Evaluation of HIVEP3 polymorphic variants and gene expression in Alzheimer’s disease

Abstract

AbstractBackgroundIt has been increasingly recognized that neuroinflammation plays an important role in the pathophysiology of Alzheimer’s disease (AD). The HIVEP3 gene encodes a transcription factor that regulates inflammatory response, and variants in this gene have been associated with increased risk for Parkinson’s disease. HIVEP3 gene expression is transiently decreased following nerve damage, consistent with a role during neuronal remodeling . In the present work, we investigate genetic variants in the HIVEP3 gene as risk factors for AD, and study HIVEP3 gene expression in human cerebral cortex.MethodWe have used three different cohorts to assess the association of HIVEP3 polymorphisms with the risk of developing AD: the International Genomics of Alzheimer’s Project (IGAP), the Quebec Founder Population Cohort (QFP) and Kunkle et al. stage 1 GWAS dataset. In the QFP cohort, we measured HIVEP3 protein levels (using ELISA) and mRNA levels (using RT‐PCR) in the frontal cortex of autopsied‐confirmed AD and control subjects.ResultWe have found that the rs10493098 C variant is associated with increased risk of AD in IGAP 2009 (p = 0.018, OR = 1.04), QFP (p< 5 × 10−8, OR = 1.37) and Kunkle et al. 2019 stage 1 IGAP GWAS (p = 0.006). In the IGAP cohort, this variant is associated with increased risk of AD only in APOE4 negative participants (p = 0.0009). Cortical HIVEP3 protein levels are increased in subjects with AD compared to controls (p = 0.029) and in subjects with at least one copy of the rs10493098 C variant compared to non‐carriers (p = 0.03). There are no changes in mRNA levels as a function of disease status or presence of the rs10493098 C variant. There is no correlation between HIVEP3 protein or mRNA levels and senile plaques or neurofibrillary tangles densities.ConclusionWe have identified a new genetic variant associated with increased risk for AD. The HIVEP3 rs10493098 C variant is associated with increased risk of AD, particularly in APOE4 negative participants. HIVEP3 proteins levels are increased in the frontal cortex of AD subjects compared to controls and in rs10493098 C carriers.