排序方式: 共有8条查询结果,搜索用时 234 毫秒
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Recent experience with several high-profile drugs demonstrates the great challenges in developing effective and safe therapeutics. A complementary approach to the popular paradigm of disease genetics is based on inherited factors that reduce the incidence and severity of disease among individuals who are genetically predisposed to disease. We propose testing specifically for modifier genes and protective alleles among at-risk individuals and studying the efficacy of therapeutics based on the genetics of health. 相似文献
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Freedman ML Reich D Penney KL McDonald GJ Mignault AA Patterson N Gabriel SB Topol EJ Smoller JW Pato CN Pato MT Petryshen TL Kolonel LN Lander ES Sklar P Henderson B Hirschhorn JN Altshuler D 《Nature genetics》2004,36(4):388-393
Population stratification refers to differences in allele frequencies between cases and controls due to systematic differences in ancestry rather than association of genes with disease. It has been proposed that false positive associations due to stratification can be controlled by genotyping a few dozen unlinked genetic markers. To assess stratification empirically, we analyzed data from 11 case-control and case-cohort association studies. We did not detect statistically significant evidence for stratification but did observe that assessments based on a few dozen markers lack power to rule out moderate levels of stratification that could cause false positive associations in studies designed to detect modest genetic risk factors. After increasing the number of markers and samples in a case-cohort study (the design most immune to stratification), we found that stratification was in fact present. Our results suggest that modest amounts of stratification can exist even in well designed studies. 相似文献
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Helgadottir A Manolescu A Helgason A Thorleifsson G Thorsteinsdottir U Gudbjartsson DF Gretarsdottir S Magnusson KP Gudmundsson G Hicks A Jonsson T Grant SF Sainz J O'Brien SJ Sveinbjornsdottir S Valdimarsson EM Matthiasson SE Levey AI Abramson JL Reilly MP Vaccarino V Wolfe ML Gudnason V Quyyumi AA Topol EJ Rader DJ Thorgeirsson G Gulcher JR Hakonarson H Kong A Stefansson K 《Nature genetics》2006,38(1):68-74
Variants of the gene ALOX5AP (also known as FLAP) encoding arachidonate 5-lipoxygenase activating protein are known to be associated with risk of myocardial infarction. Here we show that a haplotype (HapK) spanning the LTA4H gene encoding leukotriene A4 hydrolase, a protein in the same biochemical pathway as ALOX5AP, confers modest risk of myocardial infarction in an Icelandic cohort. Measurements of leukotriene B4 (LTB4) production suggest that this risk is mediated through upregulation of the leukotriene pathway. Three cohorts from the United States also show that HapK confers a modest relative risk (1.16) in European Americans, but it confers a threefold larger risk in African Americans. About 27% of the European American controls carried at least one copy of HapK, as compared with only 6% of African American controls. Our analyses indicate that HapK is very rare in Africa and that its occurrence in African Americans is due to European admixture. Interactions with other genetic or environmental risk factors that are more common in African Americans are likely to account for the greater relative risk conferred by HapK in this group. 相似文献
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9p21 DNA variants associated with coronary artery disease impair interferon-γ signalling response 总被引:1,自引:0,他引:1
Harismendy O Notani D Song X Rahim NG Tanasa B Heintzman N Ren B Fu XD Topol EJ Rosenfeld MG Frazer KA 《Nature》2011,470(7333):264-268
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The central role played by the αIIbβ3 receptor in platelet aggregation, and hence in platelet thrombosis, has led to the development of a number of parenteral
and oral glycoprotein (GP) IIb/IIIa inhibitors for use in cardiovascular disease states, such as acute coronary syndromes
and stroke. The predominant effect of these agents is to inhibit platelet aggregation, although studies of αIIbβ3 receptor function and various GP IIb/IIIa inhibitors have demonstrated the potential for these agents to produce effects
on other aspects of platelet function, in addition to non-platelet effects. Overall, clinical studies have demonstrated an
impressive beneficial effect for parenteral agents in reducing ischemic complications following percutaneous intervention,
and a more modest beneficial effect in the treatment of patients with acute coronary syndromes. Trials with oral GP IIb/IIIa
inhibitors in similar patient populations have demonstrated toxicity, manifested by an increased mortality in treated patients.
Increased understanding of molecular aspects of both αIIbβ3 receptor function and the effects of GP IIb/IIIa inhibition may help explain some of the inconsistency in recently reported
clinical studies with parenteral agents, and the frank toxicity of oral agents. Such studies may also hold the key to the
development of newer agents with enhanced therapeutic benefit.
Received 10 September 2001; received after revision 22 October 2001; accepted 2 November 2001 相似文献
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The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke 总被引:29,自引:0,他引:29
Helgadottir A Manolescu A Thorleifsson G Gretarsdottir S Jonsdottir H Thorsteinsdottir U Samani NJ Gudmundsson G Grant SF Thorgeirsson G Sveinbjornsdottir S Valdimarsson EM Matthiasson SE Johannsson H Gudmundsdottir O Gurney ME Sainz J Thorhallsdottir M Andresdottir M Frigge ML Topol EJ Kong A Gudnason V Hakonarson H Gulcher JR Stefansson K 《Nature genetics》2004,36(3):233-239
We mapped a gene predisposing to myocardial infarction to a locus on chromosome 13q12-13. A four-marker single-nucleotide polymorphism (SNP) haplotype in this locus spanning the gene ALOX5AP encoding 5-lipoxygenase activating protein (FLAP) is associated with a two times greater risk of myocardial infarction in Iceland. This haplotype also confers almost two times greater risk of stroke. Another ALOX5AP haplotype is associated with myocardial infarction in individuals from the UK. Stimulated neutrophils from individuals with myocardial infarction produce more leukotriene B4, a key product in the 5-lipoxygenase pathway, than do neutrophils from controls, and this difference is largely attributed to cells from males who carry the at-risk haplotype. We conclude that variants of ALOX5AP are involved in the pathogenesis of both myocardial infarction and stroke by increasing leukotriene production and inflammation in the arterial wall. 相似文献
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The resequencing imperative 总被引:2,自引:0,他引:2
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