2型糖尿病易感基因的连锁和关联研究

2型糖尿病（T2DM）是由于胰岛素抵抗和β细胞分泌缺陷导致高血糖的一种复杂多基因疾病。遗传因素在T2DM的发生发展中起着重要的作用,其遗传率估计为70％～80％。鉴定2型糖尿病基因将有助于阐明其发病机制,发展更好的诊断、预防和治疗策略。2型糖尿病易感基因的鉴定方法主要有候选基因关联研究和全基因组连锁分析。有3种类型的候选基因：功能候选基因、图位候选基因和表达候选基因。虽然许多候选基因与T2DM的关联分析已经进行,但多数都没有得到一致的重复,过氧化物酶体增殖物激活受-γ,体和β-细胞ATP敏感性钾通道基因是目前最好重复的基因。迄今为止,T2DM的全基因组扫描已在20多个不同的群体中进行,包括欧洲人、美国白人、墨西哥裔美国人、美国本地印度人、非洲裔美国人和亚洲人,这些研究鉴定了一些与T2DM相关的QTLs区域。与T2DM显著和证实连锁的区域包括1q25、2q37．3q28、3p24、6q22、8p23、10q26、12q24、18p11、20q13等,与T2DM提示连锁的区域有1q42、2p21、2q24、4q34、5q13、5q31、7q32、9p24、9q21、10p14、11p13、11q13、12q15、14q23、20p12、Xq23等。鉴定这些区域的T2DMQTLs基因及其作用机制是未来的主要挑战。把DNA微阵列和蛋白质组学技术结合起来应用于传统的连锁分析和关联研究,研究基因-基因间、基因-环境间的互作和多个基因对T2DM的加性效应和综合作用,进一步加强国际协作,T2DM的遗传机制可望在不远的将来得到阐明。本文总结了2型糖尿病基因鉴定的现状,重点在一些得到重复的区域和未来的展望。     

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.     

Genome-wide linkage scan to identify loci associated with type 2 diabetes and blood lipid phenotypes in the Sikh Diabetes Study

In this investigation, we have carried out an autosomal genome-wide linkage analysis to map genes associated with type 2 diabetes (T2D) and five quantitative traits of blood lipids including total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, very low-density lipoprotein (VLDL) cholesterol, and triglycerides in a unique family-based cohort from the Sikh Diabetes Study (SDS). A total of 870 individuals (526 male/344 female) from 321 families were successfully genotyped using 398 polymorphic microsatellite markers with an average spacing of 9.26 cM on the autosomes. Results of non-parametric multipoint linkage analysis using S_all statistics (implemented in Merlin) did not reveal any chromosomal region to be significantly associated with T2D in this Sikh cohort. However, linkage analysis for lipid traits using QTL-ALL analysis revealed promising linkage signals with p≤0.005 for total cholesterol, LDL cholesterol, and HDL cholesterol at chromosomes 5p15, 9q21, 10p11, 10q21, and 22q13. The most significant signal (p = 0.0011) occurred at 10q21.2 for HDL cholesterol. We also observed linkage signals for total cholesterol at 22q13.32 (p = 0.0016) and 5p15.33 (p = 0.0031) and for LDL cholesterol at 10p11.23 (p = 0.0045). Interestingly, some of linkage regions identified in this Sikh population coincide with plausible candidate genes reported in recent genome-wide association and meta-analysis studies for lipid traits. Our study provides the first evidence of linkage for loci associated with quantitative lipid traits at four chromosomal regions in this Asian Indian population from Punjab. More detailed examination of these regions with more informative genotyping, sequencing, and functional studies should lead to rapid detection of novel targets of therapeutic importance.     

