23(7／18)和18p11(8／18)区域的丢失为喉癌的特征性变化,说明这些区域中存在与喉癌发生发展密切相关的癌基因、抑癌基因或其他相关基因。     

播散性浅表性光线性汗孔角化症DSAP1位点的精细定位和候选基因的突变检测

播散性浅表性光线性汗孔角化症(DSAP)是一种以多个浅表的角化性皮损,边缘轻微嵴状角化性隆起为特征的少见的慢性角化性皮肤病,呈常染色体显性遗传。以往的研究将该病基因定位于12q23．2—24．1区域(DSAP1)和15q25．1-26．1区域(DSAP2)。本研究对2个无关的六代DSAP家系进行了全基因组扫描和连锁分析,结果显示,这2个DSAP家系在D12窝4位点的最高累积LOD值为8．28(θ=0．00)。单倍型分析结果显示,这2个DSAP家系致病基因位于12q24．1-q24．2(D12S330和D12S354)之间8．0cM的区域内。该区域与DSAP1的致病区域部分重叠。对重叠区域内6个候选基因(CRY1,PWP1,ASCL4,PRDM4,KIAA0789和CMKLR1)的编码区进行序列分析,在DSAP病人中未发现突变位点。提示该6个候选基因可能与这2个DSAP家系的发病机理无关。     

一先天性并指中国家系的遗传学研究

先天性并指(syndactyly)是一种以手脚发育异常为主要症状的常染色体显性遗传性疾病。I临床症状主要为手指间由蹼相连。其中I、Ⅱ、Ⅲ型先天性并指分别定位于2q34～36、2q31～q32和6q21～23．2。并指多指(synpoly-dactyly;SPD)为Ⅱ型并指(syndactyly,typeⅡ),通常情况下多为第3、4手指和第4、5脚趾受累,两指(趾)间由蹼相连接,不能分离。目前认为本病致病基因为HOXD13,定位于2q31～q32。HOXD13位于HOXD基因簇中。HOXD基因簇中的9个同源基因(HOXD1,-D3,-D4,-D8,-D9,-D10,-D11,-D12,-D13)根据其距着丝粒的远近,按由远到近的顺序在染色体上依次排列。HOXD基因簇中不同基因或其上游调控因子的重复或缺失都可能影响手指关节的发育,从而造成指(趾)数目或形态的异常。作者对湖南怀化地区一出生后即发现双手并指,双足并趾畸形患儿的常染色体显性先天性并指多指家系进行了连锁分析。结果显示,在SPD遗传基因座2q31～q32发现紧密连锁(两点间最大LOD：6．78;θ=0．00)。多点连锁分析最大LOD值为7．02。本家系单倍型分析遗传区间从D2s2302到D2s315之间,间距为20．61cM。我们对HOXD13基因的编码区,内含子-外显子交接区,和部分启动子区域进行序列分析未发现突变。结果证明了在中国人群中存在Ⅱ型并指的遗传位点,并表明该家系致病基因有可能为HOXD13基因相临近的其他基因。     

糖尿病肾病遗传学研究进展

糖尿病肾病是糖尿病最严重的慢性并发症之一, 不同种族的发病率分析和家族聚集性研究显示遗传因素是糖尿病肾病发生、发展的重要因素。文章从3个方面对糖尿病肾病的遗传学研究进展进行综述：“候选基因”的关联研究、连锁分析和全基因组关联研究。关联研究及荟萃分析显示一些候选基因与糖尿病肾病显著相关, 包括ACE、AGT和PPARG等基因; 连锁分析及全基因组连锁分析发现多个糖尿病肾病的易感染色体位点; 随着高通量测序技术和芯片技术的发展, 全基因组关联研究已成为糖尿病肾病遗传学研究的重要途径。虽然遗传因素在糖尿病肾病发病中占据重要的位置, 但还不能完全解释糖尿病肾病的发病原因, 因为糖尿病肾病的发生还受环境因素的影响, 然而糖尿病肾病的遗传学研究可为糖尿病肾病发病机制研究以及药物治疗靶点研究提供一定的理论依据。     

