| 311. |
- Willer, Cristen J., et al.
(author)
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Six new loci associated with body mass index highlight a neuronal influence on body weight regulation
- 2009
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 41:1, s. 25-34
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Journal article (peer-reviewed)abstract
- Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 x 10(-8)): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity.
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| 312. |
- Winckler, W, et al.
(author)
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Association of common variation in the HNF1 alpha gene region with risk of type 2 diabetes
- 2005
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In: Diabetes. - 1939-327X. ; 54:8, s. 2336-2342
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Journal article (peer-reviewed)abstract
- It is currently unclear how often genes that are mutated to cause rare, early-onset monogenic forms of disease also harbor common variants that contribute to the more typical polygenic form of each disease. The gene for MODY3 diabetes, HNF1 alpha, lies in a region that has shown linkage to late-onset type 2 diabetes (12q24, NIDDM2), and previous association studies have suggested a weak trend toward association for common missense variants in HNF1a with glucose-related traits. Based on genotyping of 79 common SNPs in the 118 kb spanning HNF1 alpha, we selected 21 haplotype tag single nucleotide polymorphisms (SNPs) and genotyped them in > 4,000 diabetic patients and control subjects from Sweden, Finland, and Canada. Several SNPs from the coding region and 5' of the gene demonstrated nominal association with type 2 diabetes, with the most significant marker (rs1920792) having an odds ratio of 1.17 and a P value of 0.002. We then genotyped three SNPs with the strongest evidence for association to type 2 diabetes (rs1920792, I27L, and A98V) in an additional 4,400 type 2 diabetic and control subjects from North America and Poland and compared our results with those of the original sample and of Weedon et al. None of the results were consistently observed across all samples, with the possible exception of a modest association of the rare (3-5%) A98V variant. These results indicate that common variants in HNF1 alpha either play no role in type 2 diabetes, a very small role, or a role that cannot be consistently observed without consideration of as yet unmeasured genetic or environmental modifiers.
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| 313. |
- Winckler, W, et al.
(author)
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Association testing of variants in the hepatocyte nuclear factor 4 alpha gene with risk of type 2 diabetes in 7,883 people
- 2005
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In: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 54:3, s. 886-892
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Journal article (peer-reviewed)abstract
- Two recent publications reported association of common polymorphisms in the P2 promoter of hepatocyte nuclear factor 4alpha (HNF4alpha) (the MODY1 gene) with risk for type 2 diabetes. We attempted to reproduce this putative association by genotyping 11 single nucleotide polymorphism (SNPs) spanning the HNF4a coding region and the P2 promoter in >3,400 patients and control subjects from Sweden, Finland, and Canada. One SNP that was consistently associated in the two previous reports (rs1884613, in the P2 promoter region) also trended in the same direction in our sample, albeit with a lower estimated odds ratio (OR) of 1.11 (P = 0.05, one-tailed). We genotyped this SNP (rs1884613) in an additional 4,400 subjects from North America and Poland. In this sample, the association was not confirmed and trended in the opposite direction (OR 0.88). Meta-analysis of our combined sample of 7,883 people (three times larger than the two initial reports combined) yielded an OR of 0.97 (P = 0.27). Finally, we provide an updated analysis of haplotype structure in the region to guide any further investigation of common variation in HNF4alpha. Although our combined results fail to replicate the previously reported association of common variants in HNF4alpha with risk for type 2 diabetes, we cannot exclude an effect smaller than that originally proposed, heterogeneity among samples, variation in as-yet-unmeasured genotypic or environmental modifiers, or true association secondary to linkage disequilibrium (LD) with as-yet-undiscovered variant(s) in the region.
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| 314. |
- Winckler, Wendy, et al.
(author)
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Evaluation of common variants in the six known maturity-onset diabetes of the young (MODY) genes for association with type 2 diabetes
- 2007
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In: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 56:3, s. 685-693
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Journal article (peer-reviewed)abstract
- An important question in human genetics is the extent to which genes causing monogenic forms of disease harbor common variants that may contribute to the more typical form of that disease. We aimed to comprehensively evaluate the extent to which common variation irk the six known maturity-onset diabetes of the young (MODY) genes, which cause a monogenic form of type 2 diabetes, is associated with type 2 diabetes. Specifically, we determined patterns of common sequence variation in the genes encoding Gck, lpf1, Tcf2, and NeuroD1 (MODY2 and MODY4-MODY6, respectively), selected a comprehensive set of 107 tag single nucleotide polymorphisms (SNPs) that captured common variation, and genotyped each in 4,206 patients and control subjects from Sweden, Finland, and Canada (including family-based studies and unrelated case-control subjects). All SNPs with a nominal P value < 0.1 for association to type 2 diabetes in this initial screen were then genotyped in an additional 4,470 subjects from North America and Poland. Of 30 nominally significant SNPs from the initial sample, 8 achieved consistent results in the replication sample. We found the strongest effect at rs757210 in intron 2 of TCF2, with corrected P values < 0.01 for an odds ratio (OR) of 1.13. This association was observed again in an independent sample of 5,891 unrelated case and control subjects and 500 families from the U.K., for an overall OR of 1.12 and a P value < 10(-6) in > 15,000 samples. We combined these results with our previous studies on HNF4 alpha and TCF1 and explicitly tested for gene-gene interactions among these variants and with several known type 2 diabetes susceptibility loci, and we found no genetic interactions between these six genes. We conclude that although rare variants in these six genes explain most cases of MODY, common variants in these same genes contribute very modestly, if at all, to the common form of type 2 diabetes.
