Search Results - (Author, Cooperation:R. A. Hegele)
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1Latest Papers from Table of Contents or Articles in PressR. Do ; N. O. Stitziel ; H. H. Won ; A. B. Jorgensen ; S. Duga ; P. Angelica Merlini ; A. Kiezun ; M. Farrall ; A. Goel ; O. Zuk ; I. Guella ; R. Asselta ; L. A. Lange ; G. M. Peloso ; P. L. Auer ; D. Girelli ; N. Martinelli ; D. N. Farlow ; M. A. DePristo ; R. Roberts ; A. F. Stewart ; D. Saleheen ; J. Danesh ; S. E. Epstein ; S. Sivapalaratnam ; G. K. Hovingh ; J. J. Kastelein ; N. J. Samani ; H. Schunkert ; J. Erdmann ; S. H. Shah ; W. E. Kraus ; R. Davies ; M. Nikpay ; C. T. Johansen ; J. Wang ; R. A. Hegele ; E. Hechter ; W. Marz ; M. E. Kleber ; J. Huang ; A. D. Johnson ; M. Li ; G. L. Burke ; M. Gross ; Y. Liu ; T. L. Assimes ; G. Heiss ; E. M. Lange ; A. R. Folsom ; H. A. Taylor ; O. Olivieri ; A. Hamsten ; R. Clarke ; D. F. Reilly ; W. Yin ; M. A. Rivas ; P. Donnelly ; J. E. Rossouw ; B. M. Psaty ; D. M. Herrington ; J. G. Wilson ; S. S. Rich ; M. J. Bamshad ; R. P. Tracy ; L. A. Cupples ; D. J. Rader ; M. P. Reilly ; J. A. Spertus ; S. Cresci ; J. Hartiala ; W. H. Tang ; S. L. Hazen ; H. Allayee ; A. P. Reiner ; C. S. Carlson ; C. Kooperberg ; R. D. Jackson ; E. Boerwinkle ; E. S. Lander ; S. M. Schwartz ; D. S. Siscovick ; R. McPherson ; A. Tybjaerg-Hansen ; G. R. Abecasis ; H. Watkins ; D. A. Nickerson ; D. Ardissino ; S. R. Sunyaev ; C. J. O'Donnell ; D. Altshuler ; S. Gabriel ; S. Kathiresan
Nature Publishing Group (NPG)
Published 2014Staff ViewPublication Date: 2014-12-10Publisher: Nature Publishing Group (NPG)Print ISSN: 0028-0836Electronic ISSN: 1476-4687Topics: BiologyChemistry and PharmacologyMedicineNatural Sciences in GeneralPhysicsKeywords: Age Factors ; Age of Onset ; *Alleles ; Apolipoproteins A/*genetics ; Case-Control Studies ; Cholesterol, LDL/blood ; Coronary Artery Disease/genetics ; Exome/*genetics ; Female ; Genetic Predisposition to Disease/*genetics ; Genetics, Population ; Heterozygote ; Humans ; Male ; Middle Aged ; Mutation/genetics ; Myocardial Infarction/blood/*genetics ; National Heart, Lung, and Blood Institute (U.S.) ; Receptors, LDL/*genetics ; Triglycerides/blood ; United StatesPublished by: -
2Articles: DFG German National LicensesStaff View
ISSN: 1432-1440Keywords: Key words Angiotensin-converting enzyme ; Angiotensinogen ; Apolipoproteins ; Fatty acid binding protein ; Paraoxonase ; Genetic predispositionSource: Springer Online Journal Archives 1860-2000Topics: MedicineNotes: Abstract The Keewatin Inuit of the Northwest Territories of Canada have a very low age-adjusted mortality rate from coronary heart disease. We hypothesized that this apparent protection from disease has a genetic basis. We determined the prevalence of the disease-associated alleles of five candidate genes for atherosclerosis-related phenotypes. Surprisingly, four of the five alleles studied, namely AGT T235, FABP2 T54, PON R192 and APOE E4, were significantly more frequent in a sample of 175 Keewatin Inuit than among a representative control sample of whites living in the region. The high frequencies of these disease-associated alleles suggests either that they have no relationship with disease susceptibility in the Inuit, or that some unmeasured genetic and/or environmental factors mitigate disease susceptibility that is associated with these alleles. This highlights the difficulty in extrapolating findings from one population to another. Also, very modest genotype-phenotype associations were observed between APOE genotype (P=0.016) and plasma low-density lipoprotein cholesterol concentration and between FABP2 genotype and plasma 2-h postprandial glucose concentration (P=0.048). The relationship between APOE alleles and plasma low-density lipoprotein cholesterol was the same as has been previously reported in many study samples. However, the relationship between FABP2 alleles and plasma 2-h postprandial glucose concentrations was the opposite to that reported in other studies. This suggests that differences in environment, such as the type of fatty acid consumed, interacts with functional differences in gene products involved in candidate metabolic pathways to produce phenotypic differences.Type of Medium: Electronic ResourceURL: -
