Abstract
The aim of the present study was to explore the role of variations with modest effects (previously identified by a large-scale meta-analysis in European populations) in the genetic background of type 2 diabetes (T2D) and diabetes-related traits in a Japanese population. We enrolled 2632 Japanese subjects with T2D and 2050 non-diabetic subjects. We analyzed nine single-nucleotide polymorphisms (SNPs), including rs340874 (PROX1), rs4607517 (GCK), rs2191349 (DGKB-TMEM195), rs7034200 (GLIS3), rs10885122 (ADRA2A), rs174550 (FADS1), rs11605924 (CRY2), rs10830963 (MTNR1B) and rs35767 (IGF1). rs340874 (PROX1) and rs174550 (FADS1) were significantly associated with T2D (P=0.0078, OR: 1.12; and P=0.0071, OR: 1.12, respectively). Subjects with more risk alleles related to nine SNPs had an increased risk of T2D (P=0.0017), as well as a higher fasting plasma glucose level (P=0.018), higher HbA1c level (P=0.013) and lower HOMA-β (P=0.033) compared with subjects who had fewer risk alleles. We identified a significant association of a SNP of FADS1 and a SNP near PROX1 with T2D in a Japanese population. The present findings suggest that inclusion of SNPs with a tendency to increase the disease risk captured more of the genetic background of T2D than that revealed by only assessing significant SNPs.
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Change history
21 December 2012
This article has been corrected since Advance Online Publication, and a corrigendum is also printed in this issue.
References
Stumvoll, M., Goldstein, B. J. & van Haeften, T. W. Type 2 diabetes: principles of pathogenesis and therapy. Lancet 365, 1333–1346 (2005).
Sladek, R., Rocheleau, G., Rung, J., Dina, C., Shen, L., Serre, D. et al. A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 445, 881–885 (2007).
Scott, L. J., Mohlke, K. L., Bonnycastle, L. L., Willer, C. J, Li, Y, Duren, W. L. et al. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 316, 1341–1345 (2007).
Dupuis, J., Langenberg, C., Prokopenko, I., Saxena, R., Soranzo, N., Jackson, A. U. et al. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat. Genet. 42, 105–U32 (2010).
Yasuda, K., Miyake, K., Horikawa, Y., Hara, K., Osawa, H., Furuta, H. et al. Variants in KCNQ1 are associated with susceptibility to type 2 diabetes mellitus. Nat. Genet. 40, 1092–1097 (2008).
Unoki, H., Takahashi, A., Kawaguchi, T., Hara, K., Horikoshi, M., Andersen, G. et al. SNPs in KCNQ1 are associated with susceptibility to type 2 diabetes in East Asian and European populations. Nat. Genet. 40, 1098–1102 (2008).
Yamauchi, T., Hara, K., Maeda, S., Yasuda, K., Takahashi, A., Horikoshi, M. et al. A genome-wide association study in the Japanese population identifies susceptibility loci for type 2 diabetes at UBE2E2 and C2CD4A-C2CD4B. Nat. Genet. 42, 864–868 (2010).
Takeuchi, F., Serizawa, M., Yamamoto, K., Fujisawa, T., Nakashima, E., Ohnaka, K. et al. Confirmation of multiple risk Loci and genetic impacts by a genome-wide association study of type 2 diabetes in the Japanese population. Diabetes 58, 1690–1699 (2009).
Mori, S., Tanaka, Y., Takahashi, A., Hirose, H., Kashiwagi, A., Kaku, K et al. Association of CDKAL1, IGF2BP2, CDKN2A/B, HHEX, SLC30A8, and KCNJ11 with susceptibility to type 2 diabetes in a Japanese population. Diabetes 57, 791–795 (2008).
Ohshige, T., Iwata, M., Omori, S., Tanaka, Y., Hirose, H., Kaku, K. et al. Association of new loci identified in European genome-wide association studies with susceptibility to type 2 diabetes in the Japanese. PLoS One 6, e26911 (2011).
Gibson, G. Rare and common variants: twenty arguments. Nat. Rev. Genet. 13, 135–145 (2011).
Alberti, K. G. & Zimmet, P. Z. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet. Med. 15, 539–553 (1998).
Horikoshi, M., Hara, K., Ito, C., Nagai, R., Froguel, P. & Kadowaki, T. A genetic variation of the transcription factor 7-like 2 gene is associated with risk of type 2 diabetes in the Japanese population. Diabetologia 50, 747–751 (2007).
Horikoshi, M., Hara, K., Ito, C., Shojima, N., Nagai, R., Ueki, K. et al. Variations in the HHEX gene are associated with increased risk of type 2 diabetes in the Japanese population. Diabetologia 50, 2461–2466 (2007).
Iwata, M., Maeda, S., Kamura, Y., Takano, A., Kato, H., Murakami, S. et al. Genetic risk score constructed using 14 susceptibility alleles for type 2 diabetes is associated with the early onset of diabetes and may predict the future requirement of insulin injections among Japanese individuals. Diabetes Care 35, 1763–1770 (2012).
Benjamini, Y. & Hochberg, Y. Controlling the false discovery rate - a practical and powerful approach to multiple testing. J. Roy. Stat. Soc. Ser. B 57, 289–300 (1995).
Hu, C., Zhang, R., Wang, C., Wang, J., Ma, X., Hou, X. et al. Variants from GIPR, TCF7L2, DGKB, MADD, CRY2, GLIS3, PROX1, SLC30A8 and IGF1 are associated with glucose metabolism in the Chinese. PLoS One 5, e15542 (2010).
Acknowledgements
We thank the participating doctors and staff from collaborating institutions for providing DNA samples. We also thank N Miyama and M Yamaguchi for technical assistance. Furthermore, we thank the technical staff at the Laboratory of the First Department of Internal Medicine, Faculty of Medicine, Toyama University; and Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine for their technical assistance.
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Fujita, H., Hara, K., Shojima, N. et al. Variations with modest effects have an important role in the genetic background of type 2 diabetes and diabetes-related traits. J Hum Genet 57, 776–779 (2012). https://doi.org/10.1038/jhg.2012.110
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DOI: https://doi.org/10.1038/jhg.2012.110
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