Meta-analysis of genome-wide linkage studies in BMI and obesity

Objective: The objective was to provide an overall assessment of genetic linkage data of BMI and BMI‐defined obesity using a nonparametric genome scan meta‐analysis. Research Methods and Procedures: We identified 37 published studies containing data on over 31,000 individuals from more than >10,000 families and obtained genome‐wide logarithm of the odds (LOD) scores, non‐parametric linkage (NPL) scores, or maximum likelihood scores (MLS). BMI was analyzed in a pooled set of all studies, as a subgroup of 10 studies that used BMI‐defined obesity, and for subgroups ascertained through type 2 diabetes, hypertension, or subjects of European ancestry. Results: Bins at chromosome 13q13.2‐ q33.1, 12q23‐q24.3 achieved suggestive evidence of linkage to BMI in the pooled analysis and samples ascertained for hypertension. Nominal evidence of linkage to these regions and suggestive evidence for 11q13.3‐22.3 were also observed for BMI‐defined obesity. The FTO obesity gene locus at 16q12.2 also showed nominal evidence for linkage. However, overall distribution of summed rank p values <0.05 is not different from that expected by chance. The strongest evidence was obtained in the families ascertained for hypertension at 9q31.1‐qter and 12p11.21‐q23 (p < 0.01). Conclusion: Despite having substantial statistical power, we did not unequivocally implicate specific loci for BMI or obesity. This may be because genes influencing adiposity are of very small effect, with substantial genetic heterogeneity and variable dependence on environmental factors. However, the observation that the FTO gene maps to one of the highest ranking bins for obesity is interesting and, while not a validation of this approach, indicates that other potential loci identified in this study should be investigated further.     

Pooled genome linkage scan of aggressive prostate cancer: results from the International Consortium for Prostate Cancer Genetics

While it is widely appreciated that prostate cancers vary substantially in their propensity to progress to a life-threatening stage, the molecular events responsible for this progression have not been identified. Understanding these molecular mechanisms could provide important prognostic information relevant to more effective clinical management of this heterogeneous cancer. Hence, through genetic linkage analyses, we examined the hypothesis that the tendency to develop aggressive prostate cancer may have an important genetic component. Starting with 1,233 familial prostate cancer families with genome scan data available from the International Consortium for Prostate Cancer Genetics, we selected those that had at least three members with the phenotype of clinically aggressive prostate cancer, as defined by either high tumor grade and/or stage, resulting in 166 pedigrees (13%). Genome-wide linkage data were then pooled to perform a combined linkage analysis for these families. Linkage signals reaching a suggestive level of significance were found on chromosomes 6p22.3 (LOD = 3.0), 11q14.1–14.3 (LOD = 2.4), and 20p11.21–q11.21 (LOD = 2.5). For chromosome 11, stronger evidence of linkage (LOD = 3.3) was observed among pedigrees with an average at diagnosis of 65 years or younger. Other chromosomes that showed evidence for heterogeneity in linkage across strata were chromosome 7, with the strongest linkage signal among pedigrees without male-to-male disease transmission (7q21.11, LOD = 4.1), and chromosome 21, with the strongest linkage signal among pedigrees that had African American ancestry (21q22.13–22.3; LOD = 3.2). Our findings suggest several regions that may contain genes which, when mutated, predispose men to develop a more aggressive prostate cancer phenotype. This provides a basis for attempts to identify these genes, with potential clinical utility for men with aggressive prostate cancer and their relatives. The names of all authors and their affiliations are listed in the Acknowledgements. The fact that Dr Schaid’s name is given here for purposes of correspondence should not be taken to imply that he played the sole leading part in writing this article. An erratum to this article can be found at     

Genome-wide association studies and type 2 diabetes

In recent years, the search for genetic determinants of type 2 diabetes (T2D) has changed dramatically. Although linkage and small-scale candidate gene studies were highly successful in the identification of genes, which, when mutated, caused monogenic forms of T2D, they were largely unsuccessful when applied to the more common forms of the disease. To date, these approaches have only identified two loci (PPARG, KCNJ11) robustly implicated in T2D susceptibility. The ability to perform large-scale association analysis, including genome-wide association studies (GWAS) in many thousands of samples from different populations, and subsequently, the shift to form large international collaborations to perform meta-analyses across many studies has taken the number of independent loci showing genome-wide significant associations with T2D to 44. This number includes six loci identified initially through the analysis of quantitative glycaemic phenotypes, illustrating the usefulness of this approach both to identify new disease genes and gain insight into the mechanisms leading to disease. Combined, these loci still only account for ～10% of the observed familial clustering in Europeans, leaving much of the variance unexplained. In this review, we will describe what GWAS have taught us about the genetic basis of T2D and discuss possible next steps to uncover the remaining heritability.     

