Movatterモバイル変換

[0]ホーム
URL:

Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Advertisement

Nature Genetics
  • Letter
  • Published:

Variants inKCNQ1 are associated with susceptibility to type 2 diabetes mellitus

Nature Geneticsvolume 40, pages1092–1097 (2008)Cite this article

Abstract

We carried out a multistage genome-wide association study of type 2 diabetes mellitus in Japanese individuals, with a total of 1,612 cases and 1,424 controls and 100,000 SNPs. The most significant association was obtained with SNPs inKCNQ1, and dense mapping within the gene revealed that rs2237892 in intron 15 showed the lowestP value (6.7 × 10−13, odds ratio (OR) = 1.49). The association ofKCNQ1 with type 2 diabetes was replicated in populations of Korean, Chinese and European ancestry as well as in two independent Japanese populations, and meta-analysis with a total of 19,930 individuals (9,569 cases and 10,361 controls) yielded aP value of 1.7 × 10−42 (OR = 1.40; 95% CI = 1.34–1.47) for rs2237892. Among control subjects, the risk allele of this polymorphism was associated with impairment of insulin secretion according to the homeostasis model assessment of β-cell function or the corrected insulin response. Our data thus implicateKCNQ1 as a diabetes susceptibility gene in groups of different ancestries.

This is a preview of subscription content,access via your institution

Access options

Access through your institution

Subscription info for Japanese customers

We have a dedicated website for our Japanese customers. Please go tonatureasia.com to subscribe to this journal.

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

￥ 4,980

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Dense mapping analysis ofKCNQ1.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Fukushima, M., Suzuki, H. & Seino, Y. Insulin secretion capacity in the development from normal glucose tolerance to type 2 diabetes.Diabetes Res. Clin. Pract.66, S37–S43 (2004).

    Article CAS PubMed  Google Scholar 

  2. Haga, H., Yamada, R., Ohnishi, Y., Nakamura, Y. & Tanaka, T. Gene-based SNP discovery as part of the Japanese Millennium Genome Project: identification of 190,562 genetic variations in the human genome.J. Hum. Genet.47, 605–610 (2002).

    Article CAS PubMed  Google Scholar 

  3. NCI-NHGRI Working Group on Replication in Association Studies. Replicating genotype-phenotype associations.Nature447, 655–660 (2007).

  4. Matthews, D.R. et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man.Diabetologia28, 412–419 (1985).

    Article CAS PubMed  Google Scholar 

  5. Ozaki, K. et al. Functional SNPs in the lymphotoxin-alpha gene that are associated with susceptibility to myocardial infarction.Nat. Genet.32, 650–654 (2002).

    Article CAS PubMed  Google Scholar 

  6. Mori, Y. et al. Genome-wide search for type 2 diabetes in Japanese affected sib-pairs confirms susceptibility genes on 3q, 15q, and 20q and identifies two new candidate loci on 7p and 11p.Diabetes51, 1247–1255 (2002).

    Article CAS PubMed  Google Scholar 

  7. Nawata, H. et al. Genome-wide linkage analysis of type 2 diabetes mellitus reconfirms the susceptibility locus on 11p13-p12 in Japanese.J. Hum. Genet.49, 629–634 (2004).

    Article CAS PubMed  Google Scholar 

  8. Zeggini, E. et al. Replication of genome-wide association signals in U.K. samples reveals risk loci for type 2 diabetes.Science316, 1336–1340 (2007).

    Article CAS PubMed PubMed Central  Google Scholar 

  9. Saxena, R. et al. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels.Science316, 1331–1336 (2007).

    Article CAS PubMed  Google Scholar 

  10. Zeggini, E. et al. Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes.Nat. Genet.40, 638–645 (2008).

    Article CAS PubMed PubMed Central  Google Scholar 

  11. Barhanin, J. et al. K(v)LQT1 and IsK (minK) proteins associate to form the I(Ks) cardiac potassium current.Nature384, 78–80 (1996).

    Article CAS PubMed  Google Scholar 

  12. Wang, Q. et al. Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias.Nat. Genet.12, 17–23 (1996).

    Article PubMed  Google Scholar 

  13. Neyroud, N. et al. A novel mutation in the potassium channel gene KvLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome.Nat. Genet.15, 186–189 (1997).

    Article CAS PubMed  Google Scholar 

  14. Chen, Y.H. et al. KCNQ1 gain-of-function mutation in familial atrial fibrillation.Science299, 251–254 (2003).

    Article CAS PubMed  Google Scholar 

  15. Demolombe, S. et al. Differential expression of KvLQT1 and its regulator IsK in mouse epithelia.Am. J. Physiol. Cell Physiol.280, C359–C372 (2001).

