特应性皮炎分子遗传学研究进展

特应性皮炎的分子遗传学研究近年来取得了一定进展 ,通过基因组扫描和遗传连锁分析已在人类 1、3、5、13、17、2 0号染色体上发现了该病的易感区域。其与 HL A的相关性研究早已开展 ,寻找该病候选基因正是目前研究的热点     

Ⅱ型糖尿病的遗传学研究进展

遗传因素在 型糖尿病 (T2 DM)的发生发展中起着重要作用。 T2 DM是一种多基因病 ,其遗传模式有主效基因、微效基因和单基因等模式。寻找 T2 DM易感基因的策略主要有基因组扫描、连锁分析和遗传关联研究。近年来 ,应用这些遗传学分析方法人们发现了一些与 T2 DM易感性关联的染色体区域和基因 ,并取得了长足的进展 ,在此简要加以综述     

特应性皮炎分子遗传学研究进展

特应性皮炎的分子遗传学研究近年来取得了一定进展，通过基因组扫描和遗传连锁分析巳在人类1、3、5、13、17、20号染色体上发现了该病的易感区域。其与HLA的相关性研究早巳开展，寻找该病候选基因正是目前研究的热点。     

Ⅱ型糖尿病的遗传学研究进展

遗传因素在Ⅱ型糖尿病(T2DM)的发生发展中起着重要作用。T2DM是一种多基因病，其遗传模式有主效基因、微效基因和单基因等模式。寻找T2DM易感基因的策略主要有基因组扫描、连锁分析和遗传关联研究。近年来，应用这些遗传学分析方法人们发现了一些与T2DM易感性关联的染色体区域和基因，并取得了长足的进展，在此简要加以综述。     

儿童失神癫痫分子遗传学研究进展

儿童失神癫痫 (childhood absence epilepsy,CAE)是特发性全身性癫痫的常见类型 ,其发病机制尚不完全清楚 ,但公认遗传因素在其发病过程中起重要作用 ,目前认为其遗传方式为多基因遗传。目前 ,国外学者通过全基因组扫描和连锁分析 ,已将 CAE易感基因分别定位于染色体 8q2 4以及染色体 3p14 .2 - p12 .1,奥地利学者研究发现 CAE与位于染色体 15 q11.2 - q12γ—氨基丁酸 (GABA) A型受体亚单位β3基因 (GABRB3)关联。同时 ,人们在 CAE动物模型进行了针对儿童失神癫痫易感基因的研究 ,获得了一系列有益的提示     

儿童失神癫痫分子遗传学研究进展

儿童失神癫痫（childhood absence epilepsy,CAE)是特发性全身性癫痫的常见类型，其发病机制尚不完全清楚，但公认遗传因素在其发病过程中起重要作用，目前认为其遗传方式为多基因遗传。目前，国外学者通过全基因组扫描和连锁分析，已将CAE易感基因分别定位于染色体8q24以及染色体3p14.2-p12.1，奥地利学者研究发现CAE与位于染色体15q11.2-q12 γ－氨基丁酸（GABA）A型受体亚单位β3基因（GABRB3）关联。同时，人们在CAE动物模型进行了针对儿童失神癫痫易感基因的研究，获得了一系列有益的提示。     

原发性高血压易感基因的定位分析研究进展

连锁分析是寻找原发性高血压（ESH）易感基因的一种较为有效的方法。近年来研究显示：血管紧张素原、脂蛋白脂酶基因等可能是ESH的易感位点，但对胰岛素及其受体、SA等基因本文未获得相似的信息。目前，大多数研究均以候选基因为线索，选取少量遗传标记作同胞对分析，应用高密度连锁分析和基因组扫描技术进行研究尚未见报道。     

强直性脊柱炎家系全基因组扫描基因定位的荟萃分析

目的 综合分析强直性脊柱炎(ankylosing spondylitis,AS)家系的全基因组扫描基因定位的结果,探讨进一步研究和确定AS的遗传易感位点的思路和方法.方法 采用基因组寻证荟萃分析(genome search meta analysis,GSMA)法,对符合该方法分析的4个AS家系的全基因组扫描结果包括参数连锁分析和非参数连锁分析的结果进行分析.根据连锁分析的最大值被赋值并按降序排列,从而计算出总的等级分值(Rsumrnk).根据每个研究的受累个体数进行加权GSMA对结果进行修正.本研究共有479个家系,1151例AS患者.总的等级分析概率(Psumrnk)和有序的等级分析概率(Pord)＜0.05被认为可能含有易感区域;GSMA Psumrnk＜0.000417时,被认为在全基因组连锁中有显著意义.结果 GSMA显示10组结果的Psumrnk和Pord均小于0.05,表明这些组内最可能含有AS的易感基因位点,这些组分别是6.2、16.3、6.1、3.3、6.3、16.4、10.5、17.1、2.5、2.9.GSMA生成的具有显著意义的全基因组连锁分析的证据位于6p22.3-p21.1(BIN6.2,Psumrnk＜0.000417),包含HLA位点.结论 本GSMA研究进一步证实了HLA位点是AS的主要易感区域,并初步提供非HLA区域包括16 q,3 p,10 q,2 p,17 p和2 q证据.     

