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Clinical review: the genetics of type 2 diabetes: a realistic appraisal in 2008.

ABSTRACT: Over the last few months, genome-wide association studies have contributed significantly to our understanding of the genetic architecture of type 2 diabetes. If and how this information will impact clinical practice is not yet clear.Primary papers reporting genome-wide association studies in type 2 diabetes or establishing a reproducible association for specific candidate genes were compiled. Further information was obtained from background articles, authoritative reviews, and relevant meeting conferences and abstracts.As many as 17 genetic loci have been convincingly associated with type 2 diabetes; 14 of these were not previously known, and most of them were unsuspected. The associated polymorphisms are common in populations of European descent but have modest effects on risk. These loci highlight new areas for biological exploration and allow the initiation of experiments designed to develop prediction models and test possible pharmacogenetic and other applications.Although substantial progress in our knowledge of the genetic basis of type 2 diabetes is taking place, these new discoveries represent but a small proportion of the genetic variation underlying the susceptibility to this disorder. Major work is still required to identify the causal variants, test their role in disease prediction and ascertain their therapeutic implications.

SUBMITTER: Florez JC

PROVIDER: S-EPMC2626447 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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Clinical review: the genetics of type 2 diabetes: a realistic appraisal in 2008.

Florez Jose C JC

The Journal of clinical endocrinology and metabolism 20080909 12

<h4>Context</h4>Over the last few months, genome-wide association studies have contributed significantly to our understanding of the genetic architecture of type 2 diabetes. If and how this information will impact clinical practice is not yet clear.<h4>Evidence acquisition</h4>Primary papers reporting genome-wide association studies in type 2 diabetes or establishing a reproducible association for specific candidate genes were compiled. Further information was obtained from background articles, ...[more]

PMID: 18782870

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Project description:Cases with Type 1 Diabetes (T1D) in the UK, were part of the Wellcome Trust Case Control Consortium (WTCCC) - <a href="http://www.wtccc.org.uk" target="_blank">http://www.wtccc.org.uk</a> - that first reported in 2007: Wellcome Trust Case Control Consortium (2007) Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature, 447, 661-678. [PubMed: <a href="http://www.ncbi.nlm.nih.gov/pubmed/17554300" target="_blank">17554300</a>] In this genome-wide association study (GWAS), funded by the NIH and JDRF, and sponsored by the Type 1 Diabetes Genetics Consortium (T1DGC), we were able to extend the case and control groups used in the WTCCC, with the intention of performing a well-powered meta-analysis. The study is written up as: Barrett, J.C., Clayton, D.G., Concannon, P., Akolkar, B., Cooper, J.D., Erlich, H.A., Julier, C., Morahan, G., Nerup, J., Nierras, C., Plagnol, V., Pociot, F., Schuilenburg, H., Smyth, D.J., Stevens, H., Todd, J.A., Walker, N.M., Rich, S.S. and The Type 1 Diabetes Genetics Consortium Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nature Genetics, PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/19430480" target="_blank">19430480</a>. Resources - data: * Case data from this study is deposited here (i.e. in dbGaP) * Control data from this experiment - with subjects from the 1958 British Birth Cohort - is deposited with the European Genotype Archive (EGA): <a href="http://www.ebi.ac.uk/ega/" target="_blank">http://www.ebi.ac.uk/ega/</a> from where the WTCCC data is also available. * A complete description of how to request all components of the meta-analysis is available at: <a href="http://www.t1dbase.org/page/PosterView/display/poster_id/324" target="_blank">http://www.t1dbase.org/page/PosterView/display/poster_id/324</a> * Additional genetic data on the same case subjects, including some HLA types, are available from the Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory (JDRF/WT-DIL): <a href="http://www-gene.cimr.cam.ac.uk/todd/" target="_blank">http://www-gene.cimr.cam.ac.uk/todd/</a> Resources - samples: Case and control DNA samples are also available: * Case DNA samples are available from the JDRF/WT-DIL, as above, and will be available from the NIDDK Genetics Repository at Rutgers: <a href="https://www.niddkrepository.org" target="_blank">https://www.niddkrepository.org</a> * Control DNA samples are available from the 1958 British Birth Cohort (aka National Child Development Study): <a href="http://www.cls.ioe.ac.uk/studies.asp?section=000100020003" target="_blank">http://www.cls.ioe.ac.uk/studies.asp?section=000100020003</a> Use restrictions: There are access limitations to both data and samples, in order to keep their use in line with subjects' consent.

Project description:Background: Adverse drug reactions (ADR) are a major clinical problem accounting for significant hospital admission rates, morbidity, mortality, and health care costs. One-third of people with diabetes experience at least one ADR. However, there is notable interindividual heterogeneity resulting in patient harm and unnecessary medical costs. Genomics is at the forefront of research to understand interindividual variability, and there are many genotype-drug response associations in diabetes with inconsistent findings. Here, we conducted a systematic review to comprehensively examine and synthesize the effect of genetic polymorphisms on the incidence of ADRs of oral glucose-lowering drugs in people with type 2 diabetes. Methods: A literature search was made to identify articles that included specific results of research on genetic polymorphism and adverse effects associated with oral glucose-lowering drugs. The electronic search was carried out on 3rd October 2020, through Cochrane Library, PubMed, and Web of Science using keywords and MeSH terms. Result: Eighteen articles consisting of 10, 383 subjects were included in this review. Carriers of reduced-function alleles of organic cation transporter 1 (OCT 1, encoded by SLC22A1) or reduced expression alleles of plasma membrane monoamine transporter (PMAT, encoded by SLC29A4) or serotonin transporter (SERT, encoded by SLC6A4) were associated with increased incidence of metformin-related gastrointestinal (GI) adverse effects. These effects were shown to exacerbate by concomitant treatment with gut transporter inhibiting drugs. The CYP2C9 alleles, * 2 (rs1799853C>T) and * 3 (rs1057910A>C) that are predictive of low enzyme activity were more common in subjects who experienced hypoglycemia after treatment with sulfonylureas. However, there was no significant association between sulfonylurea-related hypoglycemia and genetic variants in the ATP-binding cassette transporter sub-family C member 8 (ABCC8)/Potassium Inwardly Rectifying Channel Subfamily J Member 11 (KCNJ11). Compared to the wild type, the low enzyme activity C allele at CYP2C8* 3 (rs1057910A>C) was associated with less weight gain whereas the C allele at rs6123045 in the NFATC2 gene was significantly associated with edema from rosiglitazone treatment. Conclusion: In spite of limited studies investigating genetics and ADR in diabetes, some convincing results are emerging. Genetic variants in genes encoding drug transporters and metabolizing enzymes are implicated in metformin-related GI adverse effects, and sulfonylurea-induced hypoglycemia, respectively. Further studies to investigate newer antidiabetic drugs such as DPP-4i, GLP-1RA, and SGLT2i are warranted. In addition, pharmacogenetic studies that account for race and ethnic differences are required.

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Clinical review: the genetics of type 2 diabetes: a realistic appraisal in 2008.

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Clinical review: the genetics of type 2 diabetes: a realistic appraisal in 2008.

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