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- Holmkvist, Johan, et al.
(author)
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Common variants in HNF-1 alpha and risk of type 2 diabetes.
- 2006
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In: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 49:Oct 11, s. 2882-2891
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Journal article (peer-reviewed)abstract
- Mutations in the hepatocyte nuclear factor 1-alpha gene (HNF-1 alpha, now known as the transcription factor 1 gene [TCF1]) cause the most common monogenic form of diabetes, MODY3, but it is not known if common variants in HNF-1a are associated with decreased transcriptional activity or phenotypes related to type 2 diabetes, or whether they predict future type 2 diabetes. We studied the effect of four common polymorphisms (rs1920792, I27L, A98V and S487N) in and upstream of the HNF-1 alpha gene on transcriptional activity in vitro, and their possible association with type 2 diabetes and insulin secretion in vivo. Certain combinations of the I27L and A98V polymorphisms in the HNF-1 alpha gene showed decreased transcriptional activity on the target promoters glucose transporter 2 (now known as solute carrier family 2 [facilitated glucose transporter], member 2) and albumin in both HeLa and INS-1 cells. In vivo, these polymorphisms were associated with a modest but significant impairment in insulin secretion in response to oral glucose. Insulin secretion deteriorated over time in individuals carrying the V allele of the A98V polymorphism (n=2,293; p=0.003). In a new case-control (=1,511 and n=2,225 respectively) data set, the I27L polymorphism was associated with increased risk of type 2 diabetes, odds ratio (OR)=1.5 (p=0.002; multiple logistic regression), particularly in elderly (age > 60 years) and overweight (BMI > 25 kg/m(2)) patients (OR=2.3, p=0.002). This study provides in vitro and in vivo evidence that common variants in the MODY3 gene, HNF-1 alpha, influence transcriptional activity and insulin secretion in vivo. These variants are associated with a modestly increased risk of late-onset type 2 diabetes in subsets of elderly overweight individuals.
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| 2. |
- Fredriksson, Jenny, et al.
(author)
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Variation in GYS1 Interacts with Exercise and Gender to Predict Cardiovascular Mortality
- 2007
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 2:3
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Journal article (peer-reviewed)abstract
- Background. The muscle glycogen synthase gene (GYS1) has been associated with type 2 diabetes (T2D), the metabolic syndrome (MetS), male myocardial infarction and a defective increase in muscle glycogen synthase protein in response to exercise. We addressed the questions whether polymorphism in GYS1 can predict cardiovascular (CV) mortality in a high-risk population, if this risk is influenced by gender or physical activity, and if the association is independent of genetic variation in nearby apolipoprotein E gene (APOE). Methodology/Principal Findings. Polymorphisms in GYS1 (XbaIC>T) and APOE (-219G>T, epsilon 2/epsilon 3/epsilon 4) were genotyped in 4,654 subjects participating in the Botnia T2D-family study and followed for a median of eight years. Mortality analyses were performed using Cox proportional-hazards regression. During the follow-up period, 749 individuals died, 409 due to CV causes. In males the GYS1 XbaI T-allele (hazard ratio (HR) 1.9 [1.2-2.9]), T2D (2.5 [1.7-3.8]), earlier CV events (1.7 [1.2-2.5]), physical inactivity (1.9 [1.2-2.9]) and smoking (1.5 [1.0-2.3]) predicted CV mortality. The GYS1 XbaI T-allele predicted CV mortality particularly in physically active males (HR 1.7 [1.3-2.0]). Association of GYS1 with CV mortality was independent of APOE (219TT/epsilon 4), which by its own exerted an effect on CV mortality risk in females (2.9 [1.9-4.4]). Other independent predictors of CV mortality in females were fasting plasma glucose (1.2 [1.1-1.2]), high body mass index (BMI) (1.0 [1.0-1.1]), hypertension (1.9 [1.2-3.1]), earlier CV events (1.9 [1.3-2.8]) and physical inactivity (1.9 [1.2-2.8]). Conclusions/Significance. Polymorphisms in GYS1 and APOE predict CV mortality in T2D families in a gender-specific fashion and independently of each other. Physical exercise seems to unmask the effect associated with the GYS1 polymorphism, rendering carriers of the variant allele less susceptible to the protective effect of exercise on the risk of CV death, which finding could be compatible with a previous demonstration of defective increase in the glycogen synthase protein in carriers of this polymorphism.