原发性高血压易感基因的定位分析研究进展

连锁分析是寻找原发性高血压（ＥＳＨ）易感基因的一种较为有效的方法。近年来研究显示：血管紧张素原、脂蛋白脂酶基因等可能是ＥＳＨ的易感位点，但对胰岛素及其受体、ＳＡ等基因本文未获得相似的信息。目前，大多数研究均以候选基因为线索，选取少量遗传标记作同胞对分析，应用高密度连锁分析和基因组扫描技术进行研究尚未见报道。     

强直性脊柱炎家系全基因组扫描基因定位的荟萃分析

目的 综合分析强直性脊柱炎（ankylosing spondylitis,AS）家系的全基因组扫描基因定位的结果,探讨进一步研究和确定AS的遗传易感位点的思路和方法.方法 采用基因组寻证荟萃分析（genome search meta analysis,GSMA）法,对符合该方法分析的4个AS家系的全基因组扫描结果包括参数连锁分析和非参数连锁分析的结果进行分析.根据连锁分析的最大值被赋值并按降序排列,从而计算出总的等级分值（Rsumrnk）.根据每个研究的受累个体数进行加权GSMA对结果进行修正.本研究共有479个家系,1151例AS患者.总的等级分析概率（Psumrnk）和有序的等级分析概率（Pord）＜0.05被认为可能含有易感区域;GSMA Psumrnk＜0.000417时,被认为在全基因组连锁中有显著意义.结果 GSMA显示10组结果的Psumrnk和Pord均小于0.05,表明这些组内最可能含有AS的易感基因位点,这些组分别是6.2、16.3、6.1、3.3、6.3、16.4、10.5、17.1、2.5、2.9.GSMA生成的具有显著意义的全基因组连锁分析的证据位于6p22.3-p21.1（BIN6.2,Psumrnk＜0.000417）,包含HLA位点.结论 本GSMA研究进一步证实了HLA位点是AS的主要易感区域,并初步提供非HLA区域包括16 q,3 p,10 q,2 p,17 p和2 q证据.     

Advances in the search for psoriasis susceptibility genes

Psoriasis (PS) is a common skin disorder affecting approximately 2% of the Caucasian population. Despite the established influence of several environmental factors, epidemiological data and twin studies have long demonstrated a genetic basis for psoriasis susceptibility. Moreover an association between PS and HLA-Cw6 has been reported in different ethnic groups. In recent years, the availability of statistical methods for complex disease linkage analysis has prompted many researchers to carry out genome-wide scans. Their results have been conflicting and linkage replication has seldom been documented. However, a few chromosome regions have been confirmed in independent studies. In particular, compelling evidence supports the existence of a susceptibility locus within the HLA region. Moreover, loci on chromosomes 17q and 1q have been reported in at least two independent genome scans. Several groups have undertaken the refinement of regions identified during genome scans, using linkage disequilibrium data. This approach has allowed the fine mapping of the 6p21 locus, now restricted to a 60-kb genomic segment. As critical regions get smaller, candidate gene analysis becomes an attractive approach. So far, three genes have been extensively investigated: S100A7 on chromosome 1q and CDSN and HCR on chromosome 6p21. Even though several SNPs have been identified within these genes, none of them seems to meet the requirement needed to prove an involvement in PS pathogenesis. These criteria include association replication in different populations and functional studies of SNP biological significance. Thus, only a collaborative and multidisciplinary approach will allow the identification of PS susceptibility genes.     

