Type 1 Diabetes Genetic Risk Contributes to Phenotypic Presentation in Monogenic Autoimmune Diabetes

Abstract

There is variability in early-onset autoimmune diabetes presentation in individuals with monogenic autoimmunity; the mechanism(s) underlying this is unclear. We examined whether type 1 diabetes (T1D) polygenic risk contributes to clinical phenotype in monogenic autoimmune diabetes. Individuals with monogenic autoimmune diabetes had higher T1D genetic risk scores compared with control cohorts, driven largely by increased presence of T1D-risk DR3-DQ2 haplotype. Established T1D polygenic risk alleles, particularly class II HLA genes, contribute to clinical presentation in monogenic autoimmunity.

Graphical abstract

Figure 1

T1D-GRS in monogenic diabetes cohorts and control cohorts. Violin plot of distributions of T1D-GRS. Black dot, mean GRS. ***P < 0.001. Error bars, 95% CIs. P values were determined from logistic regression.

Figure 2

Contribution of class II HLA T1D-GRS and non-HLA T1D-GRS. Error bars, 95% CIs. Individuals with monogenic autoimmune diabetes had higher class II HLA T1D-GRSs compared with nonautoimmune NDM (P = 2.8 × 10⁻⁴) and control participants (P = 8.2 × 10⁻⁵). The class II HLA T1D-GRS for type 1 diabetes was higher than monogenic autoimmune diabetes (P = 1.1 × 10⁻¹³). P values were determined from logistic regression.

Figure 3

DR3-DQ2 HLA allele frequency in monogenic diabetes cohorts and control cohorts. ***P < 0.001, **P < 0.01. Error bars, SEs. The high type 1 diabetes risk DR3-DQ2 haplotype had a higher frequency in the monogenic autoimmune diabetes group compared with nonautoimmune NDM group and control group but was lower compared with type 1 diabetes group. P values were determined from logistic regression.