共查询到20条相似文献,搜索用时 31 毫秒
1.
Smith J 《Current opinion in lipidology》2003,14(5):499-504
PURPOSE OF REVIEW: Atherosclerosis is a complex trait with both environmental and genetic aspects. Although some progress has been made in defining genes associated with atherosclerosis in humans, animal models have been useful in learning about pathways and genes involved in atherogenesis. This review describes an unbiased genetic mapping method called quantitative trait locus mapping and progress in using this method to identify genes that alter atherosclerosis susceptibility in mice. RECENT FINDINGS: Approximately 10 well defined genetic loci have been described that are associated with lesion severity in diet-induced or gene knockout mouse models of atherosclerosis. Recently, two of these genetic loci were narrowed considerably by analysis of genetic recombinants within these loci. In addition, a computational method to discover quantitative trait loci has been applied to atherosclerosis. However, none of the genes responsible for these atherosclerosis quantitative trait loci has been definitively identified. The recent completion of the mouse draft genome should facilitate the task of identifying these genes. SUMMARY: Quantitative trait locus mapping studies in mouse models of atherosclerosis have defined genetic regions that alter lesion severity. The identification of the responsible genes may lead to insights into the pathogenesis of atherosclerosis as well as to candidates for human genetic association studies. 相似文献
2.
Pedrazzoli M Secolin R Esteves LO Pereira DS Koike Bdel V Louzada FM Lopes-Cendes I Tufik S 《Genetics and molecular biology》2010,33(4):627-632
Several studies have shown that mutations and polymorphisms in clock genes are associated with abnormal circadian parameters in humans and also with more subtle non-pathological phenotypes like chronotypes. However, there have been conflicting results, and none of these studies analyzed the combined effects of more than one clock gene. Up to date, association studies in humans have focused on the analysis of only one clock gene per study. Since these genes encode proteins that physically interact with each other, combinations of polymorphisms in different clock genes could have a synergistic or an inhibitory effect upon circadian phenotypes. In the present study, we analyzed the combined effects of four polymorphisms in four clock genes (Per2, Per3, Clock and Bmal1) in people with extreme diurnal preferences (morning or evening). We found that a specific combination of polymorphisms in these genes is more frequent in people who have a morning preference for activity and there is a different combination in individuals with an evening preference for activity. Taken together, these results show that it is possible to detect clock gene interactions associated with human circadian phenotypes and bring an innovative idea of building a clock gene variation map that may be applied to human circadian biology. 相似文献
3.
Jean W. MacCluer Candace M. Kammerer John L. VandeBerg Min-Lee Cheng Glen E. Mott Henry C. McGill Jr. 《Genetica》1987,73(1-2):159-168
Statistical methods for detecting the contribution of major genes to quantitative phenotypes have been widely applied in human family studies. Some of these methods are reviewed, and their application to analysis of an animal model for a human disease is described. Analysis of lipoprotein concentrations in pedigreed baboons provides evidence for genetic effects on specific lipoprotein components that have been associated with reduced susceptibility to atherosclerosis in humans. 相似文献
4.
Chromosomal inversion polymorphisms continue to be identified from an increasing number of populations of insects, plants, bacteria and humans. In the fruit fly Drosophila, chromosomal polymorphisms were used in classic studies of natural selection. Recent molecular genetic studies suggest that inversion polymorphisms are dynamical systems. These studies also indicate patterns of disequilibrium and variation that are consistent with co-adapted gene complexes. Although these complexes have yet to be identified, recent studies have identified traits, such as body size, that are linked to inversion polymorphisms. Selection acting on these polymorphisms is strong because latitudinal clines in inversion frequency become re-established rapidly after a new continent is colonized. A combined molecular and phenotypic approach is helping to identify the role of inversion polymorphisms in adaptive divergence, but the genes responsible for associations between traits and inversion polymorphisms remain to be identified. 相似文献
5.
Defining the spectrum of alleles that contribute to blood lipid concentrations in humans 总被引:1,自引:0,他引:1
PURPOSE OF REVIEW: Recently, genome-wide genetic screening of common DNA sequence variants has proven a successful approach to identify novel genetic contributors to complex traits. This review summarizes recent genome-wide association studies for lipid phenotypes, and evaluates the next steps needed to obtain a full picture of genotype-phenotype correlation and apply these findings to inform clinical practice. RECENT FINDINGS: So far, genome-wide association studies have defined at least 19 genomic regions that contain common DNA single nucleotide polymorphisms associated with LDL cholesterol, HDL cholesterol and/or triglycerides. Of these, eight represent novel loci in humans, whereas 11 genes have been previously implicated in lipoprotein metabolism. Many of the same loci with common variants have already been shown to lead to monogenic lipid disorders in humans and/or mice, suggesting that a spectrum of common and rare alleles at each validated locus contributes to blood lipid concentrations. SUMMARY: At least 19 loci harbor common variations that contribute to blood lipid concentrations in humans. Larger scale genome-wide association studies should identify additional loci, and sequencing of these loci should pinpoint all relevant alleles. With a full catalog of DNA polymorphisms in hand, a panel of lipid-related variants can be studied to provide clinical risk stratification and targeting of therapeutic interventions. 相似文献
6.
