Disease-causing variants in key immune homeostasis genes can lead to monogenic autoimmune diabetes. Some individuals carrying disease-causing variants do not develop autoimmune diabetes, even though they develop other autoimmune disease. We aimed to determine whether type 1 diabetes polygenic risk contributes to phenotypic presentation in monogenic autoimmune diabetes. We used a 67 SNP type 1 diabetes genetic risk score (T1D-GRS) to determine polygenic risk in 62 individuals with monogenic autoimmune diabetes and 180 non-autoimmune neonatal diabetes (NDM) controls. We used population-based controls (n=10,405) and individuals with type 1 diabetes (n=285) as a comparator. Individuals with monogenic autoimmune diabetes had higher T1D-GRSs compared to non-autoimmune NDM (mean 11.3 vs. 9.8; P=1.7×10-5) and controls (mean 10.3; P=7.5×10-6) but were markedly lower than type 1 diabetes (14.9; P= 3.3 × 10-21). These differences were explained by monogenic autoimmune diabetes cases having higher Class II HLA genetic risk, specifically from the DRB1*03:01-DQA1*05:01-DQB1*02:01 haplotype (DR3-DQ2) (P<0.01). In the presence of monogenic autoimmunity, the polygenic class II HLA susceptibility contributes to development of autoimmune diabetes. This suggests a role of class II HLA in targeting the dysregulated immune response towards the beta-cell.
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http://dx.doi.org/10.2337/db24-0485 | DOI Listing |
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