SH2衔接蛋白1基因在体内能量代谢调节中的作用

肥胖是指体内脂肪细胞的体积和数目增加,体脂占体重的百分比异常增高或在某些局部（如腹部）过多沉积,对健康造成一定影响的慢性代谢性疾病.肥胖的发病机制十分复杂,环境因素与遗传易感性相互作用占主导地位.近来的全基因组关联性研究（GWAS）发现了一批与肥胖症及能量代谢相关的新基因,如跨膜蛋白18、葡糖胺-6-磷酸脱氨酶、含钾通道四聚化结构域15及SH2衔接蛋白1（SH2B1）等,但大部分的具体功能仍不清楚.本文着重介绍SH2B1在能量代谢中的作用,及其基因多态性与肥胖、胰岛素抵抗等代谢性指标的相关性.     

IgA肾病全基因组关联分析研究

已有研究表明,遗传因素在IgA肾病发病机制中起着重要作用。近年兴起的全基因组关联分析研究(GWAS)为遗传学研究提供了新的工具和思路。中山大学附属第一医院肾内科进行了中国汉族人群IgA肾病GWAS研究,发现两个中国汉族人群特有的遗传易感位点(17p13和8p23),同时还验证了在欧美研究中发现的两个易感位点(22q12和MHC区域),并发现多个易感基因与IgA肾病各临床表型相关联。GWAS研究对于明确IgA肾病的遗传发病机制,进一步探索IgA肾病特异性治疗方法及干预新靶点具有重要的科学意义和实用价值。     

环球要刊巡览

发现中国汉族人群冠心病的易感基因新位点6p24．1 在中国，冠心病每年导致70000人死亡。先前的全基因组关联研究（Genome—wide association study，GWAS）报道了欧裔人群中几个与冠心病相关的基因位点，但在中国汉族人群没有类似报道。华中科技大学与卫生部     

银屑病关节炎易感基因

银屑病关节炎(psoriatic arthritis, PsA)是一种临床异质性强的炎性骨关节疾病,目前认为遗传因素在疾病发病中扮演重要角色。近年来针对银屑病关节炎易感基因的研究取得了较多进展,其中MHC区域相关基因早已得到公认,同时在MHC区域外同样发现了大量PsA相关基因。得益于GWAS技术推广,更多易感基因/位点得到进一步确认。其中PsA特异性基因HLA-B、IL-13、IL-23R、PTPN22可能有助于从银屑病患者中更早识别出潜在PsA,基因多态性也有助于指导治疗药物的选择,本文就MHC区域、非MHC区域PsA相关易感基因、以及针对PsA进行的GWAS结果做一综述。     

IgA肾病遗传学研究——现状,机遇和挑战

原发性IgA肾病(IgA nephropathy,IgAN)是最常见的肾小球肾炎,家族聚集起病及发病率的人种差异均提示遗传因素为重要致病机制之一。尽管迄今为止仍未找到明确的致病基因,但随着遗传学研究方法的改进,特别是高密度基因芯片的出现及广泛应用以及人类基因组计划(HGP)的推进,在该领域出现了许多振奋人心的研究成果。连锁分析对家族性IgA肾病基因定位至少已得到4个易感区段;关联分析提示IgAN发病可能与IgA1糖基化过程中的关键酶相关;基因表达谱研究通过对外周血白细胞和肾组织的表达谱分析,发现了一系列与IgAN起病与进展潜在相关的基因;借助IgAN动物模型,则有助于明确候选基因功能和阐明致病机制。近年来全基因组关联研究(GWAS)成为遗传学研究的热点,该方法应用高密度基因芯片,无需假设易感基因,定位微效及中效易感基因效能要强于连锁分析,最近已有2项IgAN的GWAS研究结果发表。复杂性疾病的基因定位极具挑战性,但随着遗传学研究方法的不断改进以及新技术的出现,特别是下一代测序方法的不断完善,必将加快推动IgAN致病基因定位工作。     

