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, 44 (3), 299-306

Reduced GLP-1 Response to a Meal Is Associated With the CTLA4 rs3087243 G/G Genotype

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Reduced GLP-1 Response to a Meal Is Associated With the CTLA4 rs3087243 G/G Genotype

András Zóka et al. Cent Eur J Immunol.

Abstract

Although insulitis is the characteristic main feature of type 1 diabetes mellitus (T1DM), many aspects of β cell loss still remain elusive. Immune dysregulation and alterations in the dipeptidyl-peptidase-4-incretin system might have a role in disease development, but their connection is poorly understood. We assessed the associations of a few selected, immunologically relevant single nucleotide gene variants with the DPP-4-incretin system in individuals with T1DM and in healthy controls. Prandial plasma (total, active) GLP-1 levels, serum DPP-4 activity, CD25 and CTLA-4 expression of T cells and DPP4 rs6741949, CTLA4 rs3087243, CD25 rs61839660 and PTPN2 rs2476601 SNPs were assessed in 33 T1DM patients and 34 age-, gender-, BMI-matched non-diabetic controls without a family history of T1DM. CTLA-4 expression was lower in the Foxp3+CD25+ regulatory T cells from individuals homozygous for the CTLA4 rs3087243-G variant compared to those who carry an A allele. Prandial plasma total GLP-1 levels 45 min after a standardized meal were reduced in individuals homozygous for the CTLA4 rs3087243 G major allele compared to A allele carriers both in the entire study population (with statistical power over 90%) and within the T1DM group. Here we report for the first time a reduced total prandial GLP-1 plasma concentration in individuals with the CTLA4 rs3087243 G/G genotype. One may speculate that immune response-related L cell damage might possibly explain this novel association.

Keywords: CTLA4; GLP-1; SNPs; association study; autoimmune; genetic; genetic susceptibility; incretin response; type 1 diabetes.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1
Lymphocytes were gated according to the forward and side scatters. T lymphocytes were gated according to their CD3 expression and CD8 non-cytotoxic (Tnc) cells were also gated. Treg cells were defined as Foxp3+ cells within the Tnc lymphocyte population. We gated the CD25+ subpopulation within the Treg cells. Representative samples are shown indicating that the CTLA-4 expression of Foxp3+CD25+ Treg cells was higher in participants with at least one rs3087243-A allele than in homozygous G allele carriers
Fig. 2
Fig. 2
We found higher CTLA-4 expression (MFI) in the Foxp3+CD25+ Treg cells of participants carrying an rs3087243-A allele than in rs3087243-G homozygous individuals in the entire study population. Columns represent means. The 95% confidence intervals are also shown
Fig. 3
Fig. 3
The postprandial plasma total GLP-1 levels were lower in homozygous rs3087243-G carriers than in individuals who carry at least one A allele in the entire study population and also in both study groups separately. No difference could be detected between the heterozygous and homozygous carriers of the rs3087243-A allele, but the peak plasma total GLP-1 levels were also higher in the heterozygous group than in homozygous G allele carriers. Group means and the 95% confidence intervals are indicated
Fig. 4
Fig. 4
Fasting serum DPP-4 enzymatic activity was higher in individuals with the rs6741949-G/G genotype than in those who carry at least one C allele. Group means and the 95% confidence intervals are indicated

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