Diabetes-related DNA Methylation of TXNIP Independently Associated with Inflammation Public

Abstract

Background: Thioredoxin-interacting protein (txnip) plays a key role in diabetes development and prognosis through pancreatic β-cell dysfunction and death as well as upregulating inflammatory response in hyperglycemia condition. However, the role of inflammation biomarkers in the association between TXNIP DNA methylation (DNAm) and type 2 diabetes (T2D) remains unclear.

Methods: We conducted an epigenetic association study of T2D-related traits and a panel of inflammatory biomarkers among 218 middle-aged male twins from the Emory Twin Study. DNA methylation and inflammation biomarkers were assessed in blood samples. Age in years, current smoking status and BMI were adjusted as covariates. Linear mixed models (LMM) were performed to model shared (between-twin effect) and unshared (within-twin effect) epigenetic associations of co-twins, as well as the batch effect due to laboratory assays. The significance threshold was corrected due to multiple testing. In addition, a stepwise generalized estimating equations (GEE) method was performed to assess the effect of inflammatory biomarkers on TXNIP-cg19693031 association with T2D.

Results: Hypomethylation of TXNIP-cg19693031 were significantly associated with diabetes traits and inflammation biomarkers (VCAM-1, ICAM-1, MMP-2, sRAGE, and sP-selectin) after multiple testing correction. Within twin pairs, 1% increase in beta- values was associated with 13.84 ng/ml (P=4.3 ́10-5), 36.03 ng/ml (P=2.8 ́10-4), 2.97 ng/ml (P=9.5 ́10-4), and 1.87 ng/ml (P=.003), decrease in ICAM-1, VCAM-1, MMP-2, and sP-selectin. Meanwhile, 1% increase of beta-values between twin pairs was associated with 23.65 ng/ml (P=6.0 ́10-5), 2.21 ng/ml (P=.001) and 26.17 pg/mL (P=.003) decrease in VCAM-1, MMP-2 and sRAGE. In the adjusted GEE models, within-twin association indicated that 1% increase of DNAm in TXNIP-cg19693031 was associated with the 24% decrease of T2D (OR=0.76, 95% CI 0.61, 0.95). Meanwhile, 1% increase of shared DNAm of twin pairs in TXNIP-cg19693031 was associated with the 18% decrease of T2D (OR=0.82, 95% CI 0.71, 0.94). The epigenetic association between TXNIP-cg19693031and T2D was independent from inflammatory biomarkers including VCAM-1, ICAM-1, MMP-2 and sRAGE.

Conclusion: Our results suggest that hypomethylation of TXNIP-cg19693031 is strongly associated with both Type 2 diabetes and higher level of inflammation biomarkers whereas the relationship between TXNIP-cg19693031 and T2D is independent from the inflammation biomarkers. 

Table of Contents

Introduction .................................................................................................... 1

Materials and Methods............................................................................... 3

Study sample ..............................................................................................3

Phenotypes..................................................................................................4

DNA methylation profiling and data processing ....................................5

Statistical analysis......................................................................................6

Results................................................................................................................ 7

Discussion ....................................................................................................... 10

Reference ........................................................................................................ 15

Tables............................................................................................................... 20

Table 1.......................................................................................................20

Table 2.......................................................................................................21

Table 3.......................................................................................................21 

About this Master's Thesis

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School	Rollins School of Public Health
Department	Epidemiology
Subfield / Discipline	Epidemiology - MPH & MSPH
Degree	M.P.H.
Submission	Master's Thesis
Language	English
Research Field	Health Sciences, Public Health Biology, Genetics Health Sciences, Epidemiology
Mot-clé	Inflammation Type 2 Diabetes (T2D) Thioredoxin interacting protein (TXNIP)
Committee Chair / Thesis Advisor	Yan Sun, Ph.D., Emory University

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