    Article CAS PubMed  Google Scholar 

  16. Chouabe, C. et al. Properties of KvLQT1 K+ channel mutations in Romano-Ward and Jervell and Lange-Nielsen inherited cardiac arrhythmias.EMBO J.16, 5472–5479 (1997).

    Article CAS PubMed PubMed Central  Google Scholar 

  17. Ullrich, S. et al. Effects of IKs channel inhibitors in insulin-secreting INS-1 cells.Pflugers Arch.451, 428–436 (2005).

    Article CAS PubMed  Google Scholar 

  18. Sato, Y. et al. Designing a multistage, SNP-based, genome screen for common diseases.J. Hum. Genet.49, 669–676 (2004).

    Article CAS PubMed  Google Scholar 

  19. Grant, S.F. et al. Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes.Nat. Genet.38, 320–323 (2006).

    Article CAS PubMed  Google Scholar 

  20. Scott, L.J. et al. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants.Science316, 1341–1345 (2007).

    Article CAS PubMed PubMed Central  Google Scholar 

  21. Sladek, R. et al. A genome-wide association study identifies novel risk loci for type 2 diabetes.Nature445, 881–885 (2007).

    Article CAS PubMed  Google Scholar 

  22. Steinthorsdottir, V. et al. A variant in CDKAL1 influences insulin response and risk of type 2 diabetes.Nat. Genet.39, 770–775 (2007).

    Article CAS PubMed  Google Scholar 

  23. Frayling, T.M. et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity.Science316, 889–894 (2007).

    Article CAS PubMed PubMed Central  Google Scholar 

  24. Miyake, K. et al. Association of TCF7L2 polymorphisms with susceptibility to type 2 diabetes in 4,087 Japanese subjects.J. Hum. Genet.53, 174–180 (2008).

    Article CAS PubMed  Google Scholar 

  25. Horikoshi, M. et al. Variations in the HHEX gene are associated with increased risk of type 2 diabetes in the Japanese population.Diabetologia50, 2461–2466 (2007).

    Article CAS PubMed  Google Scholar 

  26. Horikawa, Y. et al. Replication of genome-wide association studies of type 2 diabetes susceptibility in Japan.J. Clin. Endocrinol. Metab. (in the press).

  27. Devlin, B. & Roeder, K. Genomic control for association studies.Biometrics55, 997–1004 (1999).

    Article CAS PubMed  Google Scholar 

  28. Ohnishi, Y. et al. A high-throughput SNP typing system for genome-wide association studies.J. Hum. Genet.46, 471–477 (2001).

    Article CAS PubMed  Google Scholar 

  29. Bannai, M. et al. Single-nucleotide-polymorphism genotyping for whole-genome-amplified samples using automated fluorescence correlation spectroscopy.Anal. Biochem.327, 215–221 (2004).

    Article CAS PubMed  Google Scholar 

  30. Barrett, J.C., Fry, B., Maller, J. & Daly, M.J. Haploview: analysis and visualization of LD and haplotype maps.Bioinformatics21, 263–265 (2005).

    Article CAS PubMed  Google Scholar 

Download references

Acknowledgements

We thank all the participants in the project; S. Sugano and S. Tsuji for support and helpful discussion throughout the project; H. Sakamoto, K. Yoshimura and N. Nishida for genotyping and quality control of the data; M. Yamaoka-Sageshima, K. Nagase, D. Suzuki and A. Berglund for technical assistance; and staff of Mitsui Knowledge Industry Inc. (Tokyo) for help with bioinformatics. This work was supported by a grant from the Program for Promotion of Fundamental Studies in Health Sciences of the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan; a grant from the National Institute of Biomedical Innovation (NIBIO) of Japan; grants from the Ministry of Health, Labour, and Welfare of Japan; a Grant-in-Aid for Scientific Research on Priority Areas (C), “Medical Genome Science (Millennium Genome Project),” “Applied Genomics” and “Comprehensive Genomics” from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; and a grant from New Energy and Industrial Technology Development Organization (NEDO). The replication 2 study was supported by a grant from Cooperative Link of Unique Science and Technology for Economy Revitalization (CLUSTER, Tokushima, Japan). The Hong Kong diabetes case-control study was supported by the Hong Kong Research Grants Committee Central Allocation Scheme CUHK 1/04C. The Korean case-control study was supported by a grant from the Korea Health 21 R&D Project of the Ministry of Health and Welfare of the Republic of Korea (00-PJ3-PG6-GN07-001 to K.S.P.). The replication 5 study and Botnia prospective study were supported by Swedish Research Council (Linne grant), Sigrid Juselius Foundation, Folkhaelsan Research Foundation, European Foundation for the Study of Diabetes and Swedish Diabetes Research Foundation.

