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A variant in CDKAL1 influences insulin response and risk of type 2 diabetes

Abstract

We conducted a genome-wide association study for type 2 diabetes (T2D) in Icelandic cases and controls, and we found that a previously described variant in the transcription factor 7-like 2 gene (TCF7L2) gene conferred the most significant risk. In addition to confirming two recently identified risk variants1, we identified a variant in the CDKAL1 gene that was associated with T2D in individuals of European ancestry (allele-specific odds ratio (OR) = 1.20 (95% confidence interval, 1.13–1.27), P = 7.7 × 10−9) and individuals from Hong Kong of Han Chinese ancestry (OR = 1.25 (1.11–1.40), P = 0.00018). The genotype OR of this variant suggested that the effect was substantially stronger in homozygous carriers than in heterozygous carriers. The ORs for homozygotes were 1.50 (1.31–1.72) and 1.55 (1.23–1.95) in the European and Hong Kong groups, respectively. The insulin response for homozygotes was approximately 20% lower than for heterozygotes or noncarriers, suggesting that this variant confers risk of T2D through reduced insulin secretion.

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Figure 1: Schematic view of the association of T2D with variants in the 6p22.3 region.
Figure 2: Association of rs7756992 and rs13266634 with insulin secretion.

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Acknowledgements

We thank the individuals with T2D and other study participants whose contribution made this work possible. We also thank the nurses at Noatun (deCODE's sample recruitment center) and personnel at the deCODE core facilities for their hard work and enthusiasm. The Denmark B studies were supported by a grant from Eugene 2. Support for the Africa America Diabetes Mellitus (AADM) study is provided by the US National Institutes of Health, including the National Center on Minority Health and Health Disparities (3T37TW00041-03S2), the National Institute of Diabetes and Digestive and Kidney Diseases (DK072128), the National Human Genome Research Institute and the National Center for Research Resources (RR03048). The Hong Kong Diabetes case-control study was supported by the Hong Kong Research Grants Committee Central Allocation Scheme CUHK 1/04C.

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Correspondence to Valgerdur Steinthorsdottir or Kari Stefansson.

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Competing interests

V.S., G.T., I.R., T. Jonsdottir, G.B.W., U.S., S. Gretarsdottir, V.E., S. Ghosh, A.B., S.S., H.B., M.G., J.R.G., U.T., A.K. and K.S. are employees and shareholders of deCODE genetics, Inc.

Supplementary information

Supplementary Fig. 1

A Q-Q plot of the genome-wide association results. (PDF 185 kb)

Supplementary Table 1

Association with T2D in the Icelandic discovery group. (PDF 88 kb)

Supplementary Table 2

Association with T2D in the primary replication group (Denmark B). (PDF 83 kb)

Supplementary Table 3

Association results for SNPs reported to have association with T2D in ref. 1. (PDF 87 kb)

Supplementary Table 4

Association with T2D and pairwise correlation for eight SNPs in CDKAL1. (PDF 146 kb)

Supplementary Table 5

Association with T2D for 61 SNPs in CDKAL1. (PDF 75 kb)

Supplementary Table 6

Association with insulin secretion and insulin sensitivity. (PDF 77 kb)

Supplementary Table 7

Characteristics of the T2D case-control groups. (PDF 68 kb)

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Steinthorsdottir, V., Thorleifsson, G., Reynisdottir, I. et al. A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nat Genet 39, 770–775 (2007). https://doi.org/10.1038/ng2043

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