TNF-alpha gene polymorphisms: association with type I (insulin-dependent) diabetes mellitus

The localization of TNF genes on the short arm of chromosome 6 between HLA B and the complement genes focused attention to that genetic region which harbors many immunologically relevant genes and is also thought to hold susceptibility genes for a variety of autoimmune diseases that are linked to specific alleles of particular loci in the HLA D region. Since the recently established HLA-DR-DQ variation accounts only for part of the genetic susceptibility to insulin-dependent diabetes mellitus (IDDM) we searched for genomic variation of the tumour necrosis factor (TNF) alpha. We have identified a TNF-alpha restriction fragment length polymorphism (RFLP) with NcoI and analysed diabetic patients including their families, controls and homozygous typing cell lines (HTC) defined by the 10th International Histocompatibility Workshop. Segregation analysis in families and HTC results show a strong linkage of the TNF-alpha 5.5 kb allele with DR types in particular with A1B8DR3. This tight linkage of TNF-alpha alleles with extended haplotypes and the significant increase of heterozygotes in patients could lead to some explanation of the DR3 association with a variety of autoimmune diseases particularly IDDM.     

The genetics of bipolar disorder

Bipolar disorder is a mood disorder characterized by impairing episodes of mania and depression. Twin studies have established that bipolar disorder is among the most heritable of medical disorders and efforts to identify specific susceptibility genes have intensified over the past two decades. The search for genes influencing bipolar disorder has been complicated by a paucity of animal models, limited understanding of pathogenesis, and the genetic and phenotypic complexity of the syndrome. Linkage studies have implicated several chromosomal regions as harboring relevant genes, but results have been inconsistent. It is now widely accepted that the genetic liability to bipolar disorder reflects the action of many genes of individually small effect, a scenario for which linkage studies are poorly suited. Thus, association studies, which are more powerful for the detection of modest effect loci, have become the focus of gene-finding research. A large number of candidate genes, including biological candidates derived from hypotheses about the pathogenesis of the disorder and positional candidates derived from linkage and cytogenetic studies, have been evaluated. Several of these genes have been associated with the disorder in independent studies (including BDNF, DAOA, DISC1, GRIK4, SLC6A4, and TPH2), but none has been established. The clinical heterogeneity of bipolar disorder and its phenotypic and genetic overlap with other disorders (especially schizophrenia, schizoaffective disorder, and major depressive disorder) have raised questions about the optimal phenotype definition for genetic studies. Nevertheless, genomewide association analysis, which has successfully identified susceptibility genes for a variety of complex disorders, has begun to implicate specific genes for bipolar disorder (DGKH, CACNA1C, ANK3). The polygenicity of the disorder means that very large samples will be needed to detect the modest effect loci that likely contribute to bipolar disorder. Detailed genetic dissection of the disorder may provide novel targets (both pharmacologic and psychosocial) for intervention.     

Genetics of celiac disease

Celiac disease (CD) is a chronic inflammatory disease of the gut resulting from ingestion of gluten, occurring in genetically susceptible individuals. The strong genetic association of CD with the DQ2 and DQ8 HLA heterodimers has been known for long, but others non-HLA genes are involved. In order to identify susceptibility genes to CD, several studies have been performed, based on either linkage analyses or candidate gene approaches. This review describes these different studies and their results. The hypothesis of the implication of the DR53 heterodimer in the HLA region has been proposed. The existence of a susceptibility locus on chromosome 5q has been evidenced through linkage analysis and candidate gene strategies have revealed the role of CTLA-4 and of the immunoglobulin gamma genes in the disease.     

Mapping genes of complex psychiatric diseases in Daghestan genetic isolates.

Genetic isolates, which provide outstanding opportunities for identification of susceptibility genes for complex diseases, can be classified as primary (having an ancient demographic history in a stable environment) or secondary (having a younger demographic history) Neel [1992: Minority populations: Genetics, demography, and health, pp. 1-13]. Daghestan contains 26 out of 50 indigenous Caucasus ethnicities that have been in existence for hundreds of generations in the same highland region. The ethnic groups are subdivided into numerous primary isolates. The founder effect and gene drift in these primary isolates may have caused aggregation of specific haplotypes with limited numbers of pathogenic alleles and loci in some isolates relative to others. These are expressed as inter-population differences in lifetime prevalence and features of certain complex clinical phenotypes and in patterns of genetic linkage and linkage disequilibrium (LD). Stable highland and ethnic-cultural environments have led to increased penetrance and a reduced number of phenocopies, which typically hamper the identification of any susceptibility genes for complex diseases. Owing to these characteristics of the primary isolates, a comparative linkage study in the primary isolates allows us to define the number of susceptibility genes for any complex disease and to identify the source of variability and non-replication of linkage analysis results. As part of an ongoing study, seven extended schizophrenia and one nonspecific mental retardation kindreds have been ascertained from Daghestan isolates. Lifetime morbid risk for schizophrenia in the isolates varied from 0 to 5%. A genome scan with markers spaced 10 cM apart was carried out on these pedigrees and linkage analysis was performed using descent graph methods, as implemented in Simwalk2. To identify regions containing susceptibility genes within these kindreds, we followed up those regions with non-parametric and parametric linkage analyses, with the choice of genetic model guided by the results obtained in the NPL. While the analyses are ongoing, the most positive findings were made in different isolated pedigrees on chromosomes 17p11, 3q24, and 22q for schizophrenia and on chromosome 12q for nonspecific mental retardation.     

