The Mexican American population is among the fastest growing aging population and has a younger onset of cognitive decline. This group is also heavily burdened with metabolic conditions such as hypertension, diabetes, and obesity. Unfortunately, limited research has been conducted in this group. Understanding methylation alterations, which are influenced by both genetic and lifestyle factors, is key to identifying and addressing the root cause for mild cognitive impairment, a clinical precursor for dementia. We conducted an epigenome-wide association study on a community-based Mexican American population using the Illumina EPIC array. Following rigorous quality control measures, we identified 10 CpG sites to be differentially methylated between normal controls and individuals with mild cognitive impairment annotated to PKIB, KLHL29, SEPT9, OR2C3, CPLX3, BCL2L2-PABPN1, and CCNY. We found four regions to be differentially methylated in TMEM232, SLC17A8, ALOX12, and SEPT8. Functional gene-set analysis identified four gene-sets, RIN3, SPEG, CTSG, and UBE2L3, as significant. The gene ontology and pathway analyses point to neuronal cell death, metabolic dysfunction, and inflammatory processes. We found 1,450 processes to be enriched using empirical Bayes gene-set enrichment. In conclusion, the functional overlap of differentially methylated genes associated with cognitive impairment in Mexican Americans implies cross-talk between metabolically-instigated systemic inflammation and disruption of synaptic vesicular transport.
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.
Background Alzheimer’s disease (AD) and type 2 diabetes (T2D) are among the leading causes of mortality among the growing aging Mexican American population (≥ 65 years old) in the US (Vega et al. 2017). In comparison to their non‐Hispanic white counterparts who most likely develop inflammation associated AD, aging Mexican Americans have an earlier onset of AD and metabolism related predisposition for AD (O'Bryant et al. 2010). Mild cognitive impairment (MCI) is a phenotype that often leads to AD and is also prevalent in this cohort (O'Bryant et al. 2013). The risks for AD, MCI and T2D are multifactorial, involving a form of epigenetic regulation called methylation where a methyl group is added to the cytosine base in DNA (Shao et al. 2017; Juvinao‐Quintero et al. 2019). We aim to elucidate an epigenetic association between cognitive impairment (identified here as AD and MCI), and T2D that is unique to the Mexican American population. Method A total of 551 aging participants from the Texas Alzheimer’s Research and Care Consortium (TARCC) consisting of 252 non‐Hispanic white individuals and 299 Mexican Americans were selected, after quality control. First, participants were stratified into groups of individuals diagnosed with cognitive impairment (CI) alone and controls without CI within each ethnic group. Secondly, this cohort was stratified into individuals with T2D alone and controls without T2D. Thirdly, participants were stratified into those with both CI and T2D versus normal healthy controls. Lastly, any differential methylation associated with each ethnic group will be compared and contrasted. Peripheral blood drawn from participants was used to obtain individual methylation profiles using the Illumina Infinium MethylationEPIC chip array. Differential methylation was assessed using the Chip Analysis Methylation Pipeline (ChAMP), limma and cate packages in R. The Beta MIxture Quantile dilation (BMIQ) method was used for data normalization. Result Results will be analyzed using gene set enrichment and pathway analysis tools. Conclusion Identifying possible methylation sites associated with CI and T2D could contribute towards developing ethnicity‐specific biomarkers for Mexican Americans.
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