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      Association of Genetic Variants with Isolated Fasting Hyperglycaemia and Isolated Postprandial Hyperglycaemia in a Han Chinese Population

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          Abstract

          Background

          Though multiple single nucleotide polymorphisms (SNPs) associated with type 2 diabetes have been identified, the genetic bases of isolated fasting hyperglycaemia (IFH) and isolated postprandial hyperglycaemia (IPH) were still unclear. In present study, we aimed to investigate the association of genome-wide association study-validated genetic variants and IFH or IPH in Han Chinese.

          Methods/Principal Findings

          We genotyped 27 validated SNPs in 6,663 unrelated individuals comprising 341 IFH, 865 IPH, 1,203 combined fasting hyperglycaemia and postprandial hyperglycaemia, and 4,254 normal glycaemic subjects of Han ancestry. The distributions of genotype frequencies of FTO, CDKAL1 and GCKR were significant different between individuals with IFH and those with IPH (SNP( p trend ): rs8050136(0.0024), rs9939609(0.0049), rs7756992(0.0122), rs780094(0.0037)). Risk allele of FTO specifically increased the risk of IFH (rs8050136: OR 1.403 [95% CI 1.125–1.750], p = 0.0027; rs9939609: 1.398 [1.120–1.744], p = 0.0030). G allele of CDKAL1 specifically increased the risk of IPH (1.217 [1.092–1.355], p = 0.0004). G allele of GCKR increased the risk of IFH (1.167 [0.999–1.362], p = 0.0513), but decreased the risk of IPH (0.891 [0.801–0.991], p = 0.0331). In addition, TCF7L2 and KCNQ1 increased the risk of both IFH and IPH. When combined, each additional risk allele associated with IFH increased the risk for IFH by 1.246-fold ( p<0.0001), while each additional risk allele associated with IPH increased the risk for IPH by 1.190-fold ( p<0.0001).

          Conclusion/Significance

          Our results indicate that genotype distributions of variants from FTO, GCKR, CDKAL1 were different between IPH and IFH in Han Chinese. Variants of genes modulating insulin sensitivity ( FTO, GCKR) contributed to the risk of IFH, while variants of genes related to beta cell function ( CDKAL1) increase the risk of IPH.

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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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              The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes.

              D. Altshuler, J. Hirschhorn, M Klannemark … (2000)
              Genetic association studies are viewed as problematic and plagued by irreproducibility. Many associations have been reported for type 2 diabetes, but none have been confirmed in multiple samples and with comprehensive controls. We evaluated 16 published genetic associations to type 2 diabetes and related sub-phenotypes using a family-based design to control for population stratification, and replication samples to increase power. We were able to confirm only one association, that of the common Pro12Ala polymorphism in peroxisome proliferator-activated receptor-gamma(PPARgamma) with type 2 diabetes. By analysing over 3,000 individuals, we found a modest (1.25-fold) but significant (P=0.002) increase in diabetes risk associated with the more common proline allele (85% frequency). Moreover, our results resolve a controversy about common variation in PPARgamma. An initial study found a threefold effect, but four of five subsequent publications failed to confirm the association. All six studies are consistent with the odds ratio we describe. The data implicate inherited variation in PPARgamma in the pathogenesis of type 2 diabetes. Because the risk allele occurs at such high frequency, its modest effect translates into a large population attributable risk-influencing as much as 25% of type 2 diabetes in the general population.
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                Author and article information

                Contributors
                Shengxu Li: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2013
                Publication date (Electronic): 19 August 2013
                Volume: 8
                Issue: 8
                Electronic Location Identifier: e71399
                Affiliations
                [1 ]Department of Endocrinology, Key Laboratory of Diabetes Prevention and Control, China-Japan Friendship Hospital, Beijing, China
                [2 ]Department of Bioinformatics, Beijing Genetics Institute, Shenzhen, Guangdong, China
                [3 ]Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, Shandong, China
                [4 ]Department of Endocrinology, Henan Provincial People's Hospital, Zhengzhou, Henan, China
                [5 ]Department of Endocrinology, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
                [6 ]Department of Endocrinology, Xinjiang Uygur Autonomous Region's Hospital, Urmqi, Xinjiang, China
                [7 ]Department of Endocrinology, Fujian Provincial Hospital, Fuzhou, Fujian, China
                [8 ]Department of Endocrinology, Peking University First Hospital, Beijing, China
                [9 ]Department of Endocrinology, Chinese People's Liberation Army General Hospital, Beijing, China
                [10 ]Department of Endocrinology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
                [11 ]Department of Endocrinology, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, China
                [12 ]Department of Endocrinology, Peking University People's Hospital, Beijing, China
                [13 ]Department of Endocrinology, First Hospital of China Medical University, Shenyang, Liaoning, China
                [14 ]Department of Endocrinology, Shanxi Provincial People's Hospital, Taiyuan, Shanxi, China
                [15 ]Department of Endocrinology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
                [16 ]Department of Endocrinology, Xijing Hospital of Fourth Military Medical University, Xi'an, Shaanxi, China
                [17 ]Department of Endocrinology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
                [18 ]Department of Endocrinology, Xiangya Second Hospital, Changsha, Hunan, China
                [19 ]Department of Epidemiology, Peking Union Medical College, Beijing, China
                Tulane School of Public Health and Tropical Medicine, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: WY JX XK. Performed the experiments: XK JH YC LC Z. Zhao QL JG GC XG J. Lu JW WJ LJ JX ZS J. Liu HT QJ DZ Z. Zhou GS WY. Analyzed the data: XK JH. Contributed reagents/materials/analysis tools: WY LC Z. Zhao QL JG GC XG J. Lu JW WJ LJ JX ZS J. Liu HT QJ DZ Z. Zhou GS. Wrote the paper: XK JH JX WY. Interpretation of data, critical review and approval of the final version of the manuscript to be published: XK JH YC LC ZZ QL JG GC XG JL JW WJ LJ JX ZS JL HT QJ DZ ZZ GS WY.

                Article
                Publisher ID: PONE-D-13-17426
                DOI: 10.1371/journal.pone.0071399
                PMC ID: 3747192
                PubMed ID: 23990951
                SO-VID: 9d2b14d0-620e-4da1-8f25-91353d59c90e
                Copyright statement: Copyright @ 2013
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 28 April 2013
                Date accepted : 28 June 2013
                Page count
                Pages: 10
                Funding
                This research project was supported by grants from Chinese Medical Association Foundation and Chinese Diabetes Society ( http://www.cma.org.cn/ensite/), National 973 Program (2011CB504001)( http://www.973.gov.cn/), China Postdoctoral Science Foundation Grant (2012M520200)( http://res.chinapostdoctor.org.cn/Program/Main.html). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Biology
                Subject: Computational Biology
                Subject: Population Genetics
                Subject: Genetic Polymorphism
                Subject: Evolutionary Biology
                Subject: Population Genetics
                Subject: Genetic Polymorphism
                Subject: Genetics
                Subject: Population Genetics
                Subject: Genetic Polymorphism
                Subject: Genetics of Disease
                Subject: Population Biology
                Subject: Population Genetics
                Subject: Genetic Polymorphism
                Subject: Medicine
                Subject: Endocrinology
                Subject: Diabetic Endocrinology
                Subject: Diabetes Mellitus Type 2
                Subject: Epidemiology
                Subject: Genetic Epidemiology
                Subject: Molecular Epidemiology

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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