Hypermethylation at CREBBP Is Associated with Cognitive Impairment in a Mexican American Cohort

Abstract

Background: The aging Mexican American (MA) population is the fastest growing ethnic minority group in the US. MAs have a unique metabolic-related risk for Alzheimer’s disease (AD) and mild cognitive impairment (MCI), compared to non-Hispanic whites (NHW). This risk for cognitive impairment (CI) is multifactorial involving genetics, environmental, and lifestyle factors. Changes in environment and lifestyle can alter patterns and even possibly reverse derangement of DNA methylation (a form of epigenetic regulation). Objective: We sought to identify ethnicity-specific DNA methylation profiles that may be associated with CI in MAs and NHWs. Methods: DNA obtained from peripheral blood of 551 participants from the Texas Alzheimer’s Research and Care Consortium was typed on the Illumina Infinium® MethylationEPIC chip array, which assesses over 850K CpG genomic sites. Within each ethnic group (N = 299 MAs, N = 252 NHWs), participants were stratified by cognitive status (control versus CI). Beta values, representing relative degree of methylation, were normalized using the Beta MIxture Quantile dilation method and assessed for differential methylation using the Chip Analysis Methylation Pipeline (ChAMP), limma and cate packages in R. Results: Two differentially methylated sites were significant: cg13135255 (MAs) and cg27002303 (NHWs) based on an FDR p < 0.05. Three suggestive sites obtained were cg01887506 (MAs) and cg10607142 and cg13529380 (NHWs). Most methylation sites were hypermethylated in CI compared to controls, except cg13529380 which was hypomethylated. Conclusion: The strongest association with CI was at cg13135255 (FDR-adjusted p = 0.029 in MAs), within the CREBBP gene. Moving forward, identifying additional ethnicity-specific methylation sites may be useful to discern CI risk in MAs.

Identification of hub genes related to Alzheimer's disease by bioinformatics analysis and observation of the pathological characteristics

“…Through bioinformatics analysis, for glioma patients, it can be regarded as a prognostic factor in the future (21). Hypermethylation of CREBBP is reported to be related to cognitive impairment in the Mexican-American population (22). CXCR4, known as CXC chemokine receptor type 4, has a wide range of regulatory functions in the immune system and has been widely studied.…”

CABG Patients Develop Global DNA Hypermethylation, That Negatively Affect the Mitochondrial Function and Promote Post-Surgical Cognitive Decline: A Proof of Concept in Small Cohort

“…Many studies in the literature emphasized that oxidative stress can modulate DNA methylation by oxidizing DNA, increasing TET-mediated hydroxymethylation, and influencing the produce the methyl donor S-adenosylmethionine by interfering with the binding of DNA methyltransferases [ 43 ]. A recent study has shown that hypermethylation at the CREBBP gene is associated with cognitive impairment in 551 participants from Mexican American cohort [ 44 ]. In fact, CREB activation is induced after ROS and is critical for the cell survival of neurons.…”