自身免疫性甲状腺病的遗传及易感性研究进展

自身免疫性甲状腺病(AITD)是常见的器官特异性自身免疫性疾病,但其发病机制尚未完全明了,目前认为其发病明显受遗传因素的影响,已发现多种免疫调节基因、甲状腺特异基因、染色体的一些区域与AITD存在一定联系.全基因组扫描发现多个位点与AITD相关,尤其是中国汉族人群的Graves病易感位点定于5q31,它们为AITD遗传易感基因的研究提供了新的方向.本文就该领域研究进展进行综述.     

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.     

1型糖尿病遗传学研究新进展

1型糖尿病是一种遗传因素和环境因素相互作用,共同参与的复杂遗传病.除家系连锁研究和候选基因关联研究发现的5个易感位点外,全基因组关联研究及后续研究已发现30余个新的易感位点.     

糖尿病肾病遗传机制研究现状与研究策略

糖尿病肾病(DN)是一种多基因遗传病,易感基因的鉴定有助于解析DN的发病机制,指导DN的临床诊断和治疗。目前,DN的遗传研究手段主要为候选基因关联研究和全基因组关联研究,已发现了一些DN的潜在易感位点,但尚需致力于致病基因的定位。将来,DN的遗传研究应形成协作以进一步扩大研究的样本量;利用精确表型诊断DN;并充分运用下一代测序分析和表观遗传研究等研究策略。     

遗传因素在原发性高血压发病中的新进展

2009年以来"全基因组关联分析"(GWAS)发现了一些血压/高血压的遗传易感位点。在此基础上识别致病基因变异、阐明它们在血压调节或高血压发病中的作用和机制,GWAS后研究更为艰巨。GWAS发现的易感位点,对血压水平及高血压发病风险的贡献很小,"遗传性缺失"(missing heritability)已成为复杂性状疾病遗传学研究的重大挑战。罕见基因变异、表观遗传、外显子组测序和全基因组测序等新策略能否挽回遗传性缺失,人们寄以希望。尽管对GWAS的评价不一,医学基因组学时代已经到来,阐明高血压发病的分子遗传机制、发现新的药物治疗靶点是今后努力方向。     

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。     

家族性心房颤动家系携带NEXN和JP H2基因突变分析

目的 使用全外显子测序技术对收集的1例心房颤动患者家系进行致病基因筛查及突变位点分析,初步探索该基因的生物学机制.方法 采集此家族成员外周静脉血,提取基因组DNA,应用全外显子测序技术对先证者进行候选基因突变检测,发现可疑致病位点后,通过Sanger测序法在其家系成员和101例健康人群中进行验证.并使用Polyphen...     

2型糖尿病易感基因定位克隆研究新进展

基因组扫描和连锁分析是目前研究 2型糖尿病易感基因位点的主要手段 ,遗传多态性标志主要采用短串联重复片断 (STR) ,随着人类基因组计划的迅猛发展 ,新一代遗传多态性标志———单核苷酸多态性(SNP)已受到人们越来越多的关注 ,人们期望利用这种高密度、性能稳定、易于自动化操作的遗传学标志进行连锁不平衡和相关分析或直接进行候选基因的突变检测 ,最终找到 2型糖尿病的易感基因     

视野

上海发现东方人糖尿病易感基因位点 作为糖尿病高发群体，中国人有没有糖尿病的特殊易感基因位点？来自中国科学院上海生命科学研究院营养科学研究所的科学家，牵头开展了中国汉族人群中迄今最大规模的2型糖尿病全基因组关联研究，研究样本达4．3万余人，发现了东方人特有的2型糖尿病易感基因位点。     

肱骨短小症致病相关基因及其变异的筛选与验证

目的寻找肱骨短小症的特异致病基因及其变异。方法利用全基因组重测序技术,采用Illumina Hi Seq X ten测序系统检测3例肱骨短小症患者和3例正常对照者全基因组,测序数据经过1000 Genomes Project和db SNP数据库过滤,将测序所得的特异性单核苷酸多态性位点(SNP)在全部患者和对照者中验证,并通过GO和KEGG Pathway分析,筛选致病相关的重要候选基因及变异。结果肱骨短小症患者没有特异致病基因,但具有31个特异性SNP,其中PLCB4rs6077510和PLAU rs2227564变异与肱骨短小症发病密切相关。结论肱骨短小症不是遗传病。但其发病与PLCB4和PLAU基因多态性有关,可能是本病发病的重要机制。     

Genetic developments in autoimmune thyroid disease: an evolutionary process

The identification of genes placing individuals at an increased risk for the development of autoimmune thyroid disease (AITD) has been a slow process. However, over the last 20 years or so real progress has been made with the mapping of novel loci, via a number of different approaches. First, through the use of traditional immunological methods, Human Leucocyte Antigen (HLA)/Major Histocompatibility Complex (MHC) was the first gene region to be associated with AITD and consistent replications have been reported. Second, the CTLA-4 gene region on 2q33 was the first non-MHC replicated locus to be primarily identified using the candidate gene method. Third, family-based linkage studies led to the mapping of a new type 1 diabetes locus, the PTPN22 gene, which has subsequently been independently replicated as a susceptibility gene for Graves' disease (GD). Fourth, despite many unsuccessful attempts at implicating the TSHR gene as a susceptibility locus for GD, a recent approach of 'tagging' all the common variation within the gene has led to its identification as the first GD specific locus. Moreover, the use of tag single nucleotide polymorphisms (SNPs) has also been used to implicate the recently identified type 1 diabetes locus, CD25 as a susceptibility gene for GD. Finally, large scale, ongoing genome-wide association studies in multiple autoimmune diseases (AID) states, including AITD seem likely to lead to the identification of additional MHC and non-MHC susceptibility loci.     

