Clinical utility of T1DM susceptibility genes
One of the goals of genetic studies of complex disease is to identify a profile of susceptibility variants that can be used to predict an individual’s risk of developing a given disease. The long prodrome for T1DM, characterized by progressive loss of β-cell mass, provides an attractive opportunity for intervention to prevent disease development if “at-risk” individuals can be identified. Currently the best markers of disease risk are a positive family history of T1DM and the presence of autoantibodies to islet cell proteins. Over 90% of T1DM patients have no affected relatives, however, so effective preventive efforts will need to target the general population. Unfortunately screening such huge numbers of individuals for islet autoantibodies is logistically unfeasible, particularly given the need for repeated annual testing for those with a negative result. Genetic markers are therefore needed to stratify risk in the general population,
to significantly decrease the target population for immunologic screening while still capturing the majority of future cases of T1DM. HLA class II genes have been widely used in research studies to identify high-risk individuals (see later), but testing for HLA alleles alone lacks specificity, sensitivity, and positive predictive value, limiting its use in disease prediction at a population level. Incorporating genotype data for susceptibility SNPs outside the MHC improves prediction slightly but it has been suggested that even if all risk loci were discovered and included in the prediction model, the achievable predictive power might still be inadequate to reliably select individuals from the general population for targeted intervention .
Although the HLA genes may have limited utility in large-scale population screening for disease prevention, they are useful markers for stratifying disease risk in research studies. Birth cohorts examining the natural history of T1DM and the impact of environmental determinants on disease development, such as Diabetes Autoimmunity Study in the Young (DAISY), BABYDIAB, and The Environmental Determinants of Diabetes in the Young (TEDDY), use HLA typing to identify newborns in the general population with high and moderate genetic risk of disease and to stratify risk in children with a family history of T1DM [15,59,60]. High genetic risk is defined by the DR3.DQ2/DR4.DQ8 genotype, while moderate risk is conferred by genotypes carrying one of these high risk haplotypes, in the absence of DR15.DQ6. Children positive for DR3.DQ2/DR4.DQ8 have a 5% risk of developing T1DM by the age of 15 years . If they also have an HLA-identical sibling with T1DM, the risk is even higher; a 65% risk of developing islet autoimmunity by the age of 7 years and a 55% risk of developing T1DM by the age of 12 years . In contrast, the presence of the highly protective DR15.DQ6 haplotype markedly reduces disease risk, even among individuals with a family history of disease and evidence of islet autoimmunity . HLA genes are also valuable tools for selecting high-risk individuals for trials of novel preventive strategies for T1DM, such as the PrePOINT trial of autoantigen vaccination with oral insulin (http://www.diabetes-point.org) and the TRIGR study of dietary intervention in infancy (http://trigr.epi.usf.edu).
One of the major benefits of the genetic studies of T1DM is the improved understanding of the immune dysregulation underlying the disease. Both innate and T cell-mediated adaptive immunity are implicated by genetic association studies and functional analyses of disease susceptibility variants suggest that impairment of autoantigen-driven TCR signaling and inefficient negative selection of autoreactive T cells are important mechanisms in the development of autoimmunity. To date, the majority of functional studies have been performed on candidate genes but extension of this approach to the large number of loci identified by GWAS will likely yield further useful information on the molecular pathways involved in disease development and provide valuable insight into the mechanisms underlying T-cell tolerance. Such information may identify novel therapeutic targets for the prevention of T1DM. As shown by PPARγ in type 2 diabetes, a gene does not have to have a large effect on disease risk to be a good target for drug treatment. In this vein, there is currently considerable interest in developing inhibitors of LYP, to treat a range of autoimmune diseases , and compounds able to manipulate thymic insulin expression, which would have therapeutic potential in the treatment of T1DM .
Although considerable progress has been made in recent years to further our understanding of the genetic basis of type 1 diabetes, there is still a substantial proportion of inherited susceptibility that is, as yet, unexplained. Furthermore the causal variants at most of the validated risk loci remain to be identified, as do the mechanisms by which they influence disease risk. Future research aiming to address these gaps in our knowledge should integrate multiple approaches, including sequence-based fine mapping, whole-exome/whole-genome sequencing to identify rare variants, transcriptomics and mechanistic studies, gene network and pathway analysis, epigenetic regulation of gene function and the analysis of gene–gene and gene–environment interactions. Such studies may identify new therapeutic targets for T1DM and/or markers of extreme genetic risk that can be utilized in targeted primary prevention.