Association Between Toll-Like Receptor 4 (TLR4) and Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) Genetic Variants and Clinical Progression of Huntington's Disease.

Abstract

While Huntington’s disease (HD) is caused by a single dominant gene, it is clear that there are genetic modifiers that may influence the age of onset and disease progression. Objectives. Here, we sought to investigate whether new inflammation-related genetic variants may contribute to the onset and progression of HD. Methods. We first used post mortem brain material from patients at different stages of HD to look at the protein expression of TLR4 and TREM2. We then genotyped the TREM2 R47H gene variant and three TLR4 SNPs in a large cohort of HD patients from the European Huntington’s Disease Network REGISTRY. Results. We found an increase in the number of cells expressing TREM2 and TLR4 in post mortem brain samples from patients dying with HD. We also found that the TREM2 R47H gene variant was associated with changes in cognitive decline in the large cohort of HD patients, whereas two out of three TLR4 SNPs assessed were associated with changes in motor progression in this same group. Conclusions. These findings identify TREM2 and TLR4 as potential genetic modifiers for HD and suggest that inflammation influences disease progression in this condition.