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| 315. |
- Yang, Beatrice, et al.
(author)
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Insulin promoter DNA methylation correlates negatively with insulin gene expression and positively with HbA(1c) levels in human pancreatic islets.
- 2011
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In: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; Dec, s. 360-367
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Journal article (peer-reviewed)abstract
- AIMS/HYPOTHESIS: Although recent studies propose that epigenetic factors influence insulin expression, the regulation of the insulin gene in type 2 diabetic islets is still not fully understood. Here, we examined DNA methylation of the insulin gene promoter in pancreatic islets from patients with type 2 diabetes and non-diabetic human donors and related it to insulin expression, HbA(1c) levels, BMI and age. METHODS: DNA methylation was analysed in 25 CpG sites of the insulin promoter and insulin mRNA expression was analysed using quantitative RT-PCR in pancreatic islets from nine donors with type 2 diabetes and 48 non-diabetic donors. RESULTS: Insulin mRNA expression (p = 0.002), insulin content (p = 0.004) and glucose-stimulated insulin secretion (p = 0.04) were reduced in pancreatic islets from patients with type 2 diabetes compared with non-diabetic donors. Moreover, four CpG sites located 234 bp, 180 and 102 bp upstream and 63 bp downstream of the transcription start site (CpG -234, -180, -102 and +63, respectively), showed increased DNA methylation in type 2 diabetic compared with non-diabetic islets (7.8%, p = 0.03; 7.1%, p = 0.02; 4.4%, p = 0.03 and 9.3%, p = 0.03, respectively). While insulin mRNA expression correlated negatively (p < 1 × 10(-6)), the level of HbA(1c) correlated positively (p ≤ 0.01) with the degree of DNA methylation for CpG -234, -180 and +63. Furthermore, DNA methylation for nine additional CpG sites correlated negatively with insulin mRNA expression (p ≤ 0.01). Also, exposure to hyperglycaemia for 72 h increased insulin promoter DNA methylation in clonal rat beta cells (p = 0.005). CONCLUSIONS/INTERPRETATIONS: This study demonstrates that DNA methylation of the insulin promoter is increased in patients with type 2 diabetes and correlates negatively with insulin gene expression in human pancreatic islets.
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| 316. |
- Yasuda, Kazuki, et al.
(author)
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Variants in KCNQ1 are associated with susceptibility to type 2 diabetes mellitus
- 2008
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 40:9, s. 1092-1097
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Journal article (peer-reviewed)abstract
- We carried out a multistage genome-wide association study of type 2 diabetes mellitus in Japanese individuals, with a total of 1,612 cases and 1,424 controls and 100,000 SNPs. The most significant association was obtained with SNPs in KCNQ1, and dense mapping within the gene revealed that rs2237892 in intron 15 showed the lowest P value (6.7 x 10(-13), odds ratio (OR) = 1.49). The association of KCNQ1 with type 2 diabetes was replicated in populations of Korean, Chinese and European ancestry as well as in two independent Japanese populations, and meta-analysis with a total of 19,930 individuals (9,569 cases and 10,361 controls) yielded a P value of 1.7 x 10(-42) (OR = 1.40; 95% CI = 1.34-1.47) for rs2237892. Among control subjects, the risk allele of this polymorphism was associated with impairment of insulin secretion according to the homeostasis model assessment of beta-cell function or the corrected insulin response. Our data thus implicate KCNQ1 as a diabetes susceptibility gene in groups of different ancestries.
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| 317. |
- Ylonen, K, et al.
(author)
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Associations of dietary fiber with glucose metabolism in nondiabetic relatives of subjects with type 2 diabetes - The Botnia Dietary Study
- 2003
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In: Diabetes Care. - 1935-5548. ; 26:7, s. 1979-1985
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Journal article (peer-reviewed)abstract
- OBJECTIVE - To study cross-sectional associations of dietary fiber intake with insulin resistance, insulin secretion, and glucose tolerance in a population at high risk for type 2 diabetes. RESEARCH DESIGN AND METHODS - The subjects consisted of 248 male and 304 female adult nondiabetic relatives of patients with type 2 diabetes. Dietary intake was measured by means of two 3-day food records. Associations of total, water-insoluble, and water-soluble fiber with measures of glucose metabolism based on an oral glucose tolerance test, were analyzed by multiple linear regression analysis adjusting for sex, age, length of education, physical activity, BMI, waist-to-hip ratio, systolic blood pressure, and serum triglyceride and HDL cholesterol concentrations. The homeostasis model assessment insulin resistance index, the incremental 30-min serum insulin concentration divided by the incremental 30-min glucose concentration, and fasting and 2-h glucose concentrations were the outcome variables. RESULTS - The dietary intake of total as well as water-insoluble and water-soluble fiber was inversely associated with insulin resistance: -0.17 (0.07), P = 0.012; -0.15 (0.07), P = 0.024; and -0.14 (0.07), P = 0.049 [regression coefficients (SE)]. Fiber variables were unrelated to insulin secretion and plasma glucose concentrations. CONCLUSIONS - The results support evidence that a high intake of dietary fiber is associated with enhanced insulin sensitivity and therefore may have a role in the prevention of type 2 diabetes.