Immunoregulatory and susceptibility genes in thyroid and polyglandular autoimmunity.

The etiology of autoimmune thyroid diseases (AITD) is based on genetic and nongenetic factors. Genome-wide screening and linkage analyses have identified several chromosomal regions that are linked to AITD. These are HT-1 (on chromosome 13q33) and HT-2 (chromosome 12q22) for Hashimoto's thyroiditis (HT), and GD-1 (chromosome 14q31), GD-2 (chromosome 20q11.2), and GD-3 (chromosome Xq21) for Graves' disease (GD). Several genes have been proposed as susceptibility or immunoregulatory genes. Most promising genes are those of the major histocompatibility complex (MHC) complex (chromosome 6), the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) gene (chromosome 2), the CD40 (chromosome 20), the thyroglobulin gene (chromosome 8), and the autoimmune regulator gene (chromosome 21). This review summarizes evidence for pathogenetic involvement of several of these genes in various forms of autoimmune thyropathies. Most genetic data refer to GD, whereas less data are available for HT and thyroid-associated ophthalmopathy. Scarce data refer to AITD within the autoimmune polyglandular syndromes I and II. The realization of family studies in large samples from different populations might provide further insight in the genetic contribution to AITD. Data are also needed on the interaction among susceptibility genes. Finally, additional functional studies are warranted to clarify the possible role of allelic variants in the underlying pathogenic mechanisms of AITD.     

Genetic factors in psoriatic arthritis

The genetic factors that are associated with psoriatic arthritis (PsA) are intricately linked with those that predispose to psoriasis itself. The strongest association is with human leukocyte antigen-Cw*0602, although true susceptibility may lie with one of the neighboring genes along a disease-associated haplotype. There are a number of interesting candidate genes within the major histocompatibility complex (MHC) region with strong functional relevance that have been investigated in PsA. In addition, several areas outside the MHC complex have been highlighted as a result of genetic linkage studies in psoriasis. PsA is a complex, multifactorial disease where multiple genes are likely to influence disease susceptibility, severity, and clinical phenotype. The current evidence for genetic factors in psoriasis and PsA will be reviewed.     

Advances in the genetics of sarcoidosis

Familial aggregation and racial differences in incidence support the notion that sarcoidosis occurs in genetically susceptible hosts. Siblings of those affected with sarcoidosis have a modestly increased disease risk, with an odds ratio of about 5. HLA genes have been the most extensively studied susceptibility genes in sarcoidosis. Many other attractive candidate genes have been evaluated using the case-control study design, but few have been confirmed. Confounding by population stratification likely explains much of the failure to replicate initial findings. A genomewide scan performed in German families with follow-up fine mapping studies has yielded a highly attractive candidate gene, BTNL2 in the MHC II region on chromosome 6. BTNL2, a member of the B7 family of costimulatory molecules, likely functions to down-regulate T-cell activation. A BTNL2 single-nucleotide polymorphism associated with sarcoidosis is predicted to result in a truncated nonfunctioning protein. Association of BTNL2 with sarcoidosis has been confirmed in both white and African Americans. A genomewide scan with follow-up fine mapping studies in African American families has identified chromosome 5 as potentially harboring candidate genes. Additional linkage analysis in the African American families stratified according to genetic ancestry demonstrated that linkage signals varied according to degree of admixture. Certain chromosomal regions were also found linked to specific phenotypes. Follow-up fine mapping studies of the linked regions are underway.     

A C/T single-nucleotide polymorphism in the region of the CD40 gene is associated with Graves' disease.

Graves' disease (GD) develops as a result of an interaction between susceptibility genes and environmental factors. We have previously mapped a susceptibility locus for GD on chromosome 20q11 (GD-2), which has recently been independently replicated. Among the genes mapped to 20q11 was the CD40 gene, an important costimulatory molecule and a good positional candidate gene for GD. We investigated whether the CD40 gene was the GD susceptibility gene on 20q11. Linkage analysis in a subset of Caucasian families showed a maximum multipoint logarithm of odds (LOD) score of 3.3 at the CD40 locus. We then sequenced all 9 exons of the CD40 gene in 8 probands and 10 controls and identified a new C/T single-nucleotide polymorphism (SNP) in the Kozak sequence of the CD40 gene at position -1. Case control association analysis of the CD40 C/T(-1) SNP in 154 Caucasian patients with GD and 118 Caucasian controls showed an association between the CC genotype and GD (p = 0.048, relative risk [RR] = 1.6). Furthermore, the association was stronger when only the probands from the linked families (n = 20) were used (p = 0.009, RR = 4.8). Transmission disequilibrium test (TDT) analysis also showed preferential transmission of the C allele of the CD40 C/T(-1) SNP to affected individuals (p = 0.02). In conclusion, our results suggested that the CD40 gene was a new susceptibility gene for GD within certain families because it was both linked and associated with GD.     