Corral J González-Conejero R Vicente V 《Journal of biological regulators and homeostatic agents》2004,18(2):166-171
Within the past decade our understanding of thromboembolic disorders has become even more sophisticated as recent discoveries have suggested the influence of gene variants on the development of atherosclerotic disease and arterial thrombosis. Candidate genes encode proteins involved in processes relevant to atherosclerosis, ranging from cholesterol metabolism to arterial thrombosis. Platelets are key elements in primary hemostasis, but also in arterial thrombosis. Moreover, a number of genetic polymorphisms of platelet proteins may also induce gain or loss of function, supporting a role predisposing some individuals to thrombotic events. However, after thousands of studies, much controversy remains whether individual platelet polymorphisms contribute to an increased likelihood of thromboembolic disorders. Although platelet polymorphisms are a promising addition to more established cardiovascular risk factors, identifying genetic variants as a single cause of cardiovascular disease would be an oversimplification; instead, the contribution of these polymorphisms should also be considered in the context of a multifactorial disease. Gene-gene and gene-environment studies would identify specific combinations associated with a high risk to suffer from these diseases. The platelet's genetic heterogeneity should also be considered in every aspect of clinical medicine, ranging from susceptibility to diseases, pathogenesis, and clinical outcome to diversity in responses to drug treatment (pharmacogenomics), and bleeding. 相似文献
7.
DNA polymorphism and the study of disease associations 总被引:13,自引:3,他引:10
Summary Recombinant DNA approaches to disease analysis may be as applicable to studies of disease association as they are to the analysis and diagnosis of single-gene defects. Population and/or family association analyses, using restriction fragment length polymorphisms around candidate genes as markers, have been employed to study conditions such as atherosclerosis and disease with an HLA-association. Progress made to date in disease-association studies using recombinant DNA methodology is reviewed, the rationale behind such studies is examined and associated problems and pitfalls discussed. 相似文献
8.
Schadt EE Molony C Chudin E Hao K Yang X Lum PY Kasarskis A Zhang B Wang S Suver C Zhu J Millstein J Sieberts S Lamb J GuhaThakurta D Derry J Storey JD Avila-Campillo I Kruger MJ Johnson JM Rohl CA van Nas A Mehrabian M Drake TA Lusis AJ Smith RC Guengerich FP Strom SC Schuetz E Rushmore TH Ulrich R 《PLoS biology》2008,6(5):e107
9.
While substance abuse disorders only occur in humans, mice and other model organisms can make valuable contributions to genetic studies of these disorders. In this review, we consider a few specific examples of how model organisms have been used in conjunction with studies in humans to study the role of genetic factors in substance use disorders. In some examples genes that were first discovered in mice were subsequently studied in humans. In other examples genes or specific polymorphisms in genes were first studied in humans and then modeled in mice. Using anatomically and temporally specific genetic, pharmacological and other environmental manipulations in conjunction with histological analyses, mechanistic insights that would be difficult to obtain in humans have been obtained in mice. We hope these examples illustrate how novel biological insights about the effect of genes on substance use disorders can be obtained when mouse and human genetic studies are successfully integrated. 相似文献
10.
Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. Irreversible airflow limitation,
both progressive and associated with an inflammatory response of the lungs to noxious particles or gases, is a hallmark of
the disease. Cigarette smoking is the most important environmental risk factor for COPD, nevertheless, only approximately
20–30% of smokers develop symptomatic disease. Epidemiological studies, case-control studies in relatives of patients with
COPD, and twin studies suggest that COPD is a genetically complex disease with environmental factors and many involved genes
interacting together. Two major strategies have been employed to identify the genes and the polymorphisms that likely contribute
to the development of complex diseases: association studies and linkage analyses. Biologically plausible pathogenetic mechanisms
are prerequisites to focus the search for genes of known function in association studies. Protease-antiprotease imbalance,
generation of oxidative stress, and chronic inflammation are recognized as the principal mechanisms leading to irreversible
airflow obstruction and parenchymal destruction in the lung. Therefore, genes which have been implicated in the pathogenesis
of COPD are involved in antiproteolysis, antioxidant barrier and metabolism of xenobiotic substances, inflammatory response
to cigarette smoke, airway hyperresponsiveness, and pulmonary vascular remodelling. Significant associations with COPD-related
phenotypes have been reported for polymorphisms in genes coding for matrix metalloproteinases, microsomal epoxide hydrolase,
glutathione-S-transferases, heme oxygenase, tumor necrosis factor, interleukines 1, 8, and 13, vitamin D-binding protein and
β-2-adrenergic receptor (ADRB2), whereas adequately powered replication studies failed to confirm most of the previously observed
associations. Genome-wide linkage analyses provide us with a novel tool to identify the general locations of COPD susceptibility
genes, and should be followed by association analyses of positional candidate genes from COPD pathophysiology, positional
candidate genes selected from gene expression studies, or dense single nucleotide polymorphism panels across regions of linkage.