Author information

Author notes

  1. Kazuya Yamagata, He-Yao Wang, Yuichiro Yamada, Yutaka Seino & Akihiro Sekine

    Present address: Present addresses: Department of Medical Biochemistry, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto 860-8556, Japan (K. Yamagata), Shanghai Institute of Materia Medica, Chinese Academy of Science, Shanghai 200031, China (H.-Y.W.), Department of Internal Medicine, Akita University School of Medicine, Akita 010-8543, Japan (Y.Y.), Kansai Electric Power Hospital, Osaka 553-0003, Japan (Y. Seino) and Genome Informatics, Center for Genomic Medicine, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto 606-8501, Japan (A.S.).,

Authors and Affiliations

  1. Department of Metabolic Disorder, Research Institute, International Medical Center of Japan, Tokyo, 162-8655, Japan

    Kazuki Yasuda & He-Yao Wang

  2. Division of Diabetes, Department of Internal Medicine, Metabolism, and Endocrinology, Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan

    Kazuaki Miyake, Yushi Hirota, Hiroyuki Mori & Masato Kasuga

  3. Department of Diabetes and Endocrinology, Division of Molecule and Structure, Gifu University School of Medicine, Gifu, 501-1194, Japan

    Yukio Horikawa & Jun Takeda

  4. Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, 113-8655, Japan

    Kazuo Hara & Takashi Kadowaki

  5. Department of Molecular and Genetic Medicine, Ehime University Graduate School of Medicine, Ehime, 791-0295, Japan

    Haruhiko Osawa & Hideichi Makino

  6. First Department of Medicine, Wakayama Medical University, Wakayama, 641-8509, Japan

    Hiroto Furuta & Kishio Nanjo

  7. Department of Clinical Sciences, Diabetes and Endocrinology, University Hospital Malmö, Lund University, Malmö, S-205 02, Sweden

    Anna Jonsson, Valeriya Lyssenko & Leif Groop

  8. Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka, 565-0871, Japan

    Yoshifumi Sato & Kazuya Yamagata

  9. Division of Molecular Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, 980-8574, Japan

    Yoshinori Hinokio & Yoshitomo Oka

  10. Division of Genetic Information, Institute for Genome Research, University of Tokushima, Tokushima, 770-8503, Japan

    Toshihito Tanahashi & Mitsuo Itakura

  11. Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Graduate School of Medical Sciences, Kyoto, 602-8566, Japan

    Naoto Nakamura

  12. Department of Medicine, Diabetes Center, Tokyo Women's Medical University, Tokyo, 162-8666, Japan

    Naoko Iwasaki & Yasuhiko Iwamoto

  13. Department of Diabetes and Clinical Nutrition, Kyoto University School of Medicine, Kyoto, 606-8501, Japan

    Yuichiro Yamada & Yutaka Seino

  14. Division of Endocrinology and Metabolism, Department of Medicine, Shiga University of Medical Science, Shiga, 520-2192, Japan

    Hiroshi Maegawa & Atsunori Kashiwagi

  15. Clinical Genome Informatics Center, Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan

    Eiichi Maeda

  16. Department of Genetic Epidemiology, SNP Genetics Inc., Seoul, 110-834, Korea

    Hyoung Doo Shin

  17. Department of Internal Medicine, Seoul National University College of Medicine, Seoul, 110-744, Korea

    Young Min Cho, Kyong Soo Park & Hong Kyu Lee

  18. Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong

    Maggie C Y Ng, Ronald C W Ma, Wing-Yee So & Juliana C N Chan

  19. Department of Medicine, Helsinki University Hospital, Helsinki, FIN-00300, Finland

    Tiinamaija Tuomi & Leif Groop

  20. Folkhaelsan Research Center, Helsinki, FIN-00014, Finland

    Tiinamaija Tuomi

  21. Department of Clinical Sciences, Medicine Research Unit, University Hospital Malmö, Lund University, Malmö, S-205 02, Sweden