Genome-wide scan of Graves' disease: evidence for linkage on chromosome 5q31 in Chinese Han pedigrees

Graves' disease (GD), which is a common organ-specific autoimmune disorder, is multifactorial and develops in genetically susceptible individuals. Despite many studies of candidate genes, only associations with human leukocyte antigen and cytotoxic T lymphocyte antigen 4 have been generally detected, and the number of susceptibility genes remains unknown. To identify chromosomal regions contributing to GD, we conducted a genome-wide scan on 322 individuals from 54 Chinese Han multiplex GD pedigrees. Parametric linkage analysis revealed the strongest evidence for linkage at D5S436 on chromosome 5q31, with a maximum two-point LOD score of 2.8 and a maximum multipoint LOD score of 2.3. To further assess the significance of this suggestive finding, we typed four additional markers around D5S436 in this chromosome region, and a maximum two-point LOD score of 4.31 and a maximum multipoint LOD score of 4.12 were obtained for marker D5S2090 (with heterogeneity, = 0.38). Nonparametric multipoint analysis also showed significant excess allele sharing, with a P value as low as 0.001, at the same locus. Our findings provide evidence for a susceptibility locus for GD on chromosome 5q31 and support the existence of genetic heterogeneity in GD.     

Update on human systemic lupus erythematosus genetics

PURPOSE OF REVIEW: Susceptibility to systemic lupus erythematosus (SLE) has a genetic component. In recent years, nine complete genome scans using family collections that differ greatly in ethnic compositions and geographic locations have identified several strong, confirmed SLE susceptibility loci. Evidence implicating individual gene polymorphisms (or haplotypes) within some of the linked intervals has been reported. This review highlights recent findings that may lead to the identification of putative genes and new insights in the pathogenesis of SLE. RECENT FINDINGS: Eight of the best-supported SLE susceptibility loci are 1q23, 1q25-31, 1q41-42, 2q35-37, 4p16-15.2, 6p11-21, 12p24, and 16q12. These are chromosomal regions exhibiting genome-wide significance for linkage in single studies and suggestive evidence for linkage in other samples. Linkage analyses conditioning on pedigrees in which one affected member manifesting a particular clinical condition have also yielded many chromosomal regions linked to SLE. The linked interval on chromosome 6p has been narrowed to 0.5 approximately 1.0 Mb (million basepairs) of 3 MHC class II containing risk haplotypes in white subjects. Cumulative results have shown that hereditary deficiencies of complement component C4A (a MHC class III gene) confer risk for SLE in almost all ethnic groups studied. The FcgammaR genes (located at 1q23) have been convincingly demonstrated to play an important role in susceptibility to SLE (and/or lupus nephritis). The evidence for the intronic single nucleotide polymorphism of program cell death gene 1 (PDCD1 at 2q37) to confer susceptibility is promising but not yet compelling. Within several established susceptibility loci, evidence for association of positional candidate genes is emerging. SUMMARY: Further replications of linkage and association are the immediate task. The respective contribution of each susceptibility gene, relationships between genotypes and phenotypes, and potential interactions between susceptibility gene products need to be elucidated. This line of investigation is now well poised to provide novel insights into how genetic variants can affect functional pathways leading to the development of SLE.     

Searching for the autoimmune thyroid disease susceptibility genes: from gene mapping to gene function

The autoimmune thyroid diseases (AITD) are complex diseases that are caused by an interaction between susceptibility genes and environmental triggers. Genetic susceptibility, in combination with external factors (e.g., dietary iodine), is believed to initiate the autoimmune response to thyroid antigens. Abundant epidemiological data, including family and twin studies, point to a strong genetic influence on the development of AITD. Various techniques have been used to identify the genes contributing to the etiology of AITD, including candidate gene analysis and whole genome screening. These studies have enabled the identification of several loci (genetic regions) that are linked with AITD, and in some of these loci putative AITD susceptibility genes have been identified. Some of these genes/loci are unique to Graves' disease (GD) and Hashimoto's thyroiditis (HT), and some are common to both diseases, indicating that there is a shared genetic susceptibility to GD and HT. The putative GD and HT susceptibility genes include both immune modifying genes (e.g., human leukocyte antigen, cytotoxic T lymphocyte antigen-4) and thyroid-specific genes (e.g., TSH receptor, thyroglobulin). Most likely these loci interact, and their interactions may influence disease phenotype and severity. It is hoped that in the near future additional AITD susceptibility genes will be identified and the mechanisms by which they induce AITD will be unraveled.