GENOMICS
preclinical T1D as this is highly predictive of progression to T1D and severe insulin deficiency.7
T1D is associated with significant heritable risk. Monozygotic twin concordance is estimated to be around 50%, while risk in first degree relatives is around 6%.8
Around half of this risk is
attributed to human leucocyte antigen (HLA) class II alleles, specifically DR and DQ genes on chromosome 6. HLA class I alleles have been independently associated with T1D development after adjusting for HLA Class II risk. Additionally, more than 70 non-HLA T1D risk variants, mostly single nucleotide polymorphisms (SNPs), have been described.9
Non-HLA variants have only
The misdiagnosis of T2D as T1D leads to unnecessary insulin therapy, higher drug and monitoring expenses and, in some cases, an increase in number and severity of symptoms.
risk scores (GRS), like those described here, may provide novel methods to help identify those at risk of T1D and to improve discrimination between subtypes of diabetes.
Type 1 diabetes
T1D is a polygenic, autoimmune disease characterised by hyperglycaemia that causes the destruction of the β-cells of the pancreatic islets and ultimately severe insulin deficiency, estimated to affect over eight million people worldwide.4
The
highest prevalence of T1D is seen in white populations, but rates are climbing rapidly in populations of African and Hispanic ancestry.5
T1D pathogenesis is not fully
understood. However, it has been shown that genetic risk, β-cell stress, diet, environment, and immune phenotype collectively contribute to autoimmunity and T1D development.6
The immune-mediated destruction of
β-cells begins when macrophages and dendritic cells present antigens from pancreatic β-cells to naïve CD4+ T cells via the major histocompatibility complex (MHC). This event triggers cytokine signalling, activating CD4+ T cells, which in turn stimulate CD8+ T cells, the direct agents of β-cell destruction. As β-cells are destroyed, more intracellular antigens are released, granting antigen-presenting cells access to previously inaccessible auto-antigens. This leads to the activation of more autoreactive T cells through a phenomenon known as epitope spreading. The progressive destruction of β-cells results in a critical reduction
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in insulin production, leading to insulin deficiency and the consequent inability to transport glucose from the bloodstream into cells.
The measurement of individual islet autoantibodies (AAbs) is the standard method of T1D identification as described in the 2021 consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).7
Glutamic
acid decarboxylase (GAD) antibodies are investigated initially and are detected in 50-80% of white patients newly diagnosed with T1D.8
If negative, this
is followed by analysis of islet tyrosine phosphatase-related islet antigen 2 (IA2) and/or zinc transport 8 (ZnT8). The prevalence of IA-2 and ZnT8 in newly diagnosed T1D patients is 55-75% and 60-80%, respectively.8
The absence
of these AAbs does not rule out T1D; approximately 5-10% of white Europeans with new-onset T1D test negative for these AAbs.7
However, patients who
test positive for one or more of these AAbs, in the absence of other clinical factors, should be considered to have
modest individual effects, however, when combined with the other known risk alleles, they may significantly contribute to overall risk. Most extensive studies of T1D genetic risk loci are limited to white European populations, however, there is known heterogeneity across risk loci in populations of different ancestry.5 Environmental factors are thought to play a significant role in the development of T1D. Rates of T1D are rising too rapidly to be attributed to genetics alone. This is thought to be partly due to an increase in successful treatment strategies, meaning natural selection is not playing as large a role. Further, prevalence rates vary even in populations of similar ancestry, suggesting risk is not attributable to genetics alone.10 Environmental factors thought to play a role in T1D development include but are not limited to, viral infections, particularly of human enteroviruses, changes in the microbiome, and diet.11
Early identification of those at risk of T1D is essential to facilitate their inclusion in monitoring and prevention trials, aid studies of the mechanisms involved in the preclinical stages and progression to clinical T1D, and to identify those who will benefit from disease-modifying therapies. However, the current methods of prediction, such as islet AAb status along with metabolic markers, namely C-peptide, are known to change throughout disease progression and are only available at the advanced stages of the autoimmune process.7
Unlike immunologic and metabolic markers of T1D, genetic risk does not change over time. Therefore, a GRS or CRS, like those described, could be included in newborn or population screening to identify those at the highest risk of developing clinical disease
OCTOBER 2024
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