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- Ingelsson, Erik, et al.
(författare)
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Detailed Physiologic Characterization Reveals Diverse Mechanisms for Novel Genetic Loci Regulating Glucose and Insulin Metabolism in Humans
- 2010
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Ingår i: Diabetes. - 0012-1797 .- 1939-327X. ; 59:5, s. 1266-1275
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Konferensbidrag (refereegranskat)abstract
- OBJECTIVE-Recent genome-wide association studies have revealed loci associated with glucose and insulin-related traits. We aimed to characterize 19 such loci using detailed measures of insulin processing, secretion, and sensitivity to help elucidate their role in regulation of glucose control, insulin secretion and/or action. RESEARCH DESIGN AND METHODS-We investigated associations of loci identified by the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) with circulating proinsulin, measures of insulin secretion and sensitivity from oral glucose tolerance tests (OGTTs), euglycemic clamps, insulin suppression tests, or frequently sampled intravenous glucose tolerance tests in nondiabetic humans (n = 29,084). RESULTS-The glucose-raising allele in MADD was associated with abnormal insulin processing (a dramatic effect on higher proinsulin levels, but no association with insulinogenic index) at extremely persuasive levels of statistical significance (P = 2.1 x 10(-71)). Defects in insulin processing and insulin secretion were seen in glucose-raising allele carriers at TCF7L2, SCL30A8, GIPR, and C2CD4B. Abnormalities in early insulin secretion were suggested in glucose-raising allele carriers at MTNR1B, GCK, FADS1, DGKB, and PROX1 (lower insulinogenic index; no association with proinsulin or insulin sensitivity). Two loci previously associated with fasting insulin (GCKR and IGF1) were associated with OGTT-derived insulin sensitivity indices in a consistent direction. CONCLUSIONS-Genetic loci identified through their effect on hyperglycemia and/or hyperinsulinemia demonstrate considerable heterogeneity in associations with measures of insulin processing, secretion, and sensitivity. Our findings emphasize the importance of detailed physiological characterization of such loci for improved understanding of pathways associated with alterations in glucose homeostasis and eventually type 2 diabetes. Diabetes 59:1266-1275, 2010
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| 2. |
- Shungin, Dmitry, et al.
(författare)
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New genetic loci link adipose and insulin biology to body fat distribution.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 187-378
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Tidskriftsartikel (refereegranskat)abstract
- Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
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| 3. |
- Speliotes, Elizabeth K., et al.
(författare)
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Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 937-948
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ~2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10−8), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
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| 4. |
- Tsuchiya, Takafumi, et al.
(författare)
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Association of the calpain-10 gene with type 2 diabetes in Europeans: Results of pooled and meta-analyses
- 2006
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Ingår i: Molecular Genetics and Metabolism. - : Elsevier BV. - 1096-7192. ; 89:1-2, s. 174-184
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Tidskriftsartikel (refereegranskat)abstract
- We conducted pooled and meta-analyses of the association of the calpain-10 gene (CAPN10) polymorphisms SNP-43, Indel-19 and SNP-63 individually and as haplotypes with type 2 diabetes (T2D) in 3237 patients and 2935 controls of European ancestry. In the pooled analyses, the common SNP-43*G allele was associated with modest but statistically significant increased risk of T2D (odds ratio (OR) = 1.11 (95% confidence interval (0), 1.02-1.20), P = 0.01). Two haplotype combinations were associated with increased risk of T2D) (1-2-1/1-2-1, OR = 1.20 (1.03-1.41), P = 0.02; and 1-1-2/1-2-1, OR = 1.26 (1.01-1.59), P = 0.04) and one with decreased risk (1-1-1/2-2-1, OR = 0.86 (0.75-0.99), P = 0.03). The meta-analysis also showed a significant effect of the 1-2-1/1-2-1 haplogenotype on risk (OR = 1.25 (1.05-1.50), P = 0.01). However, there was evidence for heterogeneity with respect to this effect (P = 0.06). The heterogeneity appeared to be due to data sets in which the cases were selected from samples used in linkage studies of T2D. Using only the population-based case-control samples removed the heterogeneity (P = 0.89) and strengthened the evidence for association with T2D) in both the pooled (SNP-43*G, OR = 1.19 (1.07-1.32), P = 0.001; 1-2-1/1-2-1 haplogenotype, OR = 1.46 (1.19-1.78), P = 0.0003; 1-1-2/1-2-1 haplogenotype, OR = 1.52 (1.12-2.06), P = 0.007; and 1-1-1/2-2-1 haplogenotype, OR = 0.83 (0.70-0.99), P = 0.03) and the meta-analysis (SNP-43*G, OR = 1.18 (1.05-1.32), P = 0.005; 1-2-1/1-2-1 haplogenotype, OR = 1.68 (1.33-2.11), P = 0.00001). The pooled and meta-analyses as well as the linkage disequilibrium and haplotype diversity studies suggest a role for genetic variation in CAPN10 affecting risk of T2D in Europeans. (c) 2006 Elsevier Inc. All rights reserved.
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