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Series GSE270223 Query DataSets for GSE270223
Status Public on Jun 22, 2024
Title A type 2 diabetes DNA methylation signature in monocytes exhibits ethnic specificity preferentially for Native Hawaiians
Organism Homo sapiens
Experiment type Methylation profiling by array
Summary Type 2 diabetes (T2D) is among the leading causes of death in the U.S. Ethnic differences in T2D prevalence are evident, including especially for Native Hawaiians (NHs) who remain disproportionately affected by it. This difference in T2D susceptibility involves an interplay between genetic and environmental factors, of which epigenetic mechanisms, including DNA methylation (DNAm) provide a novel approach to investigating gene-environment interactions of health and disease. Monocytes, an innate immune cell intrinsic to the inflammatory response, are a fundamental immune cell component that likely underlies T2D pathogenesis, given their involvement in inflammation and inflammation-associated insulin resistance and metabolic dysfunction. From participants enrolled into the Multiethnic Cohort Study (MEC), who self-identified as NH (n=152), Japanese American (JA; n=119), or White (n=121), we investigated monocyte-specific DNAm patterns in participants at a baseline visit, when free of T2D, using the HumanMethylation850K (850K) to determine whether monocytes harbor an ethnic-specific epigenetic signature of T2D risk that precedes T2D diagnosis. Using an epigenome-wide association study (EWAS), we found 904 significantly (q < 0.01) differentially methylated loci (DML) at a 5% difference in DNAm between participants who remained T2D free at a 15-year follow-up (i.e., controls) and those that would be diagnosed with T2D by follow-up (i.e., incident T2D) after adjusted for age, sex, and education level. These methylation differences were enriched at regulatory regions of the genome, including intergenic and intragenic regions. Notably, these DML were able to distinctly stratify NHs by T2D risk groups, however, this signature was inapparent in Whites and JAs. Likewise, NHs in the incident T2D group displayed a higher degree of DNAm variability. Sensitivity analysis with traditional risk factors (fasting glucose and body mass index [BMI]) and neighborhood socioeconomic status (nSES) found these risk factors had minimal effect on T2D risk-associated DML. Next, using a similar approach we found ethnic-specific DML in monocytes that was able to uniquely stratify NHs, JAs, and Whites, however, in NHs this epigenetic landscape displayed a higher degree of DNAm variability. Similarly, these DML were enriched at regulatory regions of the genome. In both cases, we found genes associated with biological functions and pathways relevant to monocyte functionality, including immune activation and cellular metabolism. Due to the higher degree of epigenetic variability in NHs, including especially NHs with T2D risk, we investigated differentially variable CpGs associated with T2D risk and ethnic-differences. We found differentially variable CpGs between T2D risk groups were able to stratify NHs with and without T2D risk, whereas it was unresolvable in JAs and Whites. Ethnic-specific DNAm variability clustered each ethnic population distinctly, and NH controls were further partitioned from NHs with T2D risk. Our findings suggest monocytes harbor a unique DNAm signature associated with T2D risk, which may be related to ethnic differences that underlie DNAm variability in monocytes. The increased epigenetic variability in monocytes from NHs may underlie epigenetic plasticity that could allow these cells to readily respond to adverse environmental conditions throughout the life course that may underlie long-term disease risk, whereas in other less susceptible populations with similar environmental exposure, this epigenetic plasticity may not be apparent in monocytes.
 
Overall design We aimed to profile DNA methylation (DNAm) patterns from bead-enriched total monocytes (CD14+ CD16+/- monocytes) from Native Hawaiians, Japanese Americans, and Whites with variable risk for type 2 diabetes (T2D) using an epigenome-wide association study (EWAS) to determine whether there exists ethnic differences in DNAm that may underlie differential susceptibility to T2D. DNA collected from enriched monocytes (enrichment >65% monocytes) from 391 participants enrolled into the Multiethnic Cohort Study were analyzed using the Infinium HumanMethylation850 (850K), including 152 Native Hawaiians, 119 Japanese Americans, and 121 Whites, of which 171 participants would be diagnosed with T2D by the follow-up visit 15 years later (incident T2D) and 214 would remain T2D-free (controls).
 
Contributor(s) Dye C, Maunakea A
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Submission date Jun 18, 2024
Last update date Jun 22, 2024
Contact name Christian Ka'ikekuponoaloha Dye
E-mail(s) ckdye@hawaii.edu, ckd2132@cumc.columbia.edu
Phone 8089896891
Organization name University of Hawaii at Manoa
Department Native Hawaiian Health
Lab Maunakea Lab
Street address 641 Ilalo St. BSB 222K
City Honolulu
State/province HI
ZIP/Postal code 96813
Country USA
 
Platforms (1)
GPL23976 Illumina Infinium HumanMethylation850 BeadChip
Samples (392)
GSM8337110 Monocyte-Specific DNA Methylation Sample 1
GSM8337111 Monocyte-Specific DNA Methylation Sample 2
GSM8337112 Monocyte-Specific DNA Methylation Sample 3
Relations
BioProject PRJNA1125446

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE270223_RAW.tar 5.4 Gb (http)(custom) TAR (of IDAT)
GSE270223_betas_processed_GEO.txt.gz 2.2 Gb (ftp)(http) TXT

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