Genetic Prediction of Future Type 2 Diabetes

Lyssenko, Valeriya; Almgren, Peter; Anevski, Dragi; Orho-Melander, Marju; Sjögren, Marketa; Saloranta, Carola; Tuomi, TiinaMaija; Groop, Leif

doi:10.1371/journal.pmed.0020345

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Genetic Prediction of Future Type 2 Diabetes

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Author(s): Valeriya Lyssenko ¹ ^, ^* , Peter Almgren ¹ , Dragi Anevski ¹ ^, ² , Marju Orho-Melander ¹ , Marketa Sjögren ¹ , Carola Saloranta ³ ^, ⁴ , Tiinamaija Tuomi ³ ^, ⁴ , Leif Groop ¹ , the Botnia Study Group

Editor(s): Andrew Hattersley

Publication date (Electronic): 1 November 2005

Journal: PLoS Medicine

Publisher: Public Library of Science

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Abstract

Background

Type 2 diabetes (T2D) is a multifactorial disease in which environmental triggers interact with genetic variants in the predisposition to the disease. A number of common variants have been associated with T2D but our knowledge of their ability to predict T2D prospectively is limited.

Methods and Findings

By using a Cox proportional hazard model, common variants in the PPARG (P12A), CAPN10 (SNP43 and 44) , KCNJ11 (E23K) , UCP2 (−866G>A), and IRS1 (G972R) genes were studied for their ability to predict T2D in 2,293 individuals participating in the Botnia study in Finland. After a median follow-up of 6 y, 132 (6%) persons developed T2D. The hazard ratio for risk of developing T2D was 1.7 (95% confidence interval [CI] 1.1–2.7) for the PPARG PP genotype, 1.5 (95% CI 1.0–2.2) for the CAPN10 SNP44 TT genotype, and 2.6 (95% CI 1.5–4.5) for the combination of PPARG and CAPN10 risk genotypes. In individuals with fasting plasma glucose ≥ 5.6 mmol/l and body mass index ≥ 30 kg/m ², the hazard ratio increased to 21.2 (95% CI 8.7–51.4) for the combination of the PPARG PP and CAPN10 SNP43/44 GG/TT genotypes as compared to those with the low-risk genotypes with normal fasting plasma glucose and body mass index < 30 kg/m ².

Conclusion

We demonstrate in a large prospective study that variants in the PPARG and CAPN10 genes predict future T2D. Genetic testing might become a future approach to identify individuals at risk of developing T2D.

Abstract

In a large prospective study, Lyssenko and colleagues show that variants in the PPARG and CAPN10 genes can help predict whether a person will develop Type 2 diabetes.

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Most cited references 40

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Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes.

Anna L Gloyn, Ewan R Pearson, Jennifer F Antcliff … (2004)

Patients with permanent neonatal diabetes usually present within the first three months of life and require insulin treatment. In most, the cause is unknown. Because ATP-sensitive potassium (K(ATP)) channels mediate glucose-stimulated insulin secretion from the pancreatic beta cells, we hypothesized that activating mutations in the gene encoding the Kir6.2 subunit of this channel (KCNJ11) cause neonatal diabetes. We sequenced the KCNJ11 gene in 29 patients with permanent neonatal diabetes. The insulin secretory response to intravenous glucagon, glucose, and the sulfonylurea tolbutamide was assessed in patients who had mutations in the gene. Six novel, heterozygous missense mutations were identified in 10 of the 29 patients. In two patients the diabetes was familial, and in eight it arose from a spontaneous mutation. Their neonatal diabetes was characterized by ketoacidosis or marked hyperglycemia and was treated with insulin. Patients did not secrete insulin in response to glucose or glucagon but did secrete insulin in response to tolbutamide. Four of the patients also had severe developmental delay and muscle weakness; three of them also had epilepsy and mild dysmorphic features. When the most common mutation in Kir6.2 was coexpressed with sulfonylurea receptor 1 in Xenopus laevis oocytes, the ability of ATP to block mutant K(ATP) channels was greatly reduced. Heterozygous activating mutations in the gene encoding Kir6.2 cause permanent neonatal diabetes and may also be associated with developmental delay, muscle weakness, and epilepsy. Identification of the genetic cause of permanent neonatal diabetes may facilitate the treatment of this disease with sulfonylureas. Copyright 2004 Massachusetts Medical Society

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

D Altshuler, J N 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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A Pro12Ala substitution in PPARgamma2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity.

S S Deeb, L Fajas, M. Nemoto … (1998)

The peroxisome proliferator-activated receptor-gamma (PPARgamma) is a transcription factor that has a pivotal role in adipocyte differentiation and expression of adipocyte-specific genes. The PPARgamma1 and gamma2 isoforms result from alternative splicing and have ligand-dependent and -independent activation domains. PPARgamma2 has an additional 28 amino acids at its amino terminus that renders its ligand-independent activation domain 5-10-fold more effective than that of PPARgamma1. Insulin stimulates the ligand-independent activation of PPARgamma1 and gamma2 (ref. 5), however, obesity and nutritional factors only influence the expression of PPARgamma2 in human adipocytes. Here, we report that a relatively common Pro12Ala substitution in PPARgamma2 is associated with lower body mass index (BMI; P=0.027; 0.015) and improved insulin sensitivity among middle-aged and elderly Finns. A significant odds ratio (4.35, P=0.028) for the association of the Pro/Pro genotype with type 2 diabetes was observed among Japanese Americans. The PPARgamma2 Ala allele showed decreased binding affinity to the cognate promoter element and reduced ability to transactivate responsive promoters. These findings suggest that the PPARgamma2 Pro12Ala variant may contribute to the observed variability in BMI and insulin sensitivity in the general population.

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Author and article information

Contributors

: Role: Academic Editor

Journal

Journal ID (nlm-ta): PLoS Med

Journal ID (publisher-id): pmed

Title: PLoS Medicine

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Print): 1549-1277

ISSN (Electronic): 1549-1676

Publication date (Print): December 2005

Publication date (Electronic): 1 November 2005

Volume: 2

Issue: 12

Electronic Location Identifier: e345

Affiliations

[1] 1Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, University Hospital Malmö, Malmö, Sweden,

[2] 2School of Mathematical Sciences, Chalmers University of Technology, Gothenburg, Sweden,

[3] 3Department of Medicine, Division of Diabetology, Helsinki University Hospital, Helsinki, Finland,

[4] 4Folkhälsan Research Center, Institute of Genetics, Helsinki, Finland

Peninsular Medical School, Exeter United Kingdom

Author notes

*To whom correspondence should be addressed. E-mail: Valeri.Lyssenko@ 123456med.lu.se

Competing Interests: LG is a member of the editorial board of PLoS Medicine.

Author Contributions: VL extracted, genotyped, and analyzed the data, and drafted the report. PA and DA were responsible for the statistical analyses, MOM and MS for genotyping, and CS and TT for the phenotype data. LG designed the study and supervised all parts of the work including drafting the final report. All researchers took part in the revision of the report and approved the final version.

Article

DOI: 10.1371/journal.pmed.0020345

PMC ID: 1274281

PubMed ID: 17570749

SO-VID: 030b91e2-35d3-40ca-9399-1a9f5009d243

Copyright © Copyright: © 2005 Lyssenko et al. 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 : 22 November 2004

Date accepted : 23 August 2005

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Genetic Prediction of Future Type 2 Diabetes

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Abstract

Background

Methods and Findings

Conclusion

Abstract

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Most cited references 40

Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes.

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

A Pro12Ala substitution in PPARgamma2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity.

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Cited by 23

Most referenced authors 1,444