Feature ranking of type 1 diabetes susceptibility genes improves prediction of type 1 diabetes

Winkler, Christiane; Krumsiek, Jan; Buettner, Florian; Angermüller, Christof; Giannopoulou, Eleni Z.; Theis, Fabian J.; Ziegler, Anette‐Gabriele; Bonifacio, Ezio

doi:10.1007/s00125-014-3362-1

Cited by 118 publications

(139 citation statements)

References 29 publications

Supporting

Mentioning

134

Contrasting

Unclassified

Order By: Relevance

“…Cyp27b1 is required for the synthesis of 1,25-OH vitamin D3, and evidence suggests that it participates in β-cell dysfunction in diabetes43. Finally, there were two transcripts that showed opposite changes in wild-type versus Foxo-deficient ALDH + cells: the lncRNA Peg3, a parentally imprinted transcript whose methylation correlates with human islet function44, and Bach2, a transcription factor that has been implicated in type 1 diabetes susceptibility4546, as well as β-cell stress47 (Table 4 and Supplementary Table 5). …”

Section: Resultsmentioning

confidence: 99%

Aldehyde dehydrogenase 1a3 defines a subset of failing pancreatic β cells in diabetic mice

et al. 2016

View full text Add to dashboard Cite

Insulin-producing β cells become dedifferentiated during diabetes progression. An impaired ability to select substrates for oxidative phosphorylation, or metabolic inflexibility, initiates progression from β-cell dysfunction to β-cell dedifferentiation. The identification of pathways involved in dedifferentiation may provide clues to its reversal. Here we isolate and functionally characterize failing β cells from various experimental models of diabetes and report a striking enrichment in the expression of aldehyde dehydrogenase 1 isoform A3 (ALDH+) as β cells become dedifferentiated. Flow-sorted ALDH+ islet cells demonstrate impaired glucose-induced insulin secretion, are depleted of Foxo1 and MafA, and include a Neurogenin3-positive subset. RNA sequencing analysis demonstrates that ALDH+ cells are characterized by: (i) impaired oxidative phosphorylation and mitochondrial complex I, IV and V; (ii) activated RICTOR; and (iii) progenitor cell markers. We propose that impaired mitochondrial function marks the progression from metabolic inflexibility to dedifferentiation in the natural history of β-cell failure.

show abstract

Section: Resultsmentioning

confidence: 99%

Aldehyde dehydrogenase 1a3 defines a subset of failing pancreatic β cells in diabetic mice

et al. 2016

View full text Add to dashboard Cite

show abstract

“…In fact, only 4 SNPs, 2 tagging HLA (DR3 and DR4), and one each in the insulin and CTLA4 genes, can give a clinically relevant predictive value (receiver operating characteristic AUC ¼ 0.72) to predict the highest risk T1D patients for potential intervention [119]. A model incorporating up to 40 SNPs was able to achieve even greater predictive value (AUC ¼ 0.87) [120]. However, the highest-risk HLA genotype in Europeans, HLA-DR3/4, only accounts for a maximum of about 40% of patients.…”

Section: Genetic Prediction Of T1dmentioning

confidence: 91%

Immunogenetics of type 1 diabetes: A comprehensive review

Noble¹

2015

Journal of Autoimmunity

175

160

View full text Add to dashboard Cite

“…We (19) were more optimistic than Clayton (18) and demonstrated a definite improvement in trial design if additional genetic markers were added to HLA and family history to define eligibility for a primary prevention trial. Admittedly, much of the predictive power comes from HLA DR-DQ genotyping.…”

Section: Hla and Family History Are Proven Markersmentioning

confidence: 99%

Predicting Type 1 Diabetes Using Biomarkers

2015

Self Cite

View full text Add to dashboard Cite

Clinical type 1 diabetes is preceded by an asymptomatic phase that can be identified by serum islet autoantibodies. This perspective proposes that there is now sufficient evidence to allow a broader use of islet autoantibodies as biomarkers to diagnose type 1 diabetes that is already at an asymptomatic stage, so that attempts to prevent clinical hyperglycemia become a feature of disease management. Prediction would first, therefore, shift toward the use of genetic and other biomarkers to determine the likelihood that islet autoimmunity will develop in an infant, and second, toward metabolic assessment to stage and biomarkers to determine the rate of progression to hyperglycemia in children in whom islet autoimmunity is diagnosed. A case is presented for future comprehensive risk assessment that commences at birth and includes attempts to predict, stage, and prevent initiation and progression of the disease process at multiple stages. The biomarkers required achieving this level of sophistication and dissemination are discussed.

show abstract

Feature ranking of type 1 diabetes susceptibility genes improves prediction of type 1 diabetes

Abstract: We provided a weighted risk model with selected SNPs that could be considered for recruitment of infants into studies of early type 1 diabetes natural history or appropriately safe prevention.

Cited by 118 publications

References 29 publications

Aldehyde dehydrogenase 1a3 defines a subset of failing pancreatic β cells in diabetic mice

Aldehyde dehydrogenase 1a3 defines a subset of failing pancreatic β cells in diabetic mice

Immunogenetics of type 1 diabetes: A comprehensive review

Predicting Type 1 Diabetes Using Biomarkers

Contact Info

Product

Resources

About