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| 318. |
- Ylonen, K, et al.
(author)
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Dietary intakes and plasma concentrations of carotenoid's and tocopherols in relation to glucose metabolism in subjects at high risk of type 2 diabetes: the Botnia Dietary Study
- 2003
-
In: American Journal of Clinical Nutrition. - 1938-3207. ; 77:6, s. 1434-1441
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Journal article (peer-reviewed)abstract
- Background: The role of antioxidants in the pathogenesis of type 2 diabetes is uncertain. Objective: We evaluated cross-sectional relations of dietary intakes and plasma concentrations of antioxidants with glucose metabolism in a high-risk population. Design: The subjects, were 81 male and 101 female first- and second-degree, nondiabetic relatives of patients with type 2 diabetes. Antioxidant intake data were based on 3-d food records. Subjects taking supplements containing beta-carotene or alpha-tocopherol were excluded. Plasma antioxidant concentrations were measured by HPLC. By using multiple linear regression analysis and adjusting for demographic, anthropometric, and lifestyle covariates, we studied whether dietary and plasma alpha- and beta-carotene, lycopene, and alpha- and gamma-tocopherol were related to fasting and 2-h concentrations of glucose and nonesterified fatty acids during an oral-glucose-tolerance test, to the homeostasis model assessment index of insulin resistance, and to measures of beta cell function (incremental 30-min serum insulin concentration during an oral-glucose-tolerance test and first-phase insulin secretion during an intravenous-glucose-tolerance test). Results: In men, dietary carotenoids were inversely associated with fasting plasma glucose concentrations (P < 0.05), plasma beta-carotene concentrations were inversely associated with insulin resistance (P = 0.003), and dietary lycopene was directly related to baseline serum concentrations of nonesterified fatty acids (P = 0.034). In women, dietary alpha-tocopherol and plasma beta-carotene concentrations were inversely and directly associated, respectively, with fasting plasma glucose concentrations (P < 0.05). In both sexes, cholesterol-adjusted alpha-tocopherol concentrations were directly associated with 2-h plasma glucose concentrations (P < 0.05). Conclusion: The data suggest an advantageous association of carotenoids, which are markers of fruit and vegetable intake, with glucose metabolism in men at high risk of type 2 diabetes.
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| 319. |
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| 320. |
- Ylonen, SK, et al.
(author)
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The Pro12Ala polymorphism of the PPAR-gamma2 gene affects associations of fish intake and marine n-3 fatty acids with glucose metabolism
- 2008
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In: European Journal of Clinical Nutrition. - : Springer Science and Business Media LLC. - 1476-5640 .- 0954-3007. ; 62:12, s. 1432-1439
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Journal article (peer-reviewed)abstract
- Background/Objectives:Data on associations between marine n-3 fatty acids and glucose metabolism are inconsistent. Therefore, we explored effects of the Pro12Ala polymorphism in peroxisome proliferator-activated receptor (PPAR)-gamma2 gene on associations of fish intake and dietary and plasma eicosapentaenoic and docosahexaenoic acid with glucose metabolism. The design comprises of the cross-sectional analysis.Subjects/Methods:The Pro12Ala variant in the PPAR-gamma2 (PPARG) gene was genotyped in 571 non-diabetic relatives of subjects with type II diabetes. The dietary intake was measured by a 3-day food record, and the plasma cholesterol ester fatty acid composition was analysed with gas chromatography. Associations of dietary and plasma variables with insulin resistance and fasting and 2-h glucose and free fatty acid concentrations were analysed with multiple linear regression analysis.Results:In men, there was a significant interaction between PPARG polymorphism and plasma docosahexaenoic acid on fasting free fatty acid concentration (P=0.036), and genotype-stratified models showed an inverse association in Pro homozygotes only (P=0.028). In women, the proportion of plasma eicosapentaenoic acid was higher in Ala-allele carriers compared to Pro homozygotes (1.67 vs 1.44% respectively, P=0.006). A significant interaction between PPARG polymorphism and fish intake on 2-h glucose was found in women (P=0.021), and genotype-stratified models suggested an inverse association in Ala-allele carriers only (P=0.039).Conclusions:The findings suggest that PPARG polymorphism might affect the plasma proportion of eicosapentaenoic acid and modulate the associations of fish intake and marine n-3 fatty acids with glucose metabolism and fasting free fatty acids.European Journal of Clinical Nutrition advance online publication, 15 August 2007; doi:10.1038/sj.ejcn.1602882.
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