    Peter Nilsson

  22. Division of Genomic Medicine, Department of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo, 162-8666, Japan

    Naoyuki Kamatani

  23. SNP Research Center, Institute of Physical and Chemical Research (RIKEN), Yokohama, 230-0045, Japan

    Akihiro Sekine & Yusuke Nakamura

  24. Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, 812-8582, Japan

    Ken Yamamoto

  25. Genetics Division, National Cancer Center Research Institute, Tokyo, 104-0045, Japan

    Teruhiko Yoshida

  26. Department of Human Genetics, Graduate School of Medicine, University of Tokyo, Tokyo, 113-0033, Japan

    Katsushi Tokunaga

Authors
  1. Kazuki Yasuda
  2. Kazuaki Miyake
  3. Yukio Horikawa
  4. Kazuo Hara
  5. Haruhiko Osawa
  6. Hiroto Furuta
  7. Yushi Hirota
  8. Hiroyuki Mori
  9. Anna Jonsson
  10. Yoshifumi Sato
  11. Kazuya Yamagata
  12. Yoshinori Hinokio
  13. He-Yao Wang
  14. Toshihito Tanahashi
  15. Naoto Nakamura
  16. Yoshitomo Oka
  17. Naoko Iwasaki
  18. Yasuhiko Iwamoto
  19. Yuichiro Yamada
  20. Yutaka Seino
  21. Hiroshi Maegawa
  22. Atsunori Kashiwagi
  23. Jun Takeda
  24. Eiichi Maeda
  25. Hyoung Doo Shin
  26. Young Min Cho
  27. Kyong Soo Park
  28. Hong Kyu Lee
  29. Maggie C Y Ng
  30. Ronald C W Ma
  31. Wing-Yee So
  32. Juliana C N Chan
  33. Valeriya Lyssenko
  34. Tiinamaija Tuomi
  35. Peter Nilsson
  36. Leif Groop
  37. Naoyuki Kamatani
  38. Akihiro Sekine
  39. Yusuke Nakamura
  40. Ken Yamamoto
  41. Teruhiko Yoshida
  42. Katsushi Tokunaga
  43. Mitsuo Itakura
  44. Hideichi Makino
  45. Kishio Nanjo
  46. Takashi Kadowaki
  47. Masato Kasuga

Contributions

Principal investigators: K. Yasuda and M.K. Manuscript writing: K. Yasuda., K.M., Y. Horikawa and M.K. Diabetes project planning and design: K. Yasuda, K.M., Y. Hirota, H. Mori, T.Y. and M.K. Ascertainment of study subjects and general data analyses in Japan: K. Yasuda, K.M., Y. Horikawa, K.H., H.O., H.F., Y. Hirota, H. Mori, Y. Sato, K. Yamagata, Y. Hinokio, H.-Y.W., T. Tanahashi, N.N., Y.O., N.I., Y.I., Y.Y., Y. Seino, H. Maegawa, A.K., J.T., E.M., N.K., M.I., H. Makino, K.N., T.K. and M.K. Genotyping and sequencing analyses in Japan: K.M., Y. Horikawa, Y. Hirota, T. Tanahashi, A.S., Y.N., K. Yamamoto, T.Y., K.T. and M.I. Statistical analyses: K.M., Y. Horikawa, Y. Hirota, E.M., T.Y., K.T. and M.I. Genetic analyses in Korea: H.D.S., Y.M.C., K.S.P. and H.K.L. Genetic analyses in Hong Kong: M.C.Y.N., R.C.W.M., W.-Y.S. and J.C.N.C. Genetic analyses in Europe: A.J., V.L., T. Tuomi, P.N. and L.G. Millennium Genome Project Human Genome Variation Team Leader: Y.N. Millennium Genome Project Diabetes Subteam Leader: M.K.

Corresponding author

Correspondence toMasato Kasuga.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–3, Supplementary Tables 1–6, Supplementary Methods (PDF 327 kb)

Rights and permissions

About this article

Cite this article

Yasuda, K., Miyake, K., Horikawa, Y.et al. Variants inKCNQ1 are associated with susceptibility to type 2 diabetes mellitus.Nat Genet40, 1092–1097 (2008). https://doi.org/10.1038/ng.207

Download citation

This article is cited by

Access through your institution
Buy or subscribe

Associated content

SNPs inKCNQ1 are associated with susceptibility to type 2 diabetes in East Asian and European populations

  • Hiroyuki Unoki
  • Atsushi Takahashi
  • Shiro Maeda
Nature GeneticsLetter

Casting a wider net for diabetes susceptibility genes

  • Mark I McCarthy
Nature GeneticsNews & Views

Advertisement

Search

Advanced search

Quick links

Nature Briefing

Sign up for theNature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox.Sign up for Nature Briefing
[8]ページ先頭
©2009-2025 Movatter.jp