Single nucleotide transcription factor 7-like 2 (TCF7L2) gene polymorphisms in antiislet autoantibody-negative patients at onset of diabetes

Abstract

Context: There is controversy as to whether type 2 diabetes genetic susceptibility contributes to type 1 diabetes, and it is not known what proportion of islet autoantibody-negative new onset subjects have type 2 diabetes risk alleles.

Objectives: We designed this study to evaluate whether two type 2 diabetes-associated single nucleotide polymorphisms (SNPs) of transcription factor 7-like 2 (TCF7L2) gene are associated with the development of islet autoantibody-negative diabetes vs. islet autoantibody-positive diabetes in young patients and whether these SNPs are associated with specific clinical phenotypes.

Design: Autoantibody against glutamic acid decarboxylase 65, islet cell antibody 512bdc (form of IA-2), insulin, ZnT8 transporter, and cytoplasmic islet cell antibody were assayed in patients with new onset diabetes seen at the Barbara Davis Center using sera obtained within 2 wk of diagnosis. We genotyped two noncoding variants in the TCF7L2 gene, rs12255372 and rs7903146, in diabetic subjects and normal controls.

Results: A total of 140 patients (15.7%) were negative for all islet autoantibodies among 893 subjects less than age 25 at the onset of diabetes. The allele and genotype frequencies of two SNPs showed that these are associated (odds ratio up to 4) with the development of diabetes in the autoantibody-negative diabetic cohort, but not in the autoantibody-positive diabetic cohort.

Conclusion: TCF7L2 type 2 diabetes susceptibility alleles are associated with islet autoantibody-negative but not autoantibody-positive new onset diabetes in young patients.

Figures

Figure 1

Study design for antiislet autoantibodies and genotyping of two sequence variants in TCF7L2 gene. Antiislet autoantibodies including GAA, ICA512AA, and IAA were measured for all 893 enrolled study subjects. The subjects without ICA512AA were tested with an IA-2ic construct. We also tested for autoantibody against ICA and ZnT8 in those negative for the above autoantigens, and 140 newly diagnosed diabetic patients were confirmed as negative for all tested antiislet autoantibodies. We genotyped two type 2 diabetes-associated noncoding variants in the TCF7L2 gene, rs12255372 and rs7903146, in 113 autoantibody-negative diabetic subjects and 573 autoantibody-positive diabetic subjects as well as 305 normal controls.

Figure 2

Distribution (%) of HLA in the study group. HLA class II alleles were present very differently between the two diabetic groups. The protective DQB*0602 allele was much more frequent in the AbnDM group compared with the AbpDM group (11.8 vs. 2%; P < 0.001), and DR3/4, the most high-risk genotype of type 1 diabetes, was much more frequent in the AbpDM group (10 vs. 24.4%; P < 0.01).

Figure 3

Distribution (%) of rs7903146 genotypes in Caucasian (top) and non-DR3/4 only (bottom). Genotypes in non-Hispanic Caucasians showed the same differential association of the T allele and T/T genotype of two sequence variants in the AbnDM group (odds ratio up to 4.10, comparing AbnDM vs. normal controls of rs7903146; P < 0.01) (top). The genotyping results for the cohort of subjects without HLA DR3/4 also showed that the T allele and T/T genotype in each SNP were statistically more frequent in the AbnDM group (odds ratio up to 3.64, comparing AbnDM vs. AbpDM for rs7903146; P < 0.001) (bottom). NC, Normal controls.

Figure 4

FU HbA1c levels by genotypes for rs7903146. The subjects with T/T genotype of rs7903146 had significantly lower FU HbA1c levels (P < 0.01). For the rs7903146, T/T homozygotes had a mean HbA1c of 6.49% compared with 8.93% for C/T and 8.40% for C/C genotypes. In contrast, there was no difference in FU HbA1c levels by TCF7L2 genotypes in the antibody-positive cohort.