Genetic and environmental factors regulate the type 1 diabetes gene CTSH via differential DNA methylation

Ye, Jody; Stefan-Lifshitz, Mihaela; Tomer, Yaron

doi:10.1016/j.jbc.2021.100774

Cited by 11 publications

(5 citation statements)

References 43 publications

(57 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Such a process is likely to cause injury to b cells, ultimately contributing to the development of T1D. Another study observed that the incidence of T1D was found to correlate with high CTSH expression, which itself is modified by other environmental factors such as epigenetics and post-translational modifications (42). Taken together, these studies highlight the role of CTSH in increased susceptibility of developing T1D.…”

Section: Cathepsin Hmentioning

confidence: 85%

Gene-environment interaction in the pathophysiology of type 1 diabetes

Mittal,

Camick,

Lemos

et al. 2024

Front. Endocrinol.

View full text Add to dashboard Cite

Type 1 diabetes (T1D) is a complex metabolic autoimmune disorder that affects millions of individuals worldwide and often leads to significant comorbidities. However, the precise trigger of autoimmunity and disease onset remain incompletely elucidated. This integrative perspective article synthesizes the cumulative role of gene-environment interaction in the pathophysiology of T1D. Genetics plays a significant role in T1D susceptibility, particularly at the major histocompatibility complex (MHC) locus and cathepsin H (CTSH) locus. In addition to genetics, environmental factors such as viral infections, pesticide exposure, and changes in the gut microbiome have been associated with the development of T1D. Alterations in the gut microbiome impact mucosal integrity and immune tolerance, increasing gut permeability through molecular mimicry and modulation of the gut immune system, thereby increasing the risk of T1D potentially through the induction of autoimmunity. HLA class II haplotypes with known effects on T1D incidence may directly correlate to changes in the gut microbiome, but precisely how the genes influence changes in the gut microbiome, and how these changes provoke T1D, requires further investigations. These gene-environment interactions are hypothesized to increase susceptibility to T1D through epigenetic changes such as DNA methylation and histone modification, which in turn modify gene expression. There is a need to determine the efficacy of new interventions that target these epigenetic modifications such as “epidrugs”, which will provide novel avenues for the effective management of T1D leading to improved quality of life of affected individuals and their families/caregivers.

show abstract

Section: Cathepsin Hmentioning

confidence: 85%

Gene-environment interaction in the pathophysiology of type 1 diabetes

Mittal,

Camick,

Lemos

et al. 2024

Front. Endocrinol.

View full text Add to dashboard Cite

show abstract

“…Recent evidence suggests that not only genetic but also environmental influences on T1D genetic loci are mediated by differential levels or patterns of DNA methylation (hypo or hypermethylation) [8,45,46]. For example, some of the genes that have been identified to be associated with T1D, such as GAD2 and HLA-DQB1, were found to be hypomethylated or hypermethylated [7].…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, individuals who carry the T1D risk variant exhibited less variability in methylation at the CpG residues in intron 1, presumably making them less responsive to cytokines. On the other hand, individuals who carry the protective variant demonstrated greater methylation variability, presumably increasing their sensitivity to cytokines, suggesting that the two populations may respond differently to environmental factors [45].…”

Section: Discussionmentioning

confidence: 99%

Alu Methylation Patterns in Type 1 Diabetes: A Case-Control Study

Katsanou,

Kostoulas,

Liberopoulos

et al. 2023

Genes

View full text Add to dashboard Cite

Evidence suggests that genome-wide hypomethylation may promote genomic instability and cellular senescence, leading to chronic complications in people with diabetes mellitus. Limited data are however available on the Alu methylation status in patients with type 1 diabetes (T1D). Methods: We investigated DNA methylation levels and patterns of Alu methylation in the peripheral blood of 36 patients with T1D and 29 healthy controls, matched for age and sex, by using the COmbined Bisulfite Restriction Analysis method (COBRA). Results: Total Alu methylation rate (mC) was similar between patients with T1D and controls (67.3% (64.4–70.9%) vs. 68.0% (62.0–71.1%), p = 0.874). However, patients with T1D had significantly higher levels of the partial Alu methylation pattern (mCuC + uCmC) (41.9% (35.8–45.8%) vs. 36.0% (31.7–40.55%), p = 0.004) compared to healthy controls. In addition, a positive correlation between levels of glycated hemoglobin (HbA1c) and the partially methylated loci (mCuC + uCmC) was observed (Spearman’s rho = 0.293, p = 0.018). Furthermore, significant differences were observed between patients with T1D diagnosed before and after the age of 15 years regarding the total methylation mC, the methylated pattern mCmC and the unmethylated pattern uCuC (p = 0.040, p = 0.044 and p = 0.040, respectively). Conclusions: In conclusion, total Alu methylation rates were similar, but the partial Alu methylation pattern (mCuC + uCmC) was significantly higher in patients with T1D compared to healthy controls. Furthermore, this pattern was associated positively with the levels of HbA1c and negatively with the age at diagnosis.

show abstract

“…It is also important to note that non-twin studies using T1D patients and healthy individuals have demonstrated differences in methylation profiles between T1D patients and controls [141,151]. Indeed, recent research has shown that DNA methylation is involved in regulating the genetic and environmental influence of T1D at the CTSH locus [149].…”

Section: Dna Methylation Signature In T1dmentioning

confidence: 99%

Epigenetic Changes Induced by Maternal Factors during Fetal Life: Implication for Type 1 Diabetes

Barchetta

Arvastsson

Sarmiento

et al. 2021

Genes

View full text Add to dashboard Cite

Organ-specific autoimmune diseases, such as type 1 diabetes, are believed to result from T-cell-mediated damage of the target tissue. The immune-mediated tissue injury, in turn, is known to depend on complex interactions between genetic and environmental factors. Nevertheless, the mechanisms whereby environmental factors contribute to the pathogenesis of autoimmune diseases remain elusive and represent a major untapped target to develop novel strategies for disease prevention. Given the impact of the early environment on the developing immune system, epigenetic changes induced by maternal factors during fetal life have been linked to a likelihood of developing an autoimmune disease later in life. In humans, DNA methylation is the epigenetic mechanism most extensively investigated. This review provides an overview of the critical role of DNA methylation changes induced by prenatal maternal conditions contributing to the increased risk of immune-mediated diseases on the offspring, with a particular focus on T1D. A deeper understanding of epigenetic alterations induced by environmental stressors during fetal life may be pivotal for developing targeted prevention strategies of type 1 diabetes by modifying the maternal environment.

show abstract

Genetic and environmental factors regulate the type 1 diabetes gene CTSH via differential DNA methylation

Cited by 11 publications

References 43 publications

Gene-environment interaction in the pathophysiology of type 1 diabetes

Gene-environment interaction in the pathophysiology of type 1 diabetes

Alu Methylation Patterns in Type 1 Diabetes: A Case-Control Study

Epigenetic Changes Induced by Maternal Factors during Fetal Life: Implication for Type 1 Diabetes

Contact Info

Product

Resources

About