Genetics and its potential to improve type 1 diabetes care

Abstract

Purpose of review: The genetic basis of type 1 diabetes (T1D) is being characterized through DNA sequence variation and cell type specificity. This review discusses the current understanding of the genes and variants implicated in risk of T1D and how genetic information can be used in prediction, intervention and components of clinical care.

Recent findings: Fine mapping and functional studies has provided resolution of the heritable basis of T1D risk, incorporating novel insights on the dominant role of human leukocyte antigen (HLA) genes as well as the lesser impact of non-HLA genes. Evaluation of T1D-associated single nucleotide polymorphisms (SNPs), there is enrichment of genetic effects restricted to specific immune cell types (CD4 and CD8 T cells, CD19 B cells and CD34 stem cells), suggesting pathways to improved prediction. In addition, T1D-associated SNPs have been used to generate genetic risk scores (GRS) as a tool to distinguish T1D from type 2 diabetes (T2D) and to provide prediagnostic data to target those for autoimmunity screening (e.g. islet autoantibodies) as a prelude for continuous monitoring and entry into intervention trials.

Summary: Genetic susceptibility accounts for nearly one-half of the risk for T1D. Although the T1D-associated SNPs in white populations account for nearly 90% of the genetic risk, with high sensitivity and specificity, the low prevalence of T1D makes the T1D GRS of limited utility. However, identifying those with highest genetic risk may permit early and targeted immune monitoring to diagnose T1D months prior to clinical onset.

Fig 1

A model for the progression to type 1 diabetes (T1D) The stage of progression in type 1 diabetes, shown with individuals having a baseline genetic risk (accounting for ~50% of total risk, with half of the genetic risk due to HLA gene variation), but with progression to the subsequent stages of disease defined by individual genetic factors (some that could be consistent across all stages, but with differing impact), leading to clinically defined T1D. Source: adapted from [4].

Fig 2

T1D loci mapped by studies during a “genomic era” The size of the effect (Odds ratio) of each locus on T1D risk using genome-wide association studies (GWAS), defined by the most significantly associated SNP and the location of that SNP (either in or near a likely candidate gene). The early era (blue, 1970–2000) is characterized by discovery of genes with large (Odds ratio > 2) effects that can be found with small sample sizes or in families. The second era (green, 2001–2006) included discovery of genes with smaller effect that required larger sample size (PTPN22, CTLA4) or scans of nonsynonymous SNPs (coding variation, IFIH1). The third era (red, 2007–2008) was the entry into large case-control studies with genome-wide coverage, led by the Wellcome Trust Case-Control Consortium (2,000 cases of 7 diseases compared to 3,000 common controls), in which more loci with small effects were identified. The recent era (yellow, 2009–present) established large consortia (Type 1 Diabetes Genetics Consortium) in which ever larger sample sizes permitted detection of loci with small effects (OR < 1.1) but potentially discovering important biology. Source: adapted from [18]