Blood pressure and lipid management fall far short in persons with type 2 diabetes: results from the DIAB-CORE Consortium including six German population-based studies

Background

Although most deaths among patients with type 2 diabetes (T2D) are attributable to cardiovascular disease, modifiable cardiovascular risk factors appear to be inadequately treated in medical practice. The aim of this study was to describe hypertension, dyslipidemia and medical treatment of these conditions in a large population-based sample.

Methods

The present analysis was based on the DIAB-CORE project, in which data from five regional population-based studies and one nationwide German study were pooled. All studies were conducted between 1997 and 2006. We assessed the frequencies of risk factors and co-morbidities, especially hypertension and dyslipidemia, in participants with and without T2D. The odds of no or insufficient treatment and the odds of pharmacotherapy were computed using multivariable logistic regression models. Types of medication regimens were described.

Results

The pooled data set comprised individual data of 15, 071 participants aged 45?C74?years, including 1287 (8.5%) participants with T2D. Subjects with T2D were significantly more likely to have untreated or insufficiently treated hypertension, i.e. blood pressure of?>?= 140/90?mmHg (OR?=?1.43, 95% CI 1.26-1.61) and dyslipidemia i.e. a total cholesterol/HDL-cholesterol ratio?>?= 5 (OR?=?1.80, 95% CI 1.59-2.04) than participants without T2D. Untreated or insufficiently treated blood pressure was observed in 48.9% of participants without T2D and in 63.6% of participants with T2D. In this latter group, 28.0% did not receive anti-hypertensive medication and 72.0% were insufficiently treated. In non-T2D participants, 28.8% had untreated or insufficiently treated dyslipidemia. Of all participants with T2D 42.5% had currently elevated lipids, 80.3% of these were untreated and 19.7% were insufficiently treated.

Conclusions

Blood pressure and lipid management fall short especially in persons with T2D across Germany. The importance of sufficient risk factor control besides blood glucose monitoring in diabetes care needs to be emphasized in order to prevent cardiovascular sequelae and premature death.     

Meta-analysis of genome-wide linkage studies of asthma and related traits

Background

Asthma and allergy are complex multifactorial disorders, with both genetic and environmental components determining disease expression. The use of molecular genetics holds great promise for the identification of novel drug targets for the treatment of asthma and allergy. Genome-wide linkage studies have identified a number of potential disease susceptibility loci but replication remains inconsistent. The aim of the current study was to complete a meta-analysis of data from genome-wide linkage studies of asthma and related phenotypes and provide inferences about the consistency of results and to identify novel regions for future gene discovery.

Methods

The rank based genome-scan meta-analysis (GSMA) method was used to combine linkage data for asthma and related traits; bronchial hyper-responsiveness (BHR), allergen positive skin prick test (SPT) and total serum Immunoglobulin E (IgE) from nine Caucasian asthma populations.

Results

Significant evidence for susceptibility loci was identified for quantitative traits including; BHR (989 pedigrees, n = 4,294) 2p12-q22.1, 6p22.3-p21.1 and 11q24.1-qter, allergen SPT (1,093 pedigrees, n = 4,746) 3p22.1-q22.1, 17p12-q24.3 and total IgE (729 pedigrees, n = 3,224) 5q11.2-q14.3 and 6pter-p22.3. Analysis of the asthma phenotype (1,267 pedigrees, n = 5,832) did not identify any region showing genome-wide significance.

Conclusion

This study represents the first linkage meta-analysis to determine the relative contribution of chromosomal regions to the risk of developing asthma and atopy. Several significant results were obtained for quantitative traits but not for asthma confirming the increased phenotype and genetic heterogeneity in asthma. These analyses support the contribution of regions that contain previously identified asthma susceptibility genes and provide the first evidence for susceptibility loci on 5q11.2-q14.3 and 11q24.1-qter.     

Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. The Breast Cancer Linkage Consortium.