脂联素基因单核苷酸多态性与Ⅱ型糖尿病合并肥胖及胰岛素抵抗相关联

脂联素是近年新发现的脂肪组织特异性的细胞因子,其mRNA是脂肪组织中含量最丰富的基因转录产物,该因子可通过多种途径影响个体对胰岛素的敏感性。脂联素基因多态性与肥胖、胰岛素抵抗和2型糖尿病密切相关,而与冠心病相关性研究的报道较少。本研究以中国汉族人群1,098例为对象,其中304例冠心病(CHD)患者,389例糖尿病患者(T2DM),及405例性别年龄相匹配的正常对照,采用PCR-RFLP技术对脂联素基因-4522C/T进行基因分型,并分别对血脂水平、胰岛素抵抗、体重指数等临床数据进行分析比较。研究结果显示,脂联素基因-4522C/T各基因型及等位基因在CHD组与对照组、T2DM组与对照组中的分布差异无显著性;经分组分析发现,T2DM合并肥胖患者BMI≥25kg/m2TT基因型及T等位基因明显多于对照组,差异有显著性,P=0.014和P=0.034;TT基因型T2DM患者胰岛素抵抗指数(HOMA-IR)显著高于携带有C等位基因的T2DM患者,P=0.0069。本研究提示脂联素基因-4522C/T与中国汉族人群T2DM合并肥胖的发生及T2DM患者胰岛素抵抗相关,是引发糖尿病患者肥胖和胰岛素抵抗的重要候选基因,而与冠心病的发生无关联。     

表观遗传学在2型糖尿病领域的研究进展

2型糖尿病(T2DM)是由遗传和环境因素共同作用而形成的多基因遗传复杂性疾病,病因和发病机制至今未完全明了.最新研究发现,表观遗传学直接或间接参与糖尿病的发病,影响胰岛β细胞的发育和分泌功能,降低机体对胰岛素的敏感性等,最终导致T2DM的发生.因此,基因的表观遗传修饰如microRNA、DNA甲基化及组蛋白修饰在糖尿病的发生发展中起到了重要的作用,对其深入研究将为T2DM预防和治疗提供新的思路.     

LMO2与T细胞白血病

Lmo2基因是LMO(LIM-only)家族的成员之一。作为一个原癌基因,Lmo2的染色体异位t(11;14)(p13;q11)或t(7;11)(q35;p13)与T细胞急性淋巴细胞白血病密切相关。LMO2是细胞中介导转录因子复合物形成的重要接头分子。现对LMO2的分子结构及其在正常和白血病细胞中的调控作用机制的差异作重点介绍。在此基础上还讨论了LMO2成为逆转录病毒介导的基因治疗X染色体连锁的严重联合免疫缺陷综合征过程中成为病毒插入靶位点的可能原因。     

2型糖尿病易感候选基因在世界不同人群中的多样性比较分析

近10年来兴起的全基因组关联分析（Genome-wide association study, GWAS）相关研究结果获得了大量与2型糖尿病相关的候选易感基因,了解这些候选基因在正常人群中的遗传多样性程度以及在不同人群间的遗传差异,不但有助于阐明2型糖尿病的遗传机理,而且对于今后在特定人群中进行2型糖尿病发病机制的深入研究具有指导意义。本研究通过对GWAS数据库和相关文献的搜索和整理确定了170个与2型糖尿病相关的基因或基因区域;随后基于千人基因组计划的全基因组测序数据对这些候选基因在世界范围内14个人群间的遗传多样性进行了比较分析;进一步确定了在人群间存在显著差异的易感基因,并分析了这些基因的多样性特征。在所研究的14个世界人群中,2型糖尿病候选易感基因的遗传多样性与基因组范围的平均水平没有显著差异;但其中8个易感基因IL20RA、RNMTL1-NXN、NOTCH2、ADRA2A-BTBD7P2、TBC1D4、RBM38-HMGB1P1、UBE2E2和PPARD在群体间呈现显著差异,其中最明显的是IL20RA基因 (FST=0.152),该易感基因在非洲人群和非非洲人群间存在显著等位基因频率和单倍型频率差异。14个人群中易感基因遗传结构差异的主要原因是由于非洲人群与非非洲人群之间的群体遗传结构的不同所造成的。进一步比较东西方人群间的2型糖尿病候选基因遗传结构差异,发现在东西方人群中同样存在明显的群体遗传结构差别,其中DGKB-AGMO(FST=0.173)和JAZF1(FST=0.182)是差异最显著的易感基因。本研究通过对群体间2型糖尿病易感基因遗传结构进行比较,鉴别出一些差异特别显著的易感基因,对今后2型糖尿病易感基因与不同人群间发病率和易感性差异的相关研究提供重要参考。     

