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- Bengtsson Boström, Kristina, et al.
(författare)
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Polymorphism in the angiotensin converting enzyme but not in the angiotensinogen gene is associated with hypertension and type 2 diabetes: the Skaraborg Hypertension and diabetes project
- 1999
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Ingår i: Journal of Hypertension. - 1473-5598. ; 17:11, s. 1569-1575
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To study the association between polymorphisms in the angiotensin converting enzyme (ACE) gene and angiotensinogen (AGT) gene and hypertension and/or type 2 diabetes in a community population. PATIENTS AND METHODS: The insertion (I)/deletion (D) polymorphism of the ACE gene and the M235T polymorphism of the AGT gene were genotyped in 773 nondiabetic individuals with hypertension, 193 normotensive patients with type 2 diabetes, 243 patients with type 2 diabetes and hypertension, and in 820 normotensive control individuals identified in a community-based study. RESULTS: The DD genotype was associated with hypertension in individuals less than 70 years [odds ratio (OR) = 1.54, confidence interval (CI) = 1.09-2.18] and remained so when patients with type 2 diabetes were excluded from the analysis (OR = 1.45, CI = 1.01-2.09). The strongest association was with the combination of type 2 diabetes and hypertension (OR = 2.19, CI = 1.09-4.38). There was no association with type 2 diabetes without hypertension. No association was observed between the M235T variant or the 3'-microsatellite polymorphism of the AGT gene and hypertension. CONCLUSION: The D-allele of the ACE gene ID polymorphism increases susceptibility to hypertension, particularly when associated with type 2 diabetes. No association was observed between the M235T variant or 3'-microsatellite polymorphism of the AGT gene and hypertension.
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| 2. |
- Orho-Melander, Marju, et al.
(författare)
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A paired-sibling analysis of the XbaI polymorphism in the muscle glycogen synthase gene
- 1999
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 42:9, s. 1138-1145
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: We have previously shown an association between a XbaI polymorphism in the muscle glycogen synthase gene (GYS1) and both Type II (non-insulin-dependent) diabetes mellitus and hypertension. Association studies are, however, hampered by the selection of the control group. To circumvent these problems we addressed the same question using a novel genotype discordant paired-sibling approach. METHODS: We identified 122 sex-matched sib-pairs discordant for the Xba1 polymorphism among a new set of 743 Finnish subjects from 227 families with Type II diabetes and paired analyses were done by McNemar test of symmetry and by permutation tests. RESULTS: Paired analysis showed that siblings with the A2 variant had more hypertension (p = 0.0067), obesity (p = 0.033) and microalbuminuria (p = 0.031) but not significantly more Type II diabetes (p = 0.27) than siblings with the A1 variant. Siblings with the A2 variant were more often treated by insulin (p = 0.050) or anti-hypertensive medication (p = 0.0060) or both. Diabetic A2 variant carriers had higher triglyceride (p = 0.023) and lower HDL cholesterol (p = 0.0059) concentrations and an earlier age at onset of diabetes (p = 0.022) than diabetic siblings with the A1 variant. In non-diabetic sib-pairs the presence of the A2 variant was associated with higher diastolic (p = 0.0014) blood pressure. Finally, the allele frequency of the XbaI polymorphism differed between 216 randomly chosen unrelated Type II diabetic patients and 115 unrelated healthy control spouses without a family history of Type II diabetes (12.7 vs. 6.5 %, p = 0.013). CONCLUSION/INTERPRETATION: The A2 allele of the XbaI polymorphism in the GYS1 confers an increased susceptibility to different features of the metabolic syndrome and Type II diabetes.
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| 3. |
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| 4. |
- Orho-Melander, Marju
(författare)
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Human glycogen synthase genes. Role in insulin resistance and hypoglycaemia
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Effective insulin-stimulated storage of excess glucose after a meal, and its rapid mobilisation in the fasting state provide basis of glucose homeostasis. Glycogen is the macromolecular storage form of glucose and glycogen synthase (GS) is the rate-limiting enzyme in glycogen synthesis. Skeletal muscle and liver are the major depots of glycogen. The present studies were undertaken to isolate and characterise the human skeletal muscle and liver GS genes (GYS1 and GYS2) and to study their role in diabetic insulin resistance and in severe childhood hypoglycaemia associated with glycogen storage disease type 0 (GSD-0). The GYS1 and GYS2 genes were composed of 16 exons and had identical exon-intron structures but differed in the size of the intronic regions. In a paired sibling analysis, the A2 allele of the XbaI polymorphism in the GYS1 gene conferred an increased susceptibility to different features of the metabolic syndrome and to type 2 diabetes. Several naturally occurring variants were identified in the GYS1 gene, but only the rare Pro442Ala mutation resulted in significantly decreased capability to synthesise glycogen when expressed in COS cells. Suggestive linkage of GSD-0 to the GYS2 gene was established in five families with 9 affected children. Mutation screening of the GYS2 gene revealed unique mutations in each family including a premature stop codon in exon 5, a 5´-donor splice site mutation of intron 6, and six missense mutations in exons 1, 7, 11 and 12. These mutations were not found in 200 healthy control subjects, and expression of the mutated enzymes in COS cells indicated severely impaired GS activity. In spite of extremely low or nil hepatic GS activity, the glycogen content in the liver was only moderately decreased in children with GSD-0. Conclusions: As the association between the XbaI polymorphism and type 2 diabetes could not be related to mutations in the GYS1 gene, it seems likely that the polymorphism is in linkage disequilibrium with another gene in the chromosome 19q13.3 region. The Pro442Ala is the first naturally occurring mutation in the GYS1 gene with functional consequences but it remains unclear whether it is enough to cause type 2 diabetes. The results demonstrate that GSD-0 is caused by different mutations in the GYS2 gene. The findings of only moderately decreased liver glycogen stores may point at a GS-independent pathway for glycogen formation in the liver. Finally, the inactivating missense mutations in the highly conserved exons 7, 11 and 12 pinpoint new sites and regions of importance for GS function.
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