Breast cancer is known to have an inherited component, consistent in some families with autosomal dominant inheritance; in such families the disease often occurs in association with ovarian cancer. Previous genetic linkage studies have established that in some such families disease occurrence is linked to markers on chromosome 17q. This paper reports the results of a collaborative linkage study involving 214 breast cancer families, including 57 breast-ovarian cancer families; this represents almost all the known families with 17q linkage data. Six markers on 17q, spanning approximately 30 cM, were typed in the families. The aims of the study were to define more precisely the localization of the disease gene, the extent of genetic heterogeneity and the characteristics of linked families and to estimate the penetrance of the 17q gene. Under the assumption of no genetic heterogeneity, the strongest linkage evidence was obtained with D17S588 (maximum LOD score [Zmax] = 21.68 at female recombination fraction [theta f] = .13) and D17S579 (Zmax = 13.02 at theta f = .16). Multipoint linkage analysis allowing for genetic heterogeneity provided evidence that the predisposing gene lies between the markers D17S588 and D17S250, an interval whose genetic length is estimated to be 8.3 cM in males and 18.0 cM in females. This position was supported over other intervals by odds of 66:1. The location of the gene with respect to D17S579 could not be determined unequivocally. Under the genetic model used in the analysis, the best estimate of the proportion of linked breast-ovarian cancer families was 1.0 (lower LOD-1 limit 0.79). In contrast, there was significant evidence of genetic heterogeneity among the families without ovarian cancer, with an estimated 45% being linked. These results suggest that a gene(s) on chromosome 17q accounts for the majority of families in which both early-onset breast cancer and ovarian cancer occur but that other genes predisposing to breast cancer exist. By examining the fit of the linkage data to different penetrance functions, the cumulative risk associated with the 17q gene was estimated to be 59% by age 50 years and 82% by age 70 years. The corresponding estimates for the breast-ovary families were 67% and 76%, and those for the families without ovarian cancer were 49% and 90%; these penetrance functions did not differ significantly from one another.     

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Meta-analysis of TNF 308 G/A polymorphism and type 2 diabetes mellitus

Background and Objectives

Many investigations have focused the association between TNF 308 G/A polymorphism and risk for type 2 diabetes mellitus (T2DM). However, the sample sizes of most of the studies were small. The aim of this study is to evaluate the precise association between this variant and risk for T2DM in a large-scale meta-analysis.

Methods

All publications were searched on the association between TNF 308 G/A polymorphism and T2DM. The key words were as follows: diabetes, tumor necrosis factor and polymorphism/variant/genotype. This meta-analysis was assessed by Review manager 5.0.

Results

There were 18 studies identified. The odd ritos (ORs) and 95% confidence intervals (CI) for GA+AA versus GG genotype of TNF 308 G/A polymorphism were 1.03 (0.95–1.12), 1.03 (0.94–1.13) and 1.03 (0.78–1.36) in overall, Caucasian and Asian populations, respectively. The sensitivity analysis further strengthened the validity of this association. No publication bias or heterogeneity was observed in this study.

Conclusion

In summary, there was no significant association detected between the TNF 308 G/A polymorphism and risk for T2DM.     

Adiponectin, type 2 diabetes and the metabolic syndrome: lessons from human genetic studies

Adiponectin, a protein exclusively secreted by adipose tissue but present at low levels in obesity, is now widely recognised as a key determinant of insulin sensitivity and of protection against obesity-associated metabolic syndrome. In this review we explain how genetic findings have contributed to a better understanding of the physiological role of adiponectin in humans. The adiponectin-encoding gene, ADIPOQ (ACDC), is very polymorphic: many frequent exonic synonymous, intronic and promoter single-nucleotide polymorphisms (SNPs) have been identified, as well as a few rare exonic amino acid substitutions. Several of these variations additively contribute to the modulation of adiponectin level and function, and associate with insulin sensitivity, type 2 diabetes and vascular complications of obesity.     

Meta-analysis of the effect of KCNQ1 gene polymorphism on the risk of type 2 diabetes

The potassium voltage-gated channel, KQT-like subfamily member 1 (KCNQ1) is a member of 11 mammalian Kv channel families that plays a key role for the repolarization of the cardiac action potential as well as water and salt transport. Genome-wide association studies have identified KCNQ1 as a type 2 diabetes (T2D) susceptibility gene in populations of Asian descent. After that, a number of studies reported that the rs2237892, rs2237895, rs2237897, rs2283228, and rs231362 polymorphism in KCNQ1 has been implicated in T2D risk. However, studies on the association between these polymorphism and T2D remain conflicting. To derive a more precise estimation of the relationship, a meta-analysis of 114,140 patients and 167,322 controls from 30 published case–control studies was performed. Overall, significantly elevated T2D risk was associated with rs2237892, rs2237895, rs2237897, rs2283228, and rs231362 risk allele when all studies were pooled into the meta-analysis. In the subgroup analysis by ethnicity, sample size, and Hardy–Weinberg equilibrium status of controls, significantly increased risks were found for these polymorphisms. In conclusion, this meta-analysis suggests that rs2237892, rs2237895, rs2237897, rs2283228, and rs231362 polymorphisms in KCNQ1 are associated with elevated T2D risk.     

