Aetiological differences between novel subtypes of diabetes derived from genetic associations

BackgroundType 2 diabetes (T2D) is a multi-organ disease defined by hyperglycemia resulting from different disease mechanisms. Using clinical parameters measured at diagnosis (age, BMI, HbA1c, HOMA2-B, HOMA2-IR and GAD autoantibodies) adult patients with diabetes have been reproducibly clustered into five subtypes, that differed clinically with respect to disease progression and outcomes.1 In this study we use genetic information to investigate if these subtypes have distinct underlying genetic drivers. MethodsGenome-wide association (GWAS) and genetic risk score (GRS) analysis was performed in Swedish (N=12230) and Finnish (N=4631) cohorts. Family history was recorded by questionnaires. ResultsSevere insulin-deficient diabetes (SIDD) and mild obesity-related diabetes (MOD) groups had the strongest family history of T2D. A GRS including known T2D loci was strongly associated with SIDD (OR per 1 SD increment [95% CI]=1.959 [1.814-2.118]), MOD (OR 1.726 [1.607-1.855]) and mild age-related diabetes (MARD) (OR 1.771 [1.671-1.879]), whereas it was less strongly associated with severe insulin-resistant diabetes (SIRD, OR 1.244 [1.157-1.337]), which was similar to severe autoimmune diabetes (SAID, OR 1.282 [1.160-1.418]). SAID showed strong association with the GRS for T1D, whereas the non-autoimmune subtype SIDD was most strongly associated with the GRS for insulin secretion rate (P<7.43x10-9). SIRD showed no association with variants in TCF7L2 or any GRS reflecting insulin secretion. Instead, only SIRD was associated with GRS for fasting insulin (P=3.10x10-8). Finally, a T2D locus, rs10824307 near the ZNF503 gene was uniquely associated with MOD (ORmeta=1.266 (1.170-1.369), P=4.3x10-9). ConclusionsNew diabetes subtypes have partially different genetic backgrounds and subtype-specific risk loci can be identified. Especially the SIRD subtype stands out by having lower heritability and less involvement of beta-cell related pathways in its pathogenesis. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSIn March 2018 we suggested a novel subclassification of diabetes into five subtypes. This classification was based on clustering using clinical parameters commonly measured at diabetes diagnosis (age at diabetes onset, HbA1c, bodymass index, presence of GAD autoantibodies and HOMA2 indices for insulin resistance and secretion). These subtypes differed with respect to clinical characteristics, disease progression and risk of complications, but it remained unclear to what extent these subtypes have different underlying pathologies. In our original publication we analysed a small set of genetic risk variants for diabetes and found differential associations between subtypes, suggesting potential aetiological differences. Added value of this studyIn this study we have conducted a full genome analysis of the original ANDIS cohort, including genome-wide association studies and polygenic risk score analysis with replication in an independent cohort. We have also compared heritability and prevalence of having a family history of diabetes in the subtypes. Implications of all the available evidenceWe demonstrate that stratification into subtypes facilitates identification of genetic risk loci and that the aetiology of the subtypes is at least partially distinct. These results are especially important for the future study and treatment of individuals belonging to the severe insulin-resistant diabetes (SIRD) subtype, whose pathogenesis appears to differ substantially from that of traditional T2D.