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| 3. |
- Kathiresan, S., et al.
(author)
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Polymorphisms associated with cholesterol and risk of cardiovascular events
- 2008
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In: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 358:12, s. 1240-1249
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Journal article (peer-reviewed)abstract
- Background: Common single-nucleotide polymorphisms (SNPs) that are associated with blood low-density lipoprotein (LDL) or high-density lipoprotein (HDL) cholesterol modestly affect lipid levels. We tested the hypothesis that a combination of such SNPs contributes to the risk of cardiovascular disease. Methods: We studied SNPs at nine loci in 5414 subjects from the cardiovascular cohort of the Malmo Diet and Cancer Study. We first validated the association between SNPs and either LDL or HDL cholesterol and subsequently created a genotype score on the basis of the number of unfavorable alleles. We used Cox proportional-hazards models to determine the time to the first cardiovascular event in relation to the genotype score. Results: All nine SNPs showed replication of an association with levels of either LDL or HDL cholesterol. With increasing genotype scores, the level of LDL cholesterol increased from 152 mg to 171 mg per deciliter (3.9 to 4.4 mmol per liter), whereas HDL cholesterol decreased from 60 mg to 51 mg per deciliter (1.6 to 1.3 mmol per liter). During follow-up (median, 10.6 years), 238 subjects had a first cardiovascular event. The genotype score was associated with incident cardiovascular disease in models adjusted for covariates including baseline lipid levels (P<0.001). The use of the genotype score did not improve the clinical risk prediction, as assessed by the C statistic. However, there was a significant improvement in risk classification with the use of models that included the genotype score, as compared with those that did not include the genotype score. Conclusions: A genotype score of nine validated SNPs that are associated with modulation in levels of LDL or HDL cholesterol was an independent risk factor for incident cardiovascular disease. The score did not improve risk discrimination but did modestly improve clinical risk reclassification for individual subjects beyond standard clinical factors.
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| 4. |
- Lyssenko, Valeriya, et al.
(author)
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Genetic prediction of future type 2 diabetes
- 2005
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In: PLoS Medicine. - : Public Library of Science (PLoS). - 1549-1277 .- 1549-1676. ; 2:12, s. 1299-1308
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Journal article (peer-reviewed)abstract
- Background: Type 2 diabetes (T2D) is a multifactorial disease in which environmental triggers interact with genetic variants in the predisposition to the disease. A number of common variants have been associated with T2D but our knowledge of their ability to predict T2D prospectively is limited. Methods and Findings: By using a Cox proportional hazard model, common variants in the PPARG (P12A), CAPN10 (SNP43 and 44), KCNJ11 (E23K), UCP2 (-866G>A), and IRS1 (G972R) genes were studied for their ability to predict T2D in 2,293 individuals participating in the Botnia study in Finland. After a median follow-up of 6 y, 132 (6%) persons developed T2D. The hazard ratio for risk of developing T2D was 1.7 (95% confidence interval [CI] 1.1-2.7) for the PPARG PP genotype, 1.5 (95% CI 1.0-2.2) for the CAPN10 SNP44 TT genotype, and 2.6 (95% CI 1.5-4.5) for the combination of PPARG and CAPN10 risk genotypes. In individuals with fasting plasma glucose ≥ 5.6 mmol/l and body mass index ≥ 30 kg/m2, the hazard ratio increased to 21.2 (95% CI 8.7-51.4) for the combination of the PPARG PP and CAPN10 SNP43/44 GG/TT genotypes as compared to those with the low-risk genotypes with normal fasting plasma glucose and body mass index < 30 kg/m2. Conclusion: We demonstrate in a large prospective study that variants in the PPARG and CAPN10 genes predict future T2D. Genetic testing might become a future approach to identify individuals at risk of developing T2D.
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