Linkage analyses of multiple endocrine neoplasia, type 2 (MEN-2) with 23 classical genetic polymorphisms

Linkage analyses were performed in a single large family with multiple endocrine neoplasia, type 2 (MEN-2) between 23 classical genetic polymorphisms and MEN-2. We exclude close linkage of the locus for MEN-2 with ABO, ACP1, BF, ESD, Fy, GALT, GLO1, Jk, MNSs, P, PGM1, Rh and TF, as well as absolute linkage with GPT. These results raise to about 6% the proportion of the genome that has been excluded in this one family. Somewhat positive lod scores were obtained for GC (0.92 at theta = 0), GPT (0.73 at theta = 0.1) and HP (1.49 at theta = 0.05); although not statistically significant, these findings suggest regions of the genome that warrant additional study.     

Multivariate linkage scan for metabolic syndrome traits in families with type 2 diabetes

The purpose of this study was to evaluate evidence for linkage to interrelated quantitative features of the metabolic syndrome (MetS). Data on eight quantitative MetS traits (body weight, waist circumference, systolic and diastolic blood pressure, high‐density lipoprotein (HDL) cholesterol, triglycerides (TGs), and fasting glucose and insulin measurements) and a 10 cM genome scan were available for 78 white families (n = 532 subjects). These data were used to conduct multipoint, multivariate linkage analyses, including tests for coincident linkage and complete pleiotropy. The strongest evidence for linkage from the bivariate analyses was observed on chromosome 1 (1p22.2) (HDL‐TG; univariate lod score equivalent (lod_eq = 3.99)) with stronger results from the trivariate analysis at the same location (HDL‐TG‐Insulin; lod_eq = 4.32). Seven additional susceptibility regions (lod_eq scores >1.9) were observed (1p36, 1q23, 2q21.2, 8q23.3, 14q23.2, 14q32.11, and 20p11.21). The results from this study indicate that several correlated traits of the MetS are influenced by the same gene(s) that account for some of the clustering of the MetS features.     

脂蛋白酯酶基因HindIII和PvuII位点多态与中国人2型糖尿病的关联及meta分析

目的：探讨脂蛋白脂酶基因HindIII（rs320）和PvuII（rs285）位点多态与中国人2型糖尿病的相关性。方法：采用聚合酶链反应-限制性片段长度多态性方法,对919个湖北地区汉人（包括2型糖尿病患者481人,健康对照438人）脂蛋白脂酶基因内含子6PvuII和内含子8HindIII位点多态进行基因分型和关联分析,同时对中国大陆人群的相关研究进行meta分析。结果：HindIII和PvuII位点湖北汉族2型糖尿病人和正常人的基因型和等位基因频率均无显著差异。5个研究包括2型糖尿病患者1252例,健康对照1075例的PvuII位点meta分析表明该位点与中国人2型糖尿病无显著相关性（P=0.39）;9个研究包括2型糖尿病患者1515例,健康对照1022例的HindIII位点meta分析表明该位点与中国人2型糖尿病也无相关性（P=0.14）。结论：脂蛋白脂酶基因HindIII和PvuII位点多态与中国人2型糖尿病的发生无关。     

Linkage studies of Usher syndrome type 1: exclusion results from the Usher syndrome consortium.

Usher Syndrome Type 1 is an autosomal recessive disease characterized by profound congenital hearing impairement and vestibular dysfunction followed by the onset of retinitis pigmentosa in childhood or early adolescence. Members of the Usher Syndrome Consortium, whose objective is to locate and isolate the genes for Usher syndrome, have pooled linkage data from 36 families with 111 affected individuals. We report the analysis of 206 blood group, protein, and DNA marker polymorphisms. No evidence of linkage heterogeneity among families was found for any of the markers studied; the negative lod scores exclude the locus for this disease from about 39% of the genome. Our results indicate the regions of the genome to which our continuing efforts should be directed.