A functional framework for interpretation of genetic associations in T1D

Abstract

Susceptibility to type 1 diabetes is attributable to genes that link disease progression to distinct steps in immune activation, expansion, and regulation. Recent studies illustrate examples of disease-associated variants that function in multiple cell types and independent pathways, some that impact different steps of a single mechanistic pathway, and some that are functionally interactive for deterministic events in setting thresholds for immune response.

Figure 1. A susceptibility gene can affect multiple pathways

PTPN22 variants that are associated with T1D and other autoimmune diseases account for blunted signaling, as shown in plots of calcium flux for human B cells (left) and T cells (right), adapted from Rieck et al. [45]. The grey lines indicate individuals carrying the 1858T variant, demonstrating reduced BCR- and TCR-mediated calcium mobilization after stimulation with anti-IgM or anti-CD3, respectively.

Figure 2. Building blocks of T1D susceptibility

T1D, like most other autoimmune diseases, occurs predominantly on a background of genetic susceptibility that is a result of several genetic elements. Presence of a high risk genotype, such as HLA-DQB1*03:02/*02:01 is sufficient to pass a susceptibility threshold (A, left panel). An alternative scenario involves multiple genes, each with moderate contributions to functional pathways, which in combination surpass the threshold barrier (A, middle panel). The most common combination of genetic risk in T1D is represented by the third model, in which HLA contributes most of the risk, but other cumulative contributions from moderate risk genes also participate (A, right panel). Functional mechanisms that facilitate the generation, survival, and activation of autoreactive cells are represented in (B), illustrating the concept that multiple steps in the progression of autoimmune disease are required and are cumulative or synergistic in reaching a clinical threshold. Specific genetic variation is tied to particular steps in this functional progression, as indicated in the speculative, but plausible, relationships shown in (C).

Figure 3. Classification of T1D susceptibility genes

The examples discussed in the text illustrate different categories of genotype-phenotype relationships: (i) those genes that function in the same mechanistic pathway, such as CD25 and PTPN2; (ii) those genes that alter function in multiple different pathways or cells, such as PTPN22; (iii) those genetic variants that independently arise in the same gene but similarly affect function; and (iv) those that combine to establish key immunological thresholds, such as HLA and INS in thymic selection of proINS specific T cells.