ICA1 is differentially methylated and expressed in familial type 1 diabetes

Abstract

There has recently been a growing interest in examining the role of epigenetic modifications, such as DNA methylation, in the etiology of type 1 diabetes (T1D). This study aimed to delineate differences in methylation patterns between T1D-affected and healthy individuals by examining the genome-wide methylation of individuals from three Arab families from Kuwait with T1D-affected mono-/dizygotic twins and non-twinned siblings. Bisulfite sequencing of DNA from the peripheral blood of affected and healthy individuals from each of the three families was performed. Methylation profiles of the affected individuals were compared to those of healthy individuals. The principal component analysis on methylation profiling based on base-pair resolution clustered the T1D-affected twins together family-wide. Sites/regions that were differentially methylated between T1D and healthy samples harbored 84 genes, of which 18 were known to be differentially methylated in T1D individuals compared to healthy individuals in publicly available gene expression data resources. We further validated two of the 18 genes—namely ICA1 and DRAM1 that were hypermethylated in T1D samples compared to healthy samples—for upregulation in T1D samples from an extended study cohort of familial T1D. The ICA1 is well-known to have a role in the development of autoimmune beta-cell destruction.

ONECUT1 variants beyond type 1 and type 2 diabetes: exploring clinical diversity and epigenetic associations in Arab cohorts

“…Interestingly, our study highlights ONECUT1 methylation as a potential marker for MODY-X, representing either a unique subtype of MODY or a form of diabetes that is yet to be classified. In this context, it is important to point out that our previous study (Dashti et al, 2022) did not find ONECUT1 as one of the observed differentially methylated and expressed genes in familial T1D. Thus, the observed ONECUT1 methylation in the MODY patients in this study can help to clarify when suspected MODY individuals are misdiagnosed as T1D patients.…”

“…Secondly, the peripheral blood sample is not the ideal biological sample as a) it contains a diverse mixture of cells and DNAm is cell-specific, and b) it may harbour DNA methylation events due to pathological differences relating to autoimmune processes that we could not consider for adjusting the results of differential methylation analysis. However, blood as biological sample has been used in other DNA methylation studies on diabetes (Disanto et al, 2013;Agardh et al, 2015;Johnson et al, 2020;Dashti et al, 2022).…”

“…The methodologies for methylation sequencing and DNAm analysis are described in detail in our previous publication (Dashti et al, 2022). A brief summary of the adopted methods is as given below.…”