| 1. |
- Holmkvist, Johan, et al.
(författare)
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Common variants in HNF-1 alpha and risk of type 2 diabetes.
- 2006
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 49:Oct 11, s. 2882-2891
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Tidskriftsartikel (refereegranskat)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. |
- Huth, Cornelia, et al.
(författare)
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IL6 gene promoter polymorphisms and type 2 diabetes - Joint analysis of individual participants' data from 21 studies
- 2006
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Ingår i: DIABETES. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 55:10, s. 2915-2921
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Tidskriftsartikel (refereegranskat)abstract
- Several lines of evidence indicate a causal role of the cytokine interleukin (IL)-6 in the development of type 2 diabetes in humans. Two common polymorphisms in the promoter of the IL-6 encoding gene IL6, −174G>C (rs1800795) and −573G>C (rs1800796), have been investigated for association with type 2 diabetes in numerous studies but with results that have been largely equivocal. To clarify the relationship between the two IL6 variants and type 2 diabetes, we analyzed individual data on >20,000 participants from 21 published and unpublished studies. Collected data represent eight different countries, making this the largest association analysis for type 2 diabetes reported to date. The GC and CC genotypes of IL6 −174G>C were associated with a decreased risk of type 2 diabetes (odds ratio 0.91, P = 0.037), corresponding to a risk modification of nearly 9%. No evidence for association was found between IL6 −573G>C and type 2 diabetes. The observed association of the IL6 −174 C-allele with a reduced risk of type 2 diabetes provides further evidence for the hypothesis that immune mediators are causally related to type 2 diabetes; however, because the association is borderline significant, additional data are still needed to confirm this finding.
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| 3. |
- Jansson, Henrik, et al.
(författare)
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Analysis of the interleukin-1 and interleukin-6 polymorphisms in patients with chronic periodontitis. A pilot study
- 2006
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Ingår i: Swedish Dental Journal. - 0347-9994. ; 30:1, s. 17-23
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to analyse whether the interleukin-1 (IL-1) and IL-6 gene polymorphisms were associated with the susceptibility of chronic periodontitis. Genomic DNA was obtained from 20 patients with chronic periodontitis and 31 periodontally healthy subjects. All subjects were of North European heritage. The test subjects were kept in a maintenance program after periodontal treatment but yet showing signs of recurrent disease. Genotyping of the IL-1 alpha[+4845C>T], IL-1 beta [-3954C>T] and IL-6 [-174G>C] polymorphisms was carried out using an allelic discrimination Assay-by-Design method on ABI PRISM 7900 Sequence Detection System. All genotypes were analyzed using the GeneMapper 2.0 software. A similar distribution of Single Nucleotide Polymorphism (SNP) was seen in both groups. Analysis by logistic regression including gender, IL-1 alpha [+4845C>T], IL-1 beta [-3954C>T], IL-6 [-174G>C] genotypes, the composite IL-1 genotype, the combination of the composite IL-1 genotype and the IL-6 -174G>C genotype and adjusting for smoking did not result in any statistically significant difference. SNPs in IL-1 alpha[+4845C>T], IL-1 beta [-3954C>T] and IL-6 [-174G>C] do not seem to increase the susceptibility to chronic periodontitis in this group of subjects.
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| 4. |
- Lyssenko, Valeriya, et al.
(författare)
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Authors' reply.
- 2006
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Ingår i: PLoS Medicine. - : Public Library of Science (PLoS). - 1549-1676. ; 3:2, s. 271-272
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Tidskriftsartikel (refereegranskat)
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| 5. |
- Saxena, Richa, et al.
(författare)
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Common single nucleotide polymorphisms in TCF7L2 are reproducibly associated with type 2 diabetes and reduce the insulin response to glucose in nondiabetic individuals
- 2006
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 55:10, s. 2890-2895
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Tidskriftsartikel (refereegranskat)abstract
- Recently, common noncoding variants in the TCF7L2 gene were strongly associated with increased risk of type 2 diabetes in samples from Iceland, Denmark, and the U.S. We genotyped 13 single nucleotide polymorphisms (SNPs) across TCF7L2 in 8,310 individuals in family-based and case-control designs from Scandinavia, Poland, and the U.S. We convincingly confirmed the previous association of TCF7L2 SNPs with the risk of type 2 diabetes (rs7903146T odds ratio 1.40 [95% CI 1.30-1.50], P = 6.74 x 10(-20)). In nondiabetic individuals, the risk genotypes were associated with a substantial reduction in the insulinogenic index derived from an oral glucose tolerance test (risk allele homozygotes have half the insulin response to glucose of noncarriers, P = 0.003) but not with increased insulin resistance. These results suggest that TCF7L2 variants may act through insulin secretion to increase the risk of type 2 diabetes.
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