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Evidence for association of the TCF7 locus with type I diabetes

Genes & Immunity volume 10, pages S54–S59 (2009)Cite this article

Abstract

The Type I Diabetes Genetics Consortium (T1DGC) has collected thousands of multiplex and simplex families with type I diabetes (T1D) with the goal of identifying genes involved in T1D susceptibility. These families have been genotyped for the HLA class I and class II loci and, recently, for a genome-wide panel of single-nucleotide polymorphisms (SNPs). In addition, multiple SNPs in specific candidate genes have been genotyped in these families in an attempt to evaluate previously reported T1D associations, including the C883A (Pro–Thr) polymorphism in exon 2 of TCF7, a T-cell transcription factor. The TCF7 883A allele was associated with T1D in subjects with T1D not carrying the high-risk HLA genotype DR3/DR4. A panel of 11 SNPs in TCF7 was genotyped in 2092 families from 9 cohorts of the T1DGC. SNPs at two positions in TCF7 were associated with T1D. One associated SNP, C883A (rs5742913), was reported earlier to have a T1D association. A second SNP, rs17653687, represents a novel T1D susceptibility allele in TCF7. After stratification on the high T1D risk DR3/DR4 genotype, the variant (A) allele of C883A was significantly associated with T1D among non-DR3/DR4 cases (transmission=55.8%, P=0.004; OR=1.26) but was not significantly associated in the DR3/DR4 patient subgroup, replicating the earlier report. The reference A allele of intronic SNP rs17653687 was modestly associated with T1D in both DR3/DR4 strata (transmission=54.4% in DR3/DR4; P=0.03; transmission=52.9% in non-DR3/DR4; P=0.03). These results support the previously reported association of the non-synonymous Pro–Thr SNP in TCF7 with T1D, and suggest that other alleles at this locus may also confer risk.

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Acknowledgements

We are grateful to all the T1D patients and family members who contributed samples and to all the participating T1DGC investigators and sites, listed at www.t1dgc.org. This research uses resources provided by the Type I Diabetes Genetics Consortium, a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of Allergy and Infectious Diseases (NIAID), the National Human Genome Research Institute (NHGRI), the National Institute of Child Health and Human Development (NICHD), and the Juvenile Diabetes Research Foundation International (JDRF) and supported by U01 DK062418. We thank John Todd and Joanna Howson for careful reading of the manuscript and valuable discussion. Genotyping was performed at the Broad Institute Center for Genotyping and Analysis is supported by grant U54 RR020278 from the National Center for Research Resources.

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Authors and Affiliations

  1. Roche Molecular Systems, Pleasanton, CA, USA

    H A Erlich

  2. King's College London School of Medicine, Twin Research Unit, London, UK

    A M Valdes

  3. Centre Nationale de Genotypage, Paris, France

    C Julier

  4. Broad Institute, Cambridge, MA, USA

    D Mirel

  5. Children's Hospital Oakland Research Institute, Oakland, CA, USA

    H A Erlich & J A Noble

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Correspondence to H A Erlich.

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Erlich, H., Valdes, A., Julier, C. et al. Evidence for association of the TCF7 locus with type I diabetes. Genes Immun 10 (Suppl 1), S54–S59 (2009). https://doi.org/10.1038/gene.2009.92

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