Linkage analysis of three candidate regions of chromosome 1 in nonsyndromic familial orofacial cleft

Linkage analysis and mouse model knockout studies indicate that loci/genes mapping in different chromosome 1 regions are good candidates for nonsyndromic orofacial cleft (OFC) malformation. On this basis, three different regions of the chromosome 1 have been analysed, by linkage analysis, in 38 families with nonsyndromic OFC. Positive scores were obtained by pairwise analysis and a non-parametric linkage approach for the 1p36 region, with markers close to the MTHFR locus. Additional results allowed us to exclude the presence of an OFC susceptibility gene in the 1q21 and 1q32-42·3 regions.     

Prediction of osteoporosis candidate genes by computational disease-gene identification strategy

Osteoporosis is a complex disease with a strong genetic component. To date, more than 20 genome-wide linkage scans across multiple populations have been launched to hunt for osteoporosis susceptibility genes. Some significant or suggestive chromosomal regions of linkage to bone mineral density have been identified and replicated in genome-wide linkage screens. However, identification of key candidate genes within these confirmed regions is challenging. We used five freely available bioinformatics tools (Prioritizer, GeneSeeker, PROSPECTR and SUSPECTS, Disease Gene Prediction, and Endeavor) to analyze the 13 well-replicated osteoporosis susceptibility loci: 1p36, 1q21-25, 2p22-24, 3p14-25, 4q25-34, 6p21, 7p14-21, 11q14-25, 12q23-24, 13q14-34, 20p12, 2q24-32, and 5q12-21. Pathways and regulatory network analyses were performed using the Ingenuity Pathways Analysis (IPA) software. We identified a subset of most likely candidate osteoporosis susceptibility genes that are largely involved in transforming growth factor (TGF)-beta signaling, granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling, axonal guidance signaling, peroxisome proliferator-activated receptor (PPAR) signaling, and Wnt/beta-catenin signaling pathway. Six nonoverlapping networks were generated by IPA 5.0 from 88 out of the 91 candidate genes. The list of most likely candidate genes and the associated pathway identified will assist researchers in prioritizing candidate disease genes for further empirical analysis and understanding the pathogenesis of osteoporosis.     

The genetics of cancer susceptibility: from mouse to man

Cancer affects approximately 1 in 3 individuals. An individual's susceptibility to cancer is partly determined by environmental exposures and by the combination of inherited cancer susceptibility and resistance genes. Initial mapping of these low penetrance cancer susceptibility genes has been done in the mouse because human low penetrance genes are extremely difficult to find using traditional methods due to heterogeneity and interacting factors. Also, the choice of candidate genes for human association studies can miss the unknown or unexpected. Mouse models also have limitations; it can be difficult to identify causal polymorphisms in the mouse because linkage disequilibrium often extends across several genes. To exploit the strengths of both systems, we outline a cross-species strategy to identify human variants associated with increased cancer risk. This approach uses linkage analysis and haplotyping, allelic imbalance in tumors, and gene expression studies in the mouse, combined with association studies and tumor imbalance studies in humans to identify causal cancer susceptibility variants. Allelic variants in both mouse and human can then be used to better understand the mechanisms behind cancer risk and as targets for intervention.     

Lessons from the NZM2410 model and related strains

SLE susceptibility requires the interplay of an unknown number of genes and equally unidentified triggering events. The past few years have seen significant advances in our understanding of SLE susceptibility through the genetic analysis of murine models. The NZM2410 strain, which is derived from the NZB/WF1 model has played a significant role in these advances. The main advantages presented by this strain over other models are the genetic homozygozity at all loci and an highly penetrant early onset lupus nephritis in both males and females, indicating that the strongest BWF1 susceptibility loci were retained in NZM2410. After identification of NZM2410 susceptibility loci via linkage analyses, congenic strains have been derived in order to convert a polygenic system into a series of monogenic traits. These congenic strains have been analyzed in an integrated process which has provided simultaneously 1) novel functional characterization of the Sle susceptibility loci, 2) high resolution genetic maps that will lead to the identification of the corresponding susceptibility genes by either candidate locus or positional cloning, and 3) insights into the mechanisms by which these loci interact to produce systemic autoimmunity with fatal end-organ damage.