RT Journal Article
SR Electronic
T1 <em>TCF7L2</em> Genetic Variants Contribute to Phenotypic Heterogeneity of Type 1 Diabetes
JF Diabetes Care
JO Diabetes Care
FD American Diabetes Association
SP 311
OP 317
DO 10.2337/dc17-0961
VO 41
IS 2
A1 Redondo, Maria J.
A1 Geyer, Susan
A1 Steck, Andrea K.
A1 Sosenko, Jay
A1 Anderson, Mark
A1 Antinozzi, Peter
A1 Michels, Aaron
A1 Wentworth, John
A1 Xu, Ping
A1 Pugliese, Alberto
A1 ,
YR 2018
UL http://care.diabetesjournals.org/content/41/2/311.abstract
AB 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.