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

Overview

Journal J Alzheimers Dis

Publisher Sage Publications

Specialties Geriatrics
Neurology

Date 2023 Mar 6

PMID 36872777

Authors

Ann Abraham Daniel

Talisa Silzer

Jie Sun

Zhengyang Zhou

Courtney Hall

Nicole Phillips

Robert Barber

Affiliations

Soon will be listed here.

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.

Citing Articles

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Boovarahan S, Kale S, Prem P, Ravindran S, Arthanarisami A, Rengaraju J J Clin Med. 2023; 12(12).

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References

Jeltsch A, Jurkowska R . New concepts in DNA methylation. Trends Biochem Sci. 2014; 39(7):310-8. DOI: 10.1016/j.tibs.2014.05.002. View

Levine M, Lu A, Quach A, Chen B, Assimes T, Bandinelli S . An epigenetic biomarker of aging for lifespan and healthspan. Aging (Albany NY). 2018; 10(4):573-591. PMC: 5940111. DOI: 10.18632/aging.101414. View

Gauthreaux K, Bonnett T, Besser L, Brenowitz W, Teylan M, Mock C . Concordance of Clinical Alzheimer Diagnosis and Neuropathological Features at Autopsy. J Neuropathol Exp Neurol. 2020; 79(5):465-473. PMC: 7160616. DOI: 10.1093/jnen/nlaa014. View

Wani A, Aiello A, Kim G, Xue F, Martin C, Ratanatharathorn A . The impact of psychopathology, social adversity and stress-relevant DNA methylation on prospective risk for post-traumatic stress: A machine learning approach. J Affect Disord. 2021; 282:894-905. PMC: 7942200. DOI: 10.1016/j.jad.2020.12.076. View

Fiorito G, Polidoro S, Dugue P, Kivimaki M, Ponzi E, Matullo G . Social adversity and epigenetic aging: a multi-cohort study on socioeconomic differences in peripheral blood DNA methylation. Sci Rep. 2017; 7(1):16266. PMC: 5701128. DOI: 10.1038/s41598-017-16391-5. View

Teschendorff A, Menon U, Gentry-Maharaj A, Ramus S, Gayther S, Apostolidou S . An epigenetic signature in peripheral blood predicts active ovarian cancer. PLoS One. 2009; 4(12):e8274. PMC: 2793425. DOI: 10.1371/journal.pone.0008274. View

Rodriguez-Lopez J, Pombo-Suarez M, Loughlin J, Tsezou A, Blanco F, Meulenbelt I . Association of a nsSNP in ADAMTS14 to some osteoarthritis phenotypes. Osteoarthritis Cartilage. 2008; 17(3):321-7. DOI: 10.1016/j.joca.2008.07.012. View

Rosenberger A, Rozemuller A, van der Flier W, Scheltens P, van der Vies S, Hoozemans J . Altered distribution of the EphA4 kinase in hippocampal brain tissue of patients with Alzheimer's disease correlates with pathology. Acta Neuropathol Commun. 2014; 2:79. PMC: 4149234. DOI: 10.1186/s40478-014-0079-9. View

Pathak G, Silzer T, Sun J, Zhou Z, Daniel A, Johnson L . Genome-Wide Methylation of Mild Cognitive Impairment in Mexican Americans Highlights Genes Involved in Synaptic Transport, Alzheimer's Disease-Precursor Phenotypes, and Metabolic Morbidities. J Alzheimers Dis. 2019; 72(3):733-749. DOI: 10.3233/JAD-190634. View

10.

Ozaki Y, Yoshino Y, Yamazaki K, Sao T, Mori Y, Ochi S . DNA methylation changes at TREM2 intron 1 and TREM2 mRNA expression in patients with Alzheimer's disease. J Psychiatr Res. 2017; 92:74-80. DOI: 10.1016/j.jpsychires.2017.04.003. View

11.

OBryant S, Xiao G, Zhang F, Edwards M, German D, Yin X . Validation of a serum screen for Alzheimer's disease across assay platforms, species, and tissues. J Alzheimers Dis. 2014; 42(4):1325-35. PMC: 4400808. DOI: 10.3233/JAD-141041. View

12.

Luo M, Zhou X, Ji H, Ma W, Liu G, Dai D . Population Difference in the Associations of KLOTH Promoter Methylation with Mild Cognitive Impairment in Xinjiang Uygur and Han Populations. PLoS One. 2015; 10(7):e0132156. PMC: 4509908. DOI: 10.1371/journal.pone.0132156. View

13.

OBryant S, Waring S, Cullum C, Hall J, Lacritz L, Massman P . Staging dementia using Clinical Dementia Rating Scale Sum of Boxes scores: a Texas Alzheimer's research consortium study. Arch Neurol. 2008; 65(8):1091-5. PMC: 3409562. DOI: 10.1001/archneur.65.8.1091. View

14.

Teschendorff A, Marabita F, Lechner M, Bartlett T, Tegner J, Gomez-Cabrero D . A beta-mixture quantile normalization method for correcting probe design bias in Illumina Infinium 450 k DNA methylation data. Bioinformatics. 2012; 29(2):189-96. PMC: 3546795. DOI: 10.1093/bioinformatics/bts680. View

15.

Aryee M, Jaffe A, Corrada-Bravo H, Ladd-Acosta C, Feinberg A, Hansen K . Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays. Bioinformatics. 2014; 30(10):1363-9. PMC: 4016708. DOI: 10.1093/bioinformatics/btu049. View

16.

Johnson W, Li C, Rabinovic A . Adjusting batch effects in microarray expression data using empirical Bayes methods. Biostatistics. 2006; 8(1):118-27. DOI: 10.1093/biostatistics/kxj037. View

17.

Han T, Jiang W, Wu H, Wei W, Lu J, Lu H . Fetal malnutrition is associated with impairment of endogenous melatonin synthesis in pineal via hypermethylation of promoters of protein kinase C alpha and cAMP response element-binding. J Pineal Res. 2021; 71(4):e12764. DOI: 10.1111/jpi.12764. View

18.

Arias E . United States life tables by Hispanic origin. Vital Health Stat 2. 2011; (152):1-33. View

19.

Hannum G, Guinney J, Zhao L, Zhang L, Hughes G, Sadda S . Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol Cell. 2012; 49(2):359-367. PMC: 3780611. DOI: 10.1016/j.molcel.2012.10.016. View

20.

Tamura K, Chiu Y, Shiohara A, Hori Y, Tomita T . EphA4 regulates Aβ production via BACE1 expression in neurons. FASEB J. 2020; 34(12):16383-16396. DOI: 10.1096/fj.202001510R. View