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Diabetes Care. 2018 Feb;41(2):311-317. doi: 10.2337/dc17-0961. Epub 2017 Oct 12.

TCF7L2 Genetic Variants Contribute to Phenotypic Heterogeneity of Type 1 Diabetes.

Author information

1
Baylor College of Medicine, Texas Children's Hospital, Houston, TX redondo@bcm.edu.
2
University of South Florida, Tampa, FL.
3
Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO.
4
University of Miami, Miami, FL.
5
University of California, San Francisco, San Francisco, CA.
6
Wake Forest School of Medicine, Winston-Salem, NC.
7
Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.

Abstract

OBJECTIVE:

The phenotypic diversity of type 1 diabetes suggests heterogeneous etiopathogenesis. We investigated the relationship of type 2 diabetes-associated transcription factor 7 like 2 (TCF7L2) single nucleotide polymorphisms (SNPs) with immunologic and metabolic characteristics at type 1 diabetes diagnosis.

RESEARCH DESIGN AND METHODS:

We studied TrialNet participants with newly diagnosed autoimmune type 1 diabetes with available TCF7L2 rs4506565 and rs7901695 SNP data (n = 810; median age 13.6 years; range 3.3-58.6). We modeled the influence of carrying a TCF7L2 variant (i.e., having 1 or 2 minor alleles) on the number of islet autoantibodies and oral glucose tolerance test (OGTT)-stimulated C-peptide and glucose measures at diabetes diagnosis. All analyses were adjusted for known confounders.

RESULTS:

The rs4506565 variant was a significant independent factor of expressing a single autoantibody, instead of multiple autoantibodies, at diagnosis (odds ratio [OR] 1.66 [95% CI 1.07, 2.57], P = 0.024). Interaction analysis demonstrated that this association was only significant in participants ≥12 years old (n = 504; OR 2.12 [1.29, 3.47], P = 0.003) but not younger ones (n = 306, P = 0.73). The rs4506565 variant was independently associated with higher C-peptide area under the curve (AUC) (P = 0.008) and lower mean glucose AUC (P = 0.0127). The results were similar for the rs7901695 SNP.

CONCLUSIONS:

In this cohort of individuals with new-onset type 1 diabetes, type 2 diabetes-linked TCF7L2 variants were associated with single autoantibody (among those ≥12 years old), higher C-peptide AUC, and lower glucose AUC levels during an OGTT. Thus, carriers of the TCF7L2 variant had a milder immunologic and metabolic phenotype at type 1 diabetes diagnosis, which could be partly driven by type 2 diabetes-like pathogenic mechanisms.

Comment in

PMID:
29025879
PMCID:
PMC5780048
[Available on 2019-02-01]
DOI:
10.2337/dc17-0961
[Indexed for MEDLINE]

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