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      Genetics of Type 2 Diabetes—Pitfalls and Possibilities

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          Abstract

          Type 2 diabetes (T2D) is a complex disease that is caused by a complex interplay between genetic, epigenetic and environmental factors. While the major environmental factors, diet and activity level, are well known, identification of the genetic factors has been a challenge. However, recent years have seen an explosion of genetic variants in risk and protection of T2D due to the technical development that has allowed genome-wide association studies and next-generation sequencing. Today, more than 120 variants have been convincingly replicated for association with T2D and many more with diabetes-related traits. Still, these variants only explain a small proportion of the total heritability of T2D. In this review, we address the possibilities to elucidate the genetic landscape of T2D as well as discuss pitfalls with current strategies to identify the elusive unknown heritability including the possibility that our definition of diabetes and its subgroups is imprecise and thereby makes the identification of genetic causes difficult.

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

          Robert Sladek, Ghislain Rocheleau, Johan Rung … (2007)
          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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            Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis.

            Benjamin Voight, Laura J. Scott, Valgerdur Steinthorsdottir … (2010)
            By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combined P<5x10(-8). These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits.
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              Gestational diabetes and the incidence of type 2 diabetes: a systematic review.

              C. Kim, K M Newton, R Knopp (2002)
              To examine factors associated with variation in the risk for type 2 diabetes in women with prior gestational diabetes mellitus (GDM). We conducted a systematic literature review of articles published between January 1965 and August 2001, in which subjects underwent testing for GDM and then testing for type 2 diabetes after delivery. We abstracted diagnostic criteria for GDM and type 2 diabetes, cumulative incidence of type 2 diabetes, and factors that predicted incidence of type 2 diabetes. A total of 28 studies were examined. After the index pregnancy, the cumulative incidence of diabetes ranged from 2.6% to over 70% in studies that examined women 6 weeks postpartum to 28 years postpartum. Differences in rates of progression between ethnic groups was reduced by adjustment for various lengths of follow-up and testing rates, so that women appeared to progress to type 2 diabetes at similar rates after a diagnosis of GDM. Cumulative incidence of type 2 diabetes increased markedly in the first 5 years after delivery and appeared to plateau after 10 years. An elevated fasting glucose level during pregnancy was the risk factor most commonly associated with future risk of type 2 diabetes. Conversion of GDM to type 2 diabetes varies with the length of follow-up and cohort retention. Adjustment for these differences reveals rapid increases in the cumulative incidence occurring in the first 5 years after delivery for different racial groups. Targeting women with elevated fasting glucose levels during pregnancy may prove to have the greatest effect for the effort required.
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                Author and article information

                Contributors
                J. Peter W. Young: Role: Academic Editor
                Journal
                Journal ID (nlm-ta): Genes (Basel)
                Journal ID (iso-abbrev): Genes (Basel)
                Journal ID (publisher-id): genes
                Title: Genes
                Publisher: MDPI
                ISSN (Electronic): 2073-4425
                Publication date (Electronic): 12 March 2015
                Publication date Collection: March 2015
                Volume: 6
                Issue: 1
                Pages: 87-123
                Affiliations
                [1 ]Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Lund University, CRC, Skåne University Hospital SUS, SE-205 02 Malmö, Sweden
                [2 ]Finnish Institute of Molecular Medicine (FIMM), Helsinki University, Helsinki 00014, Finland
                Author notes
                [* ]Authors to whom correspondence should be addressed; E-Mails: rashmi.prasad@ 123456med.lu.se (R.B.P.); leif.groop@ 123456med.lu.se (L.G.).
                Article
                Publisher ID: genes-06-00087
                DOI: 10.3390/genes6010087
                PMC ID: 4377835
                PubMed ID: 25774817
                SO-VID: ac9e11f3-913a-4e68-ad1b-8b23a433a166
                Copyright © © 2015 by the authors; licensee MDPI, Basel, Switzerland.
                License:

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 09 December 2014
                Date accepted : 27 February 2015
                Categories
                Subject: Review

                Keywords: type 2 diabetes,genetics,heritability,genome-wide association studies,common variants,rare variants,parent-of-origin,systems biology
                Data availability:
                Keywords: type 2 diabetes, genetics, heritability, genome-wide association studies, common variants, rare variants, parent-of-origin, systems biology

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