多种因素导致全球某些族裔糖尿病发病率高

美国和澳大利亚科学家最近研究发现，美国印第安人、墨西哥裔、非洲裔美国人及澳大利亚土著人患糖尿病比率较高是由社会、环境及基因等多种因素造成的，而并非此前认为的主要由基因遗传造成的。     

Linkage and Association Studies of the Susceptibility Genes for Type 2 Diabetes

Type 2 diabetes mellitus (T2DM) is a complex disease characterized by hyperglycemia, insulin resistance, and impaired insulin secretion. T2DM is under strong genetic control. Identification and characterization of genes involved in determining T2DM will contribute to a greater understanding of the pathogenesis of T2DM, and ultimately might lead to the development of better diagnosis, prevention and treatment strategies. Efforts to identify T2DM susceptibility genes have focused on candidate gene approach (association studies) and genome-wide scans (linkage analyses). In this article, we review the current status for mapping and identification of genes for T2DM, with a focus on some promising regions (or genes) and future prospects.     

ABCC8 genetic variants and risk of diabetes mellitus

Diabetes mellitus (DM) is a major health problem worldwide and it will rapidly increase. This disease is characterized by hyperglycemia caused by defects in insulin secretion, insulin action or both. DM has three types: T1DM, T2M and gestational DM (GDM), of them T2DM is more frequent. Multiple genes and their interactions are involved in insulin secretion pathway. Sulfonylurea receptor encoded by ABCC8 gene, together with inward-rectifier potassium ion channel (Kir6.2) regulates insulin secretion by ATP-sensitive K⁺ (KATP) channel located in the plasma membranes. Disruption of these molecules by different mutations is responsible for risk of DM. Several single nucleotide polymorphisms (SNPs) of ABCC8 gene and their interaction are involved in pathogenicity of DM. This review summarizes the current evidence of contribution of ABC8 genetic variants to the development of DM.     

A Genetic Strategy to Measure Circulating Drosophila Insulin Reveals Genes Regulating Insulin Production and Secretion

Insulin is a major regulator of metabolism in metazoans, including the fruit fly Drosophila melanogaster. Genome-wide association studies (GWAS) suggest a genetic basis for reductions of both insulin sensitivity and insulin secretion, phenotypes commonly observed in humans with type 2 diabetes mellitus (T2DM). To identify molecular functions of genes linked to T2DM risk, we developed a genetic tool to measure insulin-like peptide 2 (Ilp2) levels in Drosophila, a model organism with superb experimental genetics. Our system permitted sensitive quantification of circulating Ilp2, including measures of Ilp2 dynamics during fasting and re-feeding, and demonstration of adaptive Ilp2 secretion in response to insulin receptor haploinsufficiency. Tissue specific dissection of this reduced insulin signaling phenotype revealed a critical role for insulin signaling in specific peripheral tissues. Knockdown of the Drosophila orthologues of human T2DM risk genes, including GLIS3 and BCL11A, revealed roles of these Drosophila genes in Ilp2 production or secretion. Discovery of Drosophila mechanisms and regulators controlling in vivo insulin dynamics should accelerate functional dissection of diabetes genetics.     