Haplotype analyses of genes with multiple polymorphic sites in linkage disequilibrium, such as the ADRB2 gene, provide another promising field that has yet to be explored in patients with COPD. In the present article we review
the current knowledge about gene polymorphisms that have been recently linked to the risk of developing COPD and/or may account
for variations in the disease course. 相似文献
11.
Xiong Q Jiao Y Hasty KA Stuart JM Postlethwaite A Kang AH Gu W 《Journal of immunology (Baltimore, Md. : 1950)》2008,181(2):859-864
Rheumatoid arthritis (RA) is an autoimmune disease, the pathogenesis of which is affected by multiple genetic and environmental factors. To understand the genetic and molecular basis of RA, a large number of quantitative trait loci (QTL) that regulate experimental autoimmune arthritis have been identified using various rat models for RA. However, identifying the particular responsible genes within these QTL remains a major challenge. Using currently available genome data and gene annotation information, we systematically examined RA-associated genes and polymorphisms within and outside QTL over the whole rat genome. By the whole genome analysis of genes and polymorphisms, we found that there are significantly more RA-associated genes in QTL regions as contrasted with non-QTL regions. Further experimental studies are necessary to determine whether these known RA-associated genes or polymorphisms are genetic components causing the QTL effect. 相似文献
12.
Wang X Ishimori N Korstanje R Rollins J Paigen B 《American journal of human genetics》2005,77(1):1-16
Susceptibility to atherosclerosis is determined by both environmental and genetic factors. Its genetic determinants have been studied by use of quantitative-trait-locus (QTL) analysis. So far, 21 atherosclerosis QTLs have been identified in the mouse: 7 in a high-fat-diet model only, 9 in a sensitized model (apolipoprotein E- or LDL [low-density lipoprotein] receptor-deficient mice) only, and 5 in both models, suggesting that different gene sets operate in each model and that a subset operates in both. Among the 27 human atherosclerosis QTLs reported, 17 (63%) are located in regions homologous (concordant) to mouse QTLs, suggesting that these mouse and human atherosclerosis QTLs have the same underlying genes. Therefore, genes regulating human atherosclerosis will be found most efficiently by first finding their orthologs in concordant mouse QTLs. Novel mouse QTL genes will be found most efficiently by using a combination of the following strategies: identifying QTLs in new crosses performed with previously unused parental strains; inducing mutations in large-scale, high-throughput mutagenesis screens; and using new genomic and bioinformatics tools. Once QTL genes are identified in mice, they can be tested in human association studies for their relevance in human atherosclerotic disease. 相似文献
13.
Hegele RA Ban MR Carrington CV Ramdath DD 《Human biology; an international record of research》2001,73(4):525-531
Trinidadians of South Asian origin have a high prevalence of cardiovascular disease and diabetes compared to Trinidadians of African origin. The degree to which these differences are related to genetic and/or environmental factors is unclear. To determine whether there might be a genetic basis for this difference in prevalence of deleterious phenotypes we examined allele frequencies for candidate genes in atherosclerosis and diabetes. We genotyped 81 consecutive neonates of African origin and 103 consecutive neonates of South Asian origin. We evaluated common polymorphisms in 11 candidate genes for atherosclerosis and diabetes. We found differences between the two subpopulations in the allele frequencies of several candidate genes, including APOE, LIPC, APOC3, PON1, PON2, and PPP1R3. However, the differences in the allele frequencies were not all consistent with the pattern of CHD expression between these two ethnic groups in adulthood. Thus, differences in genetic architecture alone may not explain the wide disparities in disease prevalence between these two subpopulations. It is very likely that environmental factors, or unmeasured genetic factors, influence the genetic susceptibility to disease in these subpopulations. 相似文献
14.
15.
