Genetic variation in the glucagon-like peptide-1 receptor protein encoding region is associated with higher heart rate variability, but not with neurodegeneration of the brain, retina, and peripheral nerves: The Maastricht study.

Background: Degeneration of organ-specific nervous systems precede major clinical conditions such as heart failure, dementia, diabetic retinopathy, and diabetic neuropathy. Glucagon-like peptide-1 receptor (GLP1R) agonists may have neuroprotective effects, independent of their glucose-lowering effects, and as such may be tools for early prevention of neurodegeneration. We investigated whether genetic variation in the GLP1R protein encoding region, assessed using a genetic score, was associated with neurodegeneration measured in the heart, brain, retina, and peripheral nerves.

Methods: Data from up to 7446 individuals from The Maastricht Study were used (mean [standard deviation (SD)] age 59.5 ([8.7] years, 49.4% men, and 20.0% with type 2 diabetes [by design]). A GLP1R score (0-8 points) was calculated using four genetic variants located in the GLP1R protein encoding region, with putative functional consequences on GLP1R activity (rs1042044, rs1004280, rs10305423, rs880067). Multivariable regression analysis was used to examine the associations between GLP1R genetic score and neural measures of the heart (time- and frequency-domain heart rate variability [HRV]), brain (magnetic resonance imaging-assessed local and global structural connectivity indices, brain volume, and global cognitive performance), retina (retinal nerve fiber layer thickness and retinal sensitivity) and peripheral nerves (conduction velocity). Associations were adjusted for age, sex, and HbA1c. Interaction with sex, age, and glucose metabolism status was examined.

Results: In fully adjusted analyses, higher GLP1R genetic score (corresponding to higher predicted GLP1R protein expression) was significantly associated with higher time-domain HRV (per SD higher GLP1R score, 0.031 (0.006, 0.056) SD) and similarly, but not statistically significantly, with higher frequency-domain HRV (0.024 (- 0.001, 0.048) SD). The GLP1R genetic score was not significantly associated with brain, retinal, or peripheral nerves measures. Associations did not consistently differ as a function of age, sex, or glucose metabolism status.

Conclusions: Higher putative GLP1R protein expression, assessed from genetic variation in the GLP1R protein encoding region, was significantly associated with lower levels of neurodegeneration in the heart, but not in the brain, retina, and peripheral nerves. Future clinical trials should test whether use of GLP1R agonists can contribute to prevention of cardiac autonomic nerve degeneration and associated clinical disease.