The Missing Heritability in T1D and Potential New Targets for Prevention

Abstract

Type 1 diabetes (T1D) is a T cell-mediated disease. It is strongly associated with susceptibility haplotypes within the major histocompatibility complex, but this association accounts for an estimated 50% of susceptibility. Other studies have identified as many as 50 additional susceptibility loci, but the effect of most is very modest (odds ratio (OR) <1.5). What accounts for the “missing heritability” is unknown and is often attributed to environmental factors. Here we review new data on the cognate ligand of MHC molecules, the T cell receptor (TCR). In rats, we found that one allele of a TCR variable gene, Vβ13A, is strongly associated with T1D (OR >5) and that deletion of Vβ13+ T cells prevents diabetes. A role for the TCR is also suspected in NOD mice, but TCR regions have not been associated with human T1D. To investigate this disparity, we tested the hypothesis in silico that previous studies of human T1D genetics were underpowered to detect MHC-contingent TCR susceptibility. We show that stratifying by MHC markedly increases statistical power to detect potential TCR susceptibility alleles. We suggest that the TCR regions are viable candidates for T1D susceptibility genes, could account for “missing heritability,” and could be targets for prevention.

Missing heritability of common diseases and treatments outside the protein-coding exome

“…Taking the view that drug therapy is but one example of new environmental stressors, variable drug response can also be accounted for by frequent variants in key genes, in addition to less frequent mutations with strong effect on disease and treatment outcomes, and specifically adverse drug effects. New therapies and preventions are likely to emerge with the insights gained from resolving outstanding genomics questions (Okada et al 2014; Pierce et al 2013). …”

“…As a consequence, therapy of full-blown disease is symptomatic and palliative rather than curative, whereas early intervention could prevent or reverse disease progression. Predicting disease risk and optimal type of therapy therefore has the potential for substantial improvements in health care (Pierce et al 2013). …”

Haplotype Analysis of the T-Cell Receptor Beta (TCRB) Locus by Long-amplicon TCRB Repertoire Sequencing

“…First, the T-cell receptor (TCR) locus is repetitive and structurally complex, impeding the measurement of variation by traditional short-read WGS or microarray-based methods; [4] second, single amino acid substitutions within the framework or CDR 1 and 2 regions of the rearranged TCRB chain are known to significantly alter TCR affinity for HLA; [5][6][7] and third, adverse events during immunotherapy may manifest as acute versions of chronic autoimmune diseases that have been separately linked to TRBV and HLA polymorphism. [8][9][10][11][12][13][14][15][16][17] These ranges from common and typically manageable cutaneous IRAEs such as eczema, pruritus, and vitiligo, where the evidence supports a role for autoreactive resident memory T cells, to rare and severe IRAEs such as fulminant type 1 diabetes, where comparatively less is understood with respect to the potentially causative T-cell populations. Of note, germline-encoded polymorphism in the cytotoxic T-lymphocyte-associated antigen 4 and programmed death-1 pathways has already been linked to autoimmune disease, [18,19] highlighting the potential mechanistic link between CPI-mediated IRAEs and chronic autoimmune disease.…”

Genetic Variation Within the HLA-DRA1 Gene Modulates Susceptibility to Type 1 Diabetes in HLA-DR3 Homozygotes

“…Although HLA genotyping can identify most persons at risk for T1D, only 1 in 15 (;7%) of individuals with even the highest risk HLA genotype (HLA-DR3/4) become diabetic (6). Recent genetic studies have improved our ability to predict T1D in the general population (7), but additional genetic risk likely remains to be discovered (8). Understanding of the detailed genetic risk conferred by HLA-DR and -DQ remains incomplete.…”