Type 2 diabetes-associated TCF7L2 genetic variants and African American race protect from loss of insulin containing islets in type 1 diabetes

Presenter

Maria Redondo, Baylor College of Medicine

Authors

Maria J. Redondo, Sarah Richardson, Daniel Perry, Charles Minard, Alice Carr, Irina Kusmartseva, Alberto Pugliese, Mark Atkinson

Purpose

The type 2 diabetes (T2D)-linked TCF7L2 variants are associated with features atypical for type 1 diabetes (T1D) suggesting that autoimmunity and beta cell loss are less severe. Hence, we determined the influence of TCF7L2 SNPs on insulin containing islet (ICI)% in T1D pancreata.

Methods

We analyzed 111 nPOD donors (www.jdrfnpod.org) with T1D who had data on the presence or absence of residual beta cells. In those donors with remaining beta cells, formalin fixed paraffin embedded (FFPE) pancreas tissue sections from regions containing beta cells (as determined by the nPOD Pathology Core) were stained for the presence of insulin-positive and glucagon-positive cells. The ICI% was calculated by quantifying the number of islets containing insulin-positive beta cells, and expressing this as a percentage of the total islets analyzed within each donor. The observed distribution of ICI% was examined to determine an interesting cutoff value. The largest difference between consecutive observations under 10% occurred between 2.2 and 6.4. Therefore, high ICI% was defined as ≥5% for this study. Mean age at T1D onset was 12.2 years (sd=7.9) (range=0-36), diabetes duration was 15.2 years (sd=13.7) (range=0-74), BMI was 24.5 (sd=4.6), 53% were male, 80% non-Hispanic white, 13% African American, and 7% Hispanic.

Summary of Results

Mean ICI% was 9.7 (sd=21.5) (range=0-92.2). At the TCF7L2 rs7903146 locus, 45.5% (50/110) of donors carried the T2D-associated T allele (41.8% as TC and 3.6% as TT). Donors with high (≥5) (n=30, 27%) vs low ICI% (<5) were older at onset (15.3±6.9 vs 11.1±7.9 years, p=0.013), had shorter diabetes duration at procurement (7.0±7.4 vs 18.3±14.3 years, p<0.001), and had higher African ancestry score (0.2±0.3 vs 0.1±0.2, p=0.043) and lower European ancestry score (0.7±0.3 vs 0.9±0.3, p=0.023). There were no significant differences in sex, BMI or TCF7L2 SNPs allele distribution but African American race was more common among high ICI (23.3%) than low ICI (8.6%, p=0.038). In multivariable logistic regression predicting high ICI % with adjustmentfor age of onset (p=0.086), diabetes duration (p<0.001), BMI (p=0.796), sex (p=0.417) and African American race (p=0.050), donors with the TCF7L2 rs7903146 T allele (TC or TT), compared to those without it (CC) were 2.91 times (95%CI=1.02-8.3) more likely to have high ICI% (p=0.046). A similar model was also fit including the interaction between African American race and rs7903146 T allele (p=0.021). Among African American donors, the odds of high ICI were 146.6 (95%CI=4.1-5300) times greater among donors with the T allele compared to those without the T allele. Among non-African American donors, the odds ratio was 1.7 (95% CI=0.5-5).

Conclusions

Among nPOD donors with T1D, carriers of the T2D-linked TCF7L2 variant had a higher number of residual ICIs, possiblyrepresenting a disease endotype characterized by T2D-like features and less severe beta cell loss.