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      The genetic susceptibility to type 2 diabetes may be modulated by obesity status: implications for association studies

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          Abstract

          Background

          Considering that a portion of the heterogeneity amongst previous replication studies may be due to a variable proportion of obese subjects in case-control designs, we assessed the association of genetic variants with type 2 diabetes (T2D) in large groups of obese and non-obese subjects.

          Methods

          We genotyped RETN, KCNJ11, HNF4A, HNF1A, GCK, SLC30A8, ENPP1, ADIPOQ, PPARG, and TCF7L2 polymorphisms in 1,283 normoglycemic (NG) and 1,581 T2D obese individuals as well as in 3,189 NG and 1,244 T2D non-obese subjects of European descent, allowing us to examine T2D risk over a wide range of BMI.

          Results

          Amongst non-obese individuals, we observed significant T2D associations with HNF1A I27L [odds ratio (OR) = 1.14, P = 0.04], GCK -30G>A (OR = 1.23, P = 0.01), SLC30A8 R325W (OR = 0.87, P = 0.04), and TCF7L2 rs7903146 (OR = 1.89, P = 4.5 × 10 -23), and non-significant associations with PPARG Pro12Ala (OR = 0.85, P = 0.14), ADIPOQ -11,377C>G (OR = 1.00, P = 0.97) and ENPP1 K121Q (OR = 0.99, P = 0.94). In obese subjects, associations with T2D were detected with PPARG Pro12Ala (OR = 0.73, P = 0.004), ADIPOQ -11,377C>G (OR = 1.26, P = 0.02), ENPP1 K121Q (OR = 1.30, P = 0.003) and TCF7L2 rs7903146 (OR = 1.30, P = 1.1 × 10 -4), and non-significant associations with HNF1A I27L (OR = 0.96, P = 0.53), GCK -30G>A (OR = 1.15, P = 0.12) and SLC30A8 R325W (OR = 0.95, P = 0.44). However, a genotypic heterogeneity was only found for TCF7L2 rs7903146 ( P = 3.2 × 10 -5) and ENPP1 K121Q ( P = 0.02). No association with T2D was found for KCNJ11, RETN, and HNF4A polymorphisms in non-obese or in obese individuals.

          Conclusion

          Genetic variants modulating insulin action may have an increased effect on T2D susceptibility in the presence of obesity, whereas genetic variants acting on insulin secretion may have a greater impact on T2D susceptibility in non-obese individuals.

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          Most cited references39

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          A genome-wide association study identifies novel risk loci for type 2 diabetes.

          Type 2 diabetes mellitus results from the interaction of environmental factors with a combination of genetic variants, most of which were hitherto unknown. A systematic search for these variants was recently made possible by the development of high-density arrays that permit the genotyping of hundreds of thousands of polymorphisms. We tested 392,935 single-nucleotide polymorphisms in a French case-control cohort. Markers with the most significant difference in genotype frequencies between cases of type 2 diabetes and controls were fast-tracked for testing in a second cohort. This identified four loci containing variants that confer type 2 diabetes risk, in addition to confirming the known association with the TCF7L2 gene. These loci include a non-synonymous polymorphism in the zinc transporter SLC30A8, which is expressed exclusively in insulin-producing beta-cells, and two linkage disequilibrium blocks that contain genes potentially involved in beta-cell development or function (IDE-KIF11-HHEX and EXT2-ALX4). These associations explain a substantial portion of disease risk and constitute proof of principle for the genome-wide approach to the elucidation of complex genetic traits.
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            Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001.

            Obesity and diabetes are increasing in the United States. To estimate the prevalence of obesity and diabetes among US adults in 2001. Random-digit telephone survey of 195 005 adults aged 18 years or older residing in all states participating in the Behavioral Risk Factor Surveillance System in 2001. Body mass index, based on self-reported weight and height and self-reported diabetes. In 2001 the prevalence of obesity (BMI > or =30) was 20.9% vs 19.8% in 2000, an increase of 5.6%. The prevalence of diabetes increased to 7.9% vs 7.3% in 2000, an increase of 8.2%. The prevalence of BMI of 40 or higher in 2001 was 2.3%. Overweight and obesity were significantly associated with diabetes, high blood pressure, high cholesterol, asthma, arthritis, and poor health status. Compared with adults with normal weight, adults with a BMI of 40 or higher had an odds ratio (OR) of 7.37 (95% confidence interval [CI], 6.39-8.50) for diagnosed diabetes, 6.38 (95% CI, 5.67-7.17) for high blood pressure, 1.88 (95% CI,1.67-2.13) for high cholesterol levels, 2.72 (95% CI, 2.38-3.12) for asthma, 4.41 (95% CI, 3.91-4.97) for arthritis, and 4.19 (95% CI, 3.68-4.76) for fair or poor health. Increases in obesity and diabetes among US adults continue in both sexes, all ages, all races, all educational levels, and all smoking levels. Obesity is strongly associated with several major health risk factors.
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              Whole-genome patterns of common DNA variation in three human populations.

              D A Hinds (2005)
              Individual differences in DNA sequence are the genetic basis of human variability. We have characterized whole-genome patterns of common human DNA variation by genotyping 1,586,383 single-nucleotide polymorphisms (SNPs) in 71 Americans of European, African, and Asian ancestry. Our results indicate that these SNPs capture most common genetic variation as a result of linkage disequilibrium, the correlation among common SNP alleles. We observe a strong correlation between extended regions of linkage disequilibrium and functional genomic elements. Our data provide a tool for exploring many questions that remain regarding the causal role of common human DNA variation in complex human traits and for investigating the nature of genetic variation within and between human populations.
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                Author and article information

                Journal
                BMC Med Genet
                BMC Medical Genetics
                BioMed Central
                1471-2350
                2008
                22 May 2008
                : 9
                : 45
                Affiliations
                [1 ]CNRS UMR8090, Institut de Biologie de Lille, Génomique et Physiologie Moléculaire des Maladies Métaboliques, Lille, France
                [2 ]Department of Surgery and Internal Medicine, Hirslanden Clinics, Bern and Zurich, Switzerland
                [3 ]INSERM U780-IFR69, Hôpital Paul Brousse, Villejuif, France
                [4 ]Université Paris-Sud, Paris, France
                [5 ]INSERM U695, Hôpital Bichat, Paris, France
                [6 ]Hôpital de Corbeil, service d'endocrinologie et de diabétologie, Corbeil-Essonnes, France
                [7 ]Genomic Medicine, Hammersmith Hospital, Imperial College London, UK
                Article
                1471-2350-9-45
                10.1186/1471-2350-9-45
                2412856
                18498634
                d9954763-4a51-4c3c-932d-a8a5c53b0a29
                Copyright © 2008 Cauchi et al; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 30 January 2008
                : 22 May 2008
                Categories
                Research Article

                Genetics
                Genetics

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