Role of DNA Methylation in Risk for Cognitive Impairment and Type 2 Diabetes in a Mexican American Cohort

Purpose: Alzheimer's disease (AD) and type 2 diabetes (T2D) are among the leading causes of mortality among the aging Mexican American population (≥ 65 years old) in the US. This cohort is expected to be the largest aging ethnic minority group in the US by 2050. In comparison to their non-Hispanic white counterparts who are most likely to develop AD associated with inflammation, aging Mexican Americans have an earlier onset of AD and metabolism related predisposition for AD. Mild cognitive impairment (MCI) is a phenotype that often leads to AD and is also prevalent in this cohort. The presence of T2D is known to double the risk of developing MCI/AD. The risk for AD, MCI and T2D is multifactorial, involving genetics and epigenetics. Methylation is a form of epigenetic regulation whereby a methyl group is added to the cytosine base in DNA. Methylation patterns in DNA can be affected and possibly reversed by a variety of environmental factors such as lifestyle and diet. Targeting changes to methylation patterns through associated lifestyle changes could be a possible prevention method for AD, MCI and T2D in the future, particularly for minority groups affected by health disparities, such as the Mexican American population. We aim to establish an epigenetic association between cognitive impairment (identified here as AD and MCI), and T2D that is unique to the Mexican American population. Methods: For this project, 551 aging participants from the Texas Alzheimer's Research and Care Consortium (TARCC) were selected, following quality control. A cross phenotype study design will be used to assess differential methylation associated with cognitive impairment (CI) alone, T2D alone and then with both CI and T2D simultaneously. For the first stage of this project, 299 Mexican American and 252 non-Hispanic white participants were stratified into groups of individuals diagnosed with CI alone and controls without CI within each ethnic group. In the second stage, this cohort will be stratified into individuals with T2D alone and controls without T2D. The third stage will stratify participants 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 will be assessed using the Chip Analysis Methylation Pipeline (ChAMP), limma and cate packages in R. The Beta MIxture Quantile dilation (BMIQ) method will be used for data normalization. Results: Gene set enrichment and pathway analysis tools will be used to analyze results. Conclusions: Identifying methylation sites associated with CI and T2D could contribute towards developing biomarkers that are ethnicity-specific for the Mexican American population and possibly lead towards more effective medical treatment in the future.