Prkar1a in the regulation of insulin secretion

The incidence of type 2 diabetes mellitus (T2DM) is rapidly increasing worldwide with significant consequences on individual quality of life as well as economic burden on states' healthcare costs. While origins of the pathogenesis of T2DM are poorly understood, an early defect in glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells is considered a hallmark of T2DM 1.Upon a glucose stimulus, insulin is secreted in a biphasic manner with an early first-phase burst of insulin, which is followed by a second, more sustained phase of insulin output 2. First phase insulin secretion is diminished early in T2DM as well is in subjects who are at risk of developing T2DM 3 4 5 6.An effective treatment of T2DM with incretin hormone glucagon-like peptide-1 (GLP-1) or its long acting peptide analogue exendin-4 (E4), restores first-phase and augments second-phase glucose stimulated insulin secretion. This effect of incretin action occurs within minutes of GLP-1/E4 infusion in T2DM humans. An additional important consideration is that incretin hormones augment GSIS only above a certain glucose threshold, which is slightly above the normal glucose range. This ensures that incretin hormones stimulate GSIS only when glucose levels are high, while they are ineffective when insulin levels are below a certain threshold 7 8.Activation of the GLP-1 receptor, which is highly expressed on pancreatic β-cells, stimulates 2 -distinct intracellular signaling pathways: a) the cAMP-protein kinase A branch and b) the cAMP-EPAC2 (EPAC=exchange protein activated by cAMP) branch. While the EPAC2 branch is considered to mediate GLP-1 effects on first-phase GSIS, the PKA branch is necessary for the former branch to be active 9 10. However, how these 2 branches interplay and converge and how their effects on insulin secretion and insulin vesicle exocytosis are coordinated is poorly understood.Thus, at the outset of our studies we have a poorly understood intracellular interplay of cAMP-dependent signaling pathways, which - when stimulated - restore glucose-dependent first phase and augment second phase insulin secretion in the ailing β-cells of T2DM.     

The effect of insulin on net lipid oxidation predicts worsening of insulin resistance and development of type 2 diabetes mellitus

Suppression of lipid oxidation (L(ox)) by insulin is impaired in obesity and type 2 diabetes mellitus (T2DM). Here we tested whether high L(ox) represents a primary or acquired characteristic in the pathogenesis of T2DM. Hood-indirect calorimetry was performed under postabsorptive conditions and during a two-step hyperinsulinemic euglycemic clamp (insulin infusion rates in mU.m(-2).min(-1): 40 low and 400 high) in 465 Pima Indians: 317 with normal glucose tolerance (NGT), 117 with impaired glucose tolerance (IGT), and 31 with T2DM. The predictive effect of net lipid oxidation (L(ox)) on development of T2DM was assessed in 296 subjects (51 of whom developed T2DM), whereas the predictive effect of L(ox) on followup changes in insulin-mediated glucose disposal (M) and acute insulin response (AIR) was studied in 190 subjects with NGT at baseline. Cross-sectionally, after adjustment for age, sex, body fat (BF), and M low, L(ox) low was increased in T2DM compared with NGT and IGT subjects (P < 0.05). Prospectively, after adjustment for followup duration, age, sex, BF, M, and AIR, increased clamp L(ox) predicted T2DM [hazard rate ratios (95% CI): L(ox) low, 1.5 (1.1, 2.0), P < 0.01; L(ox) high, 1.3 (1.0, 1.8), P = 0.05]. High L(ox) low at baseline was also associated with subsequent worsening of M low (P = 0.04). These data indicate that the inability of insulin to suppress L(ox) may represent an early risk marker for insulin resistance and T2DM that is independent of adiposity, acute insulin secretion, and insulin action on glucose uptake.     

Clinical relevance of epigenetics in the onset and management of type 2 diabetes mellitus

Epigenetics is involved in the altered expression of gene networks that underlie insulin resistance and insufficiency. Major genes controlling β-cell differentiation and function, such as PAX4, PDX1, and GLP1 receptor, are epigenetically controlled. Epigenetics can cause insulin resistance through immunomediated pro-inflammatory actions related to several factors, such as NF-kB, osteopontin, and Toll-like receptors. Hereafter, we provide a critical and comprehensive summary on this topic with a particular emphasis on translational and clinical aspects. We discuss the effect of epigenetics on β-cell regeneration for cell replacement therapy, the emerging bioinformatics approaches for analyzing the epigenetic contribution to type 2 diabetes mellitus (T2DM), the epigenetic core of the transgenerational inheritance hypothesis in T2DM, and the epigenetic clinical trials on T2DM. Therefore, prevention or reversion of the epigenetic changes occurring during T2DM development may reduce the individual and societal burden of the disease.