Lee ML Schoenfeld D Wang X Penfornis A Faustman D 《Biostatistics (Oxford, England)》2001,2(3):309-322
Many genetic studies are based on analysing multiple DNA regions of cases and controls. Usually each is tested separately for association with disease. However, some diseases may require interacting polymorphisms at several regions, and most disease susceptibility is polygenic. In this paper, we develop new methods for determining combinations of polymorphisms that affect the risk of disease. For example, two different genes might produce normal proteins, but these proteins improperly function when they occur together. We consider a Bayesian approach to analyse studies where DNA data from cases and controls have been analysed for polymorphisms at multiple regions and a polygenic etiology is suspected. The method of Gibbs sampling is used to incorporate data from individuals who have not had every region analysed at the DNA sequence or amino acid level. The Gibbs sampling algorithm alternatively generates a sample from the posterior distribution of the sequence of combinations of polymorphisms in cases and controls and then uses this sample to impute the data that are missing. After convergence the algorithm is used to generate a sample from the posterior distribution for the probability of each combination in order to identify groups of polymorphisms that best discriminate cases from controls. We apply the methods to a genetic study of type I diabetes. The protein encoded by the TAP2 gene is important in T cell function, and thus may affect the development of autoimmune diseases such as insulin dependent diabetes mellitus (IDDM). We determine pairs of polymorphisms of genetic fragments in the coding regions of linked HLA genes that may impact the risk of IDDM. 相似文献
16.
17.
PURPOSE OF REVIEW: Quantitative trait locus analysis has been used in both humans and mice for the purpose of finding new genes regulating plasma lipid levels. We review these methods and discuss new approaches that can help find quantitative trait locus genes. RECENT FINDINGS: Many quantitative trait loci have been found that regulate plasma levels for HDL cholesterol (37 in mice and 30 in humans), LDL cholesterol (25 in mice and 20 in humans) and triglycerides (19 in mice and 30 in humans). Most of the human quantitative trait loci have concordant mouse quantitative trait loci mapping to homologous regions (93% for HDL cholesterol, 100% for LDL cholesterol and 80% for triglycerides), suggesting that many genes identified in mice may also regulate the same traits in humans. New approaches based on recently developed genomic and bioinformatic technologies and resources should greatly facilitate finding these genes. SUMMARY: New genes regulating plasma lipid levels can be found in mice and then tested in humans. Some of these genes could be potential therapeutic targets for human atherosclerosis. 相似文献
18.
19.
Lohse MJ 《Trends in molecular medicine》2004,10(2):55-58
Many polymorphisms have been described for the genes encoding the beta 1, beta 2, and alpha 2c-adrenoceptors that result in altered signaling and/or regulatory properties of the receptors. Several studies have investigated whether these properties affect the cardiovascular function of these receptors in mice or in humans, but have yielded mixed results. Some studies suggest that adrenoceptor polymorphisms might alter the risk for heart failure and the response to treatment with beta-blockers. However, the complex haplotypes resulting from combinations of individual polymorphisms have not yet been investigated, and firm conclusions or recommendations cannot be made because of the low patient numbers in each of the study programs. 相似文献
20.
Lack of genetic diversity across diverse immune genes in an endangered mammal,the Tasmanian devil (Sarcophilus harrisii)
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Katrina M. Morris Belinda Wright Catherine E. Grueber Carolyn Hogg Katherine Belov 《Molecular ecology》2015,24(15):3860-3872
The Tasmanian devil (Sarcophilus harrisii) is threatened with extinction due to the spread of devil facial tumour disease. Polymorphisms in immune genes can provide adaptive potential to resist diseases. Previous studies in diversity at immune loci in wild species have almost exclusively focused on genes of the major histocompatibility complex (MHC); however, these genes only account for a fraction of immune gene diversity. Devils lack diversity at functionally important immunity loci, including MHC and Toll‐like receptor genes. Whether there are polymorphisms at devil immune genes outside these two families is unknown. Here, we identify polymorphisms in a wide range of key immune genes, and develop assays to type single nucleotide polymorphisms (SNPs) within a subset of these genes. A total of 167 immune genes were examined, including cytokines, chemokines and natural killer cell receptors. Using genome‐level data from ten devils, SNPs within coding regions, introns and 10 kb flanking genes of interest were identified. We found low polymorphism across 167 immune genes examined bioinformatically using whole‐genome data. From this data, we developed long amplicon assays to target nine genes. These amplicons were sequenced in 29–220 devils and found to contain 78 SNPs, including eight SNPS within exons. Despite the extreme paucity of genetic diversity within these genes, signatures of balancing selection were exhibited by one chemokine gene, suggesting that remaining diversity may hold adaptive potential. The low functional diversity may leave devils highly vulnerable to infectious disease, and therefore, monitoring and preserving remaining diversity will be critical for the long‐term management of this species. Examining genetic variation in diverse immune genes should be a priority for threatened wildlife species. This study can act as a model for broad‐scale immunogenetic diversity analysis in threatened species. 相似文献