3Articles: DFG German National LicensesHegele, R. A. ; Sun, Fang ; Harris, Stewart B. ; Anderson, Carol ; Hanley, Anthony J. G. ; Zinman, Bernard
Springer
Published 1999Staff ViewISSN: 1435-232XKeywords: Key words Complex disease ; Carbohydrate ; Insulin ; Aboriginal populationsSource: Springer Online Journal Archives 1860-2000Topics: BiologyMedicineNotes: Abstract We undertook a genome-wide scan using 190 markers with an average separation of 20 cM in 49 Canadian Oji-Cree sib pairs affected with type 2 diabetes. Four of these markers, one each on chromosomes 6, 8, 16, and 22, showed both suggestive linkage and suggestive association with type 2 diabetes in the Oji-Cree. None of these markers corresponded to any chromosomal region or marker that has so far been linked with type 2 diabetes in other populations. Thus, there might be several genetic loci that confer susceptibility to type 2 diabetes in this study sample. We are following up on these preliminary leads by increasing the density of the markers within these linked and associated regions, and also by increasing the number of study subjects. Also, we found instances in which there were wide disparities between the Oji-Cree and reference Caucasians with respect to marker heterozygosity. This suggests that a particular set of markers for genome-wide scanning will have different informativeness in different ethnic groups. Thus, different marker sets will likely be required for different ethnic groups in order to maximize their information content for linkage calculations.Type of Medium: Electronic ResourceURL: -
4Articles: DFG German National LicensesHegele, R. A. ; Hanley, A. J. G. ; Zinman, B. ; Harris, S. B. ; Anderson, C. M.
Springer
Published 2000Staff ViewISSN: 1435-232XKeywords: Key words Complex disease ; Polygenic disease ; Gene environmentSource: Springer Online Journal Archives 1860-2000Topics: BiologyMedicineNotes: Abstract In parallel experiments designed to find the genetic determinants of type 2 diabetes in Oji-Cree, we identified several linked chromosomal regions, using genomic scanning, in addition to a private diabetes-associated mutation, namely HNF1A G319S, using candidate gene sequencing. The genome scan did not identify the region harboring HNF1A as being linked with diabetes. Also, the HNF1A mutation, when used directly in sib-pair linkage analysis, was not linked with diabetes. However, HNF1A G319S was very strongly associated with diabetes, predicted the clinical severity of diabetes, and performed well as a diagnostic predictive test for diabetes in the Oji-Cree. Despite the failure of linkage analysis to identify HNF1A as a determinant of type 2 diabetes, we feel justified in interpreting that G319S has a very important pathogenic role in Oji-Cree diabetes, based upon the highly suggestive association studies. The probable etiologic heterogeneity of type 2 diabetes in the Oji-Cree created a situation in which association analysis was much more sensitive to detect a relationship between HNF1A S319 and diabetes than was linkage analysis. The effectiveness of linkage analysis will probably be limited in study samples that have an even greater complexity of genetic background and/or disease etiology. Thus, the absence of linkage does not always mean that a genomic variant is not an impor-tant determinant of a complex disease. Furthermore, our experience confirms the value of using several complementary strategies to identify susceptibility genes for a complex disease.Type of Medium: Electronic ResourceURL: -
