TCF7L2 genetic variants contribute to phenotypic heterogeneity of type 1 diabetes

Type 1 Diabetes TrialNet Study Group

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

OBJECTIVE The phenotypic diversity of type 1 diabetes suggests heterogeneous etiopathogen-esis. 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.

Original languageEnglish (US)
Pages (from-to)311-317
Number of pages7
JournalDiabetes Care
Volume41
Issue number2
DOIs
StatePublished - Feb 1 2018

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T Cell Transcription Factor 1
Type 1 Diabetes Mellitus
Autoantibodies
Area Under Curve
C-Peptide
Single Nucleotide Polymorphism
Glucose Tolerance Test
Glucose
Odds Ratio
Type 2 Diabetes Mellitus
Alleles
Phenotype

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Advanced and Specialized Nursing

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TCF7L2 genetic variants contribute to phenotypic heterogeneity of type 1 diabetes. / Type 1 Diabetes TrialNet Study Group.

In: Diabetes Care, Vol. 41, No. 2, 01.02.2018, p. 311-317.

Research output: Contribution to journalArticle

Type 1 Diabetes TrialNet Study Group. / TCF7L2 genetic variants contribute to phenotypic heterogeneity of type 1 diabetes. In: Diabetes Care. 2018 ; Vol. 41, No. 2. pp. 311-317.
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abstract = "OBJECTIVE The phenotypic diversity of type 1 diabetes suggests heterogeneous etiopathogen-esis. 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.",
author = "{Type 1 Diabetes TrialNet Study Group} and Redondo, {Maria J.} and Susan Geyer and Steck, {Andrea K.} and Sosenko, {Jay M} and Mark Anderson and Peter Antinozzi and Aaron Michels and John Wentworth and Ping Xu and Alberto Pugliese",
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T1 - TCF7L2 genetic variants contribute to phenotypic heterogeneity of type 1 diabetes

AU - Type 1 Diabetes TrialNet Study Group

AU - Redondo, Maria J.

AU - Geyer, Susan

AU - Steck, Andrea K.

AU - Sosenko, Jay M

AU - Anderson, Mark

AU - Antinozzi, Peter

AU - Michels, Aaron

AU - Wentworth, John

AU - Xu, Ping

AU - Pugliese, Alberto

PY - 2018/2/1

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N2 - OBJECTIVE The phenotypic diversity of type 1 diabetes suggests heterogeneous etiopathogen-esis. 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.

AB - OBJECTIVE The phenotypic diversity of type 1 diabetes suggests heterogeneous etiopathogen-esis. 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.

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