TYPE 2 DIABETES GENETIC RISK VARIANTS WITHIN TCF7L2 ARE ASSOCIATED WITH SMALLER AMYGDALAR VOLUME AMONG DIABETIC ELDERLY PATIENTS

Abstract

Type 2 diabetes (T2D) is associated with poorer cognitive function, accelerated cognitive decline, and higher risk for dementia, accompanied by atrophy in different brain structures. The association of the Transcription factor 7-like 2 (TCF7L2) gene with T2D is one of the most reproducible findings in T2D genetics. Since TCF7L2 is expressed in the brain, we investigated the association between volumes of the hippocampus, amygdala and frontal cortex of cognitively normal T2D elderly. Our hypothesis was that T2D genetic risk variants within TCF7L2will be associated with greater brain atrophy among diabetic patients. T2D subjects (n=177) from the Israel Diabetes and Cognitive Decline study who were both genotyped for the TCF7L2single nucleotide polymorphisms (SNPs) rs7903146, rs11196205, rs12255372 and underwent brain MRI, were included in this analysis. Images were processed and regional volumes were calculated with SPM software. For each SNP, we used ANCOVA to investigate the association of the T2D risk allele with volume of hippocampus, amygdala and frontal cortex under a recessive model of inheritance - controlling for relevant demographic and clinical variables (sex, age, years of education, duration of T2D, HBA1C, total cholesterol, systolic and diastolic blood pressure, BMI, and ICV [intra-cranial volume]). In all three TCF7L2 SNPs, amygdalar volume was 9–12% lower among carriers of the TD2 risk allele homozygous genotype: rs7903146: TT genotype vs. CT+TT genotypes (p=0.003); rs11196205 CC genotype vs. CG+GG genotypes (p=0.001), and rs12255372TT genotype vs. GT+GG genotypes (p=0.003). These SNPs were not associated with hippocampal or frontal cortex volumes. TCF7L2 genetic variants are associated with smaller amygdalar volume in T2D elderly, suggesting an atrophic process in the amygdala in those with the risk variants. In addition, the amygdala has been implicated in supporting memory processes affected in dementia. Further study of TCF7L2 role in this region is needed, as amygdalar atrophy has been reported in T2D and the amygdala has been recently reported as a glucose sensing region.