5Articles: DFG German National LicensesHegele, R. A. ; Harris, Stewart B. ; Hanley, Anthony J. G. ; Sun, Fang ; Connelly, Philip W. ; Zinman, Bernard
Springer
Published 1998Staff ViewISSN: 1435-232XKeywords: Key words Atherosclerosis ; Hypertension ; Gene expression ; Linkage disequilibrium ; Small genetic effectsSource: Springer Online Journal Archives 1860-2000Topics: BiologyMedicineNotes: Abstract We previously reported significant associations between variation in the AGT gene at codon 235 and both systolic pressure and hypertension in Canadian Oji-Cree. Recently, Inoue et al suggested that the AGT T235 variant was not causative, but was rather in linkage disequilibrium with a variant in the AGT promoter, namely −6A, that was associated with increased in vitro expression of angiotensinogen and was thus a strong candidate to be the functional basis of the previously observed associations. We genotyped 518 adult Oji-Cree for the AGT promoter polymorphism and tested for its association with blood pressure and hypertension. We found that the frequency of the −6A variant was 0.85 in the Oji-Cree, which is much higher than the frequency observed in other human samples. We also found strong linkage disequilibrium between the AGT−6A and T235 variants. However, genetic variation of the AGT promoter was only marginally associated with variation in systolic pressure, with a trend to significantly higher systolic pressure seen in AGT−6A/A homozygotes than in subjects with other genotypes. In addition, genetic variation of the AGT promoter tended to be associated with a diagnosis of hypertension. Despite the very high prevalence of −6A, our native sample was essentially normotensive. Our findings are consistent with a marginally deleterious effect of the AGT−6A allele on blood pressure, but linkage disequilibrium with another causative variant cannot be ruled out in this sample of aboriginal Canadians.Type of Medium: Electronic ResourceURL: -
6Articles: DFG German National LicensesBoright, Andrew P. ; Connelly, Phillip W. ; Brunt, J. Howard ; Morgan, Kenneth ; Hegele, R. A.
Springer
Published 1998Staff ViewISSN: 1435-232XKeywords: Key words Atherosclerosis ; Intermediate trait ; Complex disease ; Small genetic effects ; LipidsSource: Springer Online Journal Archives 1860-2000Topics: BiologyMedicineNotes: Abstract The role of common variation in the low density lipoprotein (LDL) receptor gene (LDLR) as a determinant of variation in plasma LDL cholesterol in normolipidemic populations is not well established. To address this question, we used both association and linkage analysis to evaluate the relationship between plasma LDL cholesterol and genetic variation in LDLR and in three other candidate genes for lipoprotein metabolism, namely, APOE, PON1, and LPL. We studied a sample of 719 normolipidemic Alberta Hutterites, who comprised 1217 sib pairs. Variation in each of the four candidate genes was significantly associated with variation in plasma LDL cholesterol, but the average effects of the alleles were small. In contrast, sib pair analysis showed that only the LDLR gene variation was linked with variation in plasma LDL cholesterol (P = 0.026). Thus, the common LDLR gene variation was both associated with and linked to variation in plasma LDL cholesterol, suggesting that there is a functional impact of structural variation in LDLR on plasma LDL cholesterol in this study sample. However, the absence of linkage of variation in LDL cholesterol with the other three candidate genes, in particular APOE, is consistent with a lower sensitivity of linkage analysis compared with association analysis for detecting modest effects on quantitative traits. Attributes such as the genetic structure of the study sample, the amount of variance attributable to the locus, and the information content of the marker appear to affect the ability to detect genotype-phenotype relationships using linkage analysis.Type of Medium: Electronic ResourceURL: