| 21. |
- Florez, JC, et al.
(författare)
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Association testing in 9,000 people fails to confirm the association of the insulin receptor substrate-1 G972R polymorphism with type 2 diabetes
- 2004
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 53:12, s. 3313-3318
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Tidskriftsartikel (refereegranskat)abstract
- The insulin receptor substrate (IRS)-1 is an important component of the insulin signal transduction cascade. Several reports suggest that a Gly-->Arg change in codon 972 is associated with type 2 diabetes and related traits, and a recent meta-analysis reported a modest but nominally significant association with type 2 diabetes (odds ratio [OR] 1.25 in favor of carriers of the Arg allele [95% CI 1.05-1.48). To test the reproducibility of the model in a recent meta-analysis, we examined genotype-phenotype correlation in three large Caucasian samples (not previously reported for this variant) totaling 9,000 individuals (estimated to have >95% power to obtain a P<0.05 for the OR of 1.25 estimated in the meta-analysis). In our combined sample, comprising 4,279 case and 3,532 control subjects, as well as 1,189 siblings discordant for type 2 diabetes, G972R was not associated with type 2 diabetes (OR 0.96 [0.84-1.10], P = 0.60). Genotype at G972R had no significant effect on various measures of insulin secretion or insulin resistance in a set of Scandinavian samples in whom we had detailed phenotypic data. In contrast, the well-documented associations of peroxisome proliferator-activated receptor gamma P12A and Kir6.2 E23K with type 2 diabetes are both robustly observed in these 9,000 subjects, including an additional (previously unpublished) confirmation of Kir6.2 E23K and type 2 diabetes in the Polish and North American samples (combined OR 1.15 [1.05-1.261, P = 0.001). Despite genotyping 9,000 people and >95% power to reproduce the estimated OR from the recent meta-analysis, we were unable to replicate the association of the IRS-1 G972R polymorphism with type 2 diabetes.
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| 22. |
- Florez, Jose C., et al.
(författare)
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Haplotype Structure and Genotype-Phenotype Correlations of the Sulfonylurea Receptor and the Islet ATP-Sensitive Potassium Channel Gene Region.
- 2004
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 53:5, s. 1360-1368
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Tidskriftsartikel (refereegranskat)abstract
- The genes for the sulfonylurea receptor (SUR1; encoded by ABCC8) and its associated islet ATP-sensitive potassium channel (Kir6.2; encoded by KCNJ11) are adjacent to one another on human chromosome 11. Multiple studies have reported association of the E23K variant of Kir6.2 with risk of type 2 diabetes. Whether and how E23K itself—or other variant(s) in either of these two closely linked genes—influences type 2 diabetes remains to be fully determined. To better understand genotype-phenotype correlation at this important candidate gene locus, we 1) characterized haplotype structures across the gene region by typing 77 working, high-frequency markers spanning 207 kb and both genes; 2) performed association studies of E23K and nearby markers in >3,400 patients (type 2 diabetes and control) not previously reported in the literature; and 3) analyzed the resulting data for measures of insulin secretion. These data independently replicate the association of E23K with type 2 diabetes with an odds ratio (OR) in the new data of 1.17 (P = 0.003) as compared with an OR of 1.14 provided by meta-analysis of previously published, nonoverlapping data (P = 0.0002). We find that the E23K variant in Kir6.2 demonstrates very strong allelic association with a coding variant (A1369S) in the neighboring SUR1 gene (r2 > 0.9) across a range of population samples, making it difficult to distinguish which gene and polymorphism in this region are most likely responsible for the reported association. We show that E23K is also associated with decreased insulin secretion in glucose-tolerant control subjects, supporting a mechanism whereby β-cell dysfunction contributes to the common form of type 2 diabetes. Like peroxisome proliferator–activated receptor γ, the SUR1/Kir6.2 gene region both contributes to the inherited risk of type 2 diabetes and encodes proteins that are targets for hypoglycemic medications, providing an intriguing link between the underlying mechanism of disease and validated targets for pharmacological treatment.
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| 23. |
- Frayling, Timothy M., et al.
(författare)
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A Genome-Wide Scan in Families With Maturity-Onset Diabetes of the Young: Evidence for Further Genetic Heterogeneity.
- 2003
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 52:3, s. 872-881
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Tidskriftsartikel (refereegranskat)abstract
- Maturity-onset diabetes of the young (MODY) is a heterogeneous single gene disorder characterized by non–insulin-dependent diabetes, an early onset and autosomal dominant inheritance. Mutations in six genes have been shown to cause MODY. Approximately 15–20% of families fitting MODY criteria do not have mutations in any of the known genes. These families provide a rich resource for the identification of new MODY genes. This will potentially enable further dissection of clinical heterogeneity and bring new insights into mechanisms of β-cell dysfunction. To facilitate the identification of novel MODY loci, we combined the results from three genome-wide scans on a total of 23 families fitting MODY criteria. We used both a strict parametric model of inheritance with heterogeneity and a model-free analysis. We did not identify any single novel locus but provided putative evidence for linkage to chromosomes 6 (nonparametric linkage [NPL]score 2.12 at 71 cM) and 10 (NPL score 1.88 at 169–175 cM), and to chromosomes 3 (heterogeneity LOD [HLOD] score 1.27 at 124 cM) and 5 (HLOD score 1.22 at 175 cM) in 14 more strictly defined families. Our results provide evidence for further heterogeneity in MODY.
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| 24. |
- Fredriksson, Jenny, et al.
(författare)
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Characterization of the human skeletal muscle glycogen synthase gene (GYS1) promoter.
- 2004
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Ingår i: European Journal of Clinical Investigation. - : Wiley. - 0014-2972 .- 1365-2362. ; 34:2, s. 113-121
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Tidskriftsartikel (refereegranskat)abstract
- Background Impaired activation of the human skeletal muscle glycogen synthase by insulin is typical for type 2 diabetic patients. Regulation of glycogen synthase occurs mainly by phosphorylation/dephoshorylation but little is known whether there also is transcriptional regulation. Therefore we studied transcriptional regulation of the human skeletal muscle glycogen synthase gene (GYS1) and evaluated the effects of insulin and forskolin on the promoter activity. Methods Seven promoter fragments were expressed in C2C12 myoblasts and myotubes and in HEK293 cells, and the luciferase assay was used to determine transcriptional activity. Results The highest luciferase activity, 350-fold of the promoterless vector, was obtained with nucleotides -692 to +59 in myotubes (P < 0·001), while the nucleotides -250 to +59 provided the highest, 45-fold, activity in the HEK293 cells (P < 0·001). Longer promoter constructs (nucleotides -971, -1707 and -2158 to +59, respectively) had low promoter activity in both cell types. Forskolin treatment for 24 h resulted in approximately 30% decreased promoter activity in myotubes (P < 0·05). Insulin treatment for 0·5-3 h did not increase GYS1 promoter activity; instead the activity was slightly but significantly decreased after 24 h in myotubes (P < 0·005). Conclusions From our results we conclude that basal GYS1 promoter activity is obtained from the first 250 nucleotides of the promoter, while the nucleotides -692 to -544 seem to be responsible for muscle-specific expression, and nucleotides -971 to -692 for negative regulation. In myotubes, the GYS1 promoter was sensitive to negative regulation by forskolin, whereas insulin did not increase GYS1 transcription.
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| 25. |
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| 26. |
- Groop, Leif
(författare)
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Pathogenesis of type 2 diabetes: the relative contribution of insulin resistance and impaired insulin secretion
- 2000
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Ingår i: International journal of clinical practice. Supplement. - 1368-504X. ; :113, s. 3-13
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Tidskriftsartikel (refereegranskat)abstract
- Type 2 diabetes is characterised by both impaired insulin secretion and insulin resistance but their relative contribution to the development of hyperglycaemia may differ due to heterogeneity of the disease. Under most circumstances, insulin resistance is the earliest detectable defect in pre-diabetic individuals but it is not known whether this is the primary defect or secondary to other abnormalities such as abdominal obesity with excessive free fatty acid turnover and increased lipid deposits in muscle. Initially, enhanced insulin secretion can compensate for the insulin resistance but early phase insulin secretion is impaired. In the transition from normal to impaired and diabetic glucose tolerance, insulin sensitivity deteriorates about 40% whereas insulin secretion deteriorates 3-4 fold. In addition to insulin resistance, the metabolic syndrome includes hypertension, dyslipidaemia, obesity and microalbuminuria. In patients with manifest diabetes, chronic hyperglycaemia can result in further deterioration of insulin sensitivity and secretion (glucotoxicity), which is aggravated by elevated free fatty acids (lipotoxicity). Abdominal obesity and insulin resistance are strongly correlated and studies have aimed at understanding the genetic basis. Candidate genes for the metabolic syndrome include those for the beta 3-adrenergic receptor, lipoprotein lipase, hormone sensitive lipase, peroxisome proliferator-activated receptor-gamma, insulin receptor substrate-1 and glycogen synthase. Therefore, type 2 diabetes is multigenic and appears to represent a collision between thrifty genes and an affluent society. Successful management will require treatments targeted at defects of both insulin secretion and insulin resistance.
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| 27. |
- Groop, Leif, et al.
(författare)
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The dysmetabolic syndrome
- 2001
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Ingår i: Journal of Internal Medicine. - : Wiley. - 1365-2796 .- 0954-6820. ; 250:2, s. 105-120
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Tidskriftsartikel (refereegranskat)abstract
- The first unifying definition for the metabolic syndrome was proposed by WHO in 1998. In accordance to this, patients with type 2 diabetes mellitus or impaired glucose tolerance have the syndrome if they fulfil two of the criteria: hypertension, dyslipidaemia, obesity/abdominal obesity and microalbuminuria. Persons with normal glucose tolerance (NGT) should also be insulin resistant. About 40% of persons with impaired glucose tolerance (IGT) and 70% of patients with type 2 diabetes have features of the syndrome. Importantly, presence of the dysmetabolic syndrome is associated with reduced survival, particularly because of increased cardiovascular mortality. The dysmetabolic syndrome most likely results from interplay between several genes and an affluent environment. Compatible with the thrifty gene theory, common variants in genes regulating lipolysis, thermogenesis and glucose uptake in skeletal muscle account for a large part of such thrifty genes. However, hitherto unknown genes may still be identified by random gene approaches.
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| 28. |
- Hirschhorn, J.N., et al.
(författare)
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Genomewide linkage analysis of stature in multiple populations reveals several regions with evidence of linkage to adult height
- 2001
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 69:1, s. 106-116
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Tidskriftsartikel (refereegranskat)abstract
- Genomewide linkage analysis has been extremely successful at identification of the genetic variation underlying single-gene disorders. However, linkage analysis has been less successful for common human diseases and other complex traits in which multiple genetic and environmental factors interact to influence disease risk. We hypothesized that a highly heritable complex trait, in which the contribution of environmental factors was relatively limited, might be more amenable to linkage analysis. We therefore chose to study stature (adult height), for which heritability is 75%-90% (Phillips and Matheny 1990; Carmichael and McGue 1995; Preece 1996; Silventoinen et al. 2000). We reanalyzed genomewide scans from four populations for which genotype and height data were available, using a variance-components method implemented in GENEHUNTER 2.0 (Pratt et al. 2000). The populations consisted of 408 individuals in 58 families from the Botnia region of Finland, 753 individuals in 183 families from other parts of Finland, 746 individuals in 179 families from Southern Sweden, and 420 individuals in 63 families from the Saguenay-Lac-St.-Jean region of Quebec. Four regions showed evidence of linkage to stature: 6q24-25, multipoint LOD score 3.85 at marker D6S1007 in Botnia (genomewide P<.06), 7q31.3-36 (LOD 3.40 at marker D7S2195 in Sweden, P<.02), 12p11.2-q14 (LOD 3.35 at markers D12S10990-D12S398 in Finland,P<.05) and 13q32-33 (LOD 3.56 at markers D13S779-D13S797 in Finland, P<.05). In a companion article (Perola et al. 2001 [in this issue]), strong supporting evidence is obtained for linkage to the region on chromosome 7. These studies suggest that highly heritable complex traits such as stature may be genetically tractable and provide insight into the genetic architecture of complex traits.
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| 29. |
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| 30. |
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