结核病易感基因的研究进展

结核病在全世界一直以来都是一种重要的感染性疾病,然而仅1／10的感染者发病。除环境和暴露因素外,宿主遗传因素对引发结核起到不可忽视的作用…。已有研究表明几个候选基因与结核病易感有关,如自然抗性相关巨噬细胞蛋白l（Nrampl或Sicl1a1）基因、维生素受体（VDR）基因、人类白细胞抗原（HLA）．DR2、甘露糖结合凝集素（MBL）基因等。这些易感基因的发现和研究对于建立和健全结核病预防和控制措施起到不可忽视的作用。     

IL-28B基因多态性与慢性肝脏疾病的研究进展

慢性肝脏疾病是由机体的遗传因素和环境因素相互作用,经过多个阶段的发展而产生的。随着全基因组关联研究（genome-wide association study,GWAS）在近年来的迅速发展,为探寻遗传易感基因的复杂性以及为临床肝病治疗提供相应理论依据及科学指导方面提供了有力的保障,因而可以在复杂性肝病鉴定基因的常见变异中发挥至关重要的作用。     

肥胖症的发病机制

肥胖症发病机制的研究，日益受到学者重视。按发病机理及病因可分为单纯性肥胖及继发性肥胖两大类。其中单纯性肥胖症又可分为体质性肥胖症与获得性肥胖病两大类。本文对肥胖症发病机制进行了探讨，阐述了肥胖基因（ob)和瘦素（leptin)、解偶联蛋白基因（ucp)、下丘脑食欲调节网络及其它相关因子在肥胖症发病机制中的作用。     

儿童非酒精性脂肪性肝病新进展

非酒精性脂肪性肝病（NAFLD）的肝脏病理改变可从单纯脂肪变性到非酒精性脂肪性肝炎（NASH）,可伴有肝纤维化,可能进展为肝硬化,甚至导致肝细胞癌。随着肥胖症患儿增多,儿童 NAFLD 开始流行［1］;由于 NAFLD 与代谢综合征密切相关［2-4］,儿童 NAFLD 的流行令人担忧。儿童 NAFLD 的发病机制并不清楚,可能像成人一样存在多种因素间的相互影响;但由于肥胖相关的 NAFLD 患儿几乎不受其他因素影响,故成为研究 NAFLD 发生的理想模型,包括研究易感基因和环境对 NAFLD 的影响［5-6］。     

血清TSH水平相关的遗传学研究进展

甲状腺激素在机体的牛理及代谢过程巾发挥重要作用.作为评价甲状腺功能的敏感指标,血清促甲状腺素(TSH)浓度在个体之间差异明显并且主要由遗传因素所决定.在经历了传统的连锁分析及候选基因关联分析之后,全基因组关联分析(GWAS)在研究血清TSH易感基因过程中取得了重大进展,并发现了许多新的易感位点.本文主要综述与血清TSH水平相关的基因,并对这些研究的未来进行了展望.     

Genome-wide association studies of sleep disorders

Sleep disorders tend to be complex diseases, with multiple genes and environmental factors interacting to contribute to phenotypes. Our understanding of the genetic underpinnings of sleep disorders has benefited from recent genome-wide association studies (GWAS). We review principles underlying GWAS and discuss recent GWAS for restless legs syndrome and narcolepsy. These studies have identified four gene variants associated with restless legs syndrome (BTBD9, MEIS1, MAP2K5/LBXCOR1, and PTPRD) and two variants associated with narcolepsy (one in the T-cell receptor α locus and another between CPT1B and CHKB). These discoveries have opened new lines of research to understand the pathophysiology of these disorders. In addition to GWAS, we expect that new technologies, such as next-generation sequencing, and continued use of animal models will provide important contributions to our understanding of the genetic basis of sleep disorders.     

Beyond the fourth wave of genome-wide obesity association studies

Obesity and related complications are major health burdens. Almost 700 million adults are currently obese globally and the prevalence is predicted to rise towards 2030. The sudden change of lifestyle with physical inactivity and excessive calorie intake undoubtedly have a major part of the epidemic development; however, some individuals seem to be more prone to be affected by an unhealthy lifestyle than others. Hence, genetic predisposition also has an essential role in determining disease susceptibility and response to lifestyle factors. Since the introduction of genome-wide association studies (GWAS), the success of identifying obesity susceptibility variants have increased, and a total of 32 variants have been identified associating genome-wide significantly with body mass index (BMI) and 18 with measures of fat distribution during four overall obesity GWAS waves. However, the immediate success of the GWAS approach has eased off, but the proportion of explained variance for BMI by the identified obesity variants remains low. This review suggests and discusses new initiatives to take GWAS of obesity to the next level, including gene–environment interactions as modulating/masking factors, low-frequent or rare variants and ways to address such analyses, and finally reflections about the applicability of epigenetic modifications when elucidating the genetic background of obesity.     

Genome-Wide Association Studies of Asthma

Bronchial asthma is a common inflammatory disease caused by a combination of genetic and environmental factors. To discover the genes and cellular pathways underlying asthma, a large number of genetic studies have been conducted. Genome-wide association studies (GWAS), which comprehensively assess genes related to multifactorial diseases and drug reactivity, have enhanced understanding of human diseases. From 2007, GWAS of susceptibility to asthma in Caucasian, Mexican, and African-ancestry populations have been conducted and several susceptible loci were identified. Recently, much larger consortium-based GWAS analyses of collaborative samples with adequate statistical power were performed, and the implicated genes suggested a role for communication of epithelial damage to the adaptive immune system and activation of airway inflammation. Furthermore, GWAS identified candidate loci associated with natural variations in lung function, blood eosinophilia and eosinophilic esophagitis, which is inflammation of the esophagus with abnormal infiltration of eosinophils in an allergic reaction. Comparing GWAS in asthma and these clinical phenotypes might help to clarify the mechanisms underlying asthma. Pharmacogenomics analyses using GWAS regarding genetic factors related to the effectiveness of inhaled corticosteroid (ICS) therapy and inhaled beta₂-adrenergic agonists are ongoing now. Although a more complete collection of associated genes and pathways is needed, biologic insights revealed by GWAS provide valuable insights into the pathophysiology of asthma and contribute to the development of better treatment and preventive strategies.     

Genome-wide association studies of obesity and metabolic syndrome

Until just a few years ago, the genetic determinants of obesity and metabolic syndrome were largely unknown, with the exception of a few forms of monogenic extreme obesity. Since genome-wide association studies (GWAS) became available, large advances have been made. The first single nucleotide polymorphism robustly associated with increased body mass index (BMI) was in 2007 mapped to a gene with for the time unknown function. This gene, now known as fat mass and obesity associated (FTO) has been repeatedly replicated in several ethnicities and is affecting obesity by regulating appetite. Since the first report from a GWAS of obesity, an increasing number of markers have been shown to be associated with BMI, other measures of obesity or fat distribution and metabolic syndrome. This systematic review of obesity GWAS will summarize genome-wide significant findings for obesity and metabolic syndrome and briefly give a few suggestions of what is to be expected in the next few years.     

Genetic Influences on Circulating Vitamin D Level: A Review

Over the last decade, there has been renewed interest in vitamin D due to increasing evidence of its importance in a wide range of health outcomes in addition to its traditional role in bone health. Although environmental factors play important roles in determining vitamin D levels, recent large-scale genetic studies also confirmed strong genetic influences. Recent genome-wide association studies (GWAS) have found genetic variations associated with vitamin D metabolism on several genes such as 7 dehydrochlesterol reductase (DHCR7), vitamin D binding protein (GC), 25-hydroxlase (CYP2R1), and 24-hydroxylase (CYP24A1). Vitamin D receptor (VDR), 25-hydroxyvitamin D 1-?? hydroxylase (CYP27B1) and another 25- and 24-hydroxylase (CYP3A4) have also shown significant association in various candidate gene studies. Despite recent success in genetic studies, currently identified genes could only explain a small fraction of genetic variation in 25-hydroxyvitamin D level. With advances in next generation sequencing technologies, additional genetic variants and epigenetic mechanisms are expected to further reveal the genetic architecture of vitamin D metabolism.     

Genome-wide association studies in aging-related processes such as diabetes mellitus, atherosclerosis and cancer

Recent technological developments allow to genotype several hundreds of thousands of genetic variants in a single person in one step. This enables genome-wide association studies (GWAS) by genotyping a large number of patients with diseases of interest and controls at reasonable costs. Compared to a hypothesis-driven candidate gene approach the hypothesis-free GWAS can identify new susceptibility genes without making any a priori biological assumptions. They permit to identify genes involved in pathways which until now were unknown to be involved in a certain phenotype. GWAS are therefore a new and very powerful tool to identify genetic contributors to aging-related phenotypes. This paper provides a short overview about design and methods of GWAS and reviews recent advances in the identification of susceptibility genes for type 2 diabetes mellitus, atherosclerosis and cancer using GWAS.     

Genetic association studies of obesity in Africa: a systematic review

Obesity is increasing in Africa, but the underlying genetic background largely remains unknown. We assessed existing evidence on genetic determinants of obesity among populations within Africa. MEDLINE and EMBASE were searched and the bibliographies of retrieved articles were examined. Included studies had to report on the association of a genetic marker with obesity indices and the presence/occurrence of obesity/obesity trait. Data were extracted on study design and characteristics, genetic determinants and effect estimates of associations with obesity indices. According to this data, over 300 polymorphisms in 42 genes have been studied in various population groups within Africa mostly through the candidate gene approach. Polymorphisms in genes such as ACE, ADIPOQ, ADRB2, AGRP, AR, CAPN10, CD36, C7orf31, DRD4, FTO, MC3R, MC4R, SGIP1 and LEP were found to be associated with various measures of obesity. Of the 36 polymorphisms previously validated by genome‐wide association studies (GWAS) elsewhere, only FTO and MC4R polymorphisms showed significant associations with obesity in black South Africans, Nigerians and Ghanaians. However, these data are insufficient to establish the true nature of genetic susceptibility to obesity in populations within Africa. There has been recent progress in describing the genetic architecture of obesity among populations within Africa. This effort needs to be sustained via GWAS studies.     

A strategy to search for common obesity and type 2 diabetes genes.

Worldwide, the incidence of type 2 diabetes is rising rapidly, mainly because of the increase in the incidence of obesity, which is an important risk factor for this condition. Both obesity and type 2 diabetes are complex genetic traits but they also share some nongenetic risk factors. Hence, it is tempting to speculate that the susceptibility to type 2 diabetes and obesity might also partly be due to shared genes. By comparing all of the published genome scans for type 2 diabetes and obesity, five overlapping chromosomal regions for both diseases (encompassing 612 candidate genes) have been identified. By analysing these five susceptibility loci for type 2 diabetes and obesity, using six freely available bioinformatics tools for disease gene identification, 27 functional candidate genes have been pinpointed that are involved in eating behaviour, metabolism and inflammation. These genes might reveal a molecular link between the two disorders.     

DNA methylation in inflammatory bowel disease and beyond

Inflammatory bowel disease(IBD)is a consequence of the complex,dysregulated interplay between genetic predisposition,environmental factors,and microbial composition in the intestine.Despite a great advancement in identifying host-susceptibility genes using genome-wide association studies(GWAS),the majority of IBD cases are still underrepresented.The immediate challenge in post-GWAS era is to identify other causative genetic factors of IBD.DNA methylation has received increasing attention for its mechanistical role in IBD pathogenesis.This stable,yet dynamic DNA modification,can directly affect gene expression that have important implications in IBD development.The alterations in DNA methylation associated with IBD are likely to outset as early as embryogenesis all the way until old-age.In this review,we will discuss the recent advancement in understanding how DNA methylation alterations can contribute to the development of IBD.     

Gene-diet interaction in relation to the prevention of obesity and type 2 diabetes: evidence from the Finnish Diabetes Prevention Study

Both genetic and environmental factors are involved in the pathogenesis of obesity and type 2 diabetes. Most of the genetic studies on common obesity are confined to the links between a given gene polymorphism or gene loci and different phenotypes of obesity or anthropometric measures. Some studies indicate that genetic factors modify the weight reduction response to energy restriction or weight gain in the long-term. Only a few studies have focused on gene-diet interaction in the development of type 2 diabetes. The Finnish Diabetes Prevention Study shows (DPS) that the success of a lifestyle intervention depends also on the polymorphisms of those genes, which are suggested to play a role in energy metabolism, lipid metabolism, insulin resistance or insulin secretion. This review deals with selected genes examined so far in the DPS.