Type 1 Diabetes Genetic Risk Score Differentiates Subgroups of Ketosis-Prone Diabetes

Abstract

OBJECTIVE To determine whether genetic risk for type 1 diabetes (T1D) differentiates the four Aβ subgroups of ketosis-prone diabetes (KPD), where A+ and A− define the presence or absence of islet autoantibodies and β+ and β− define the presence or absence of β-cell function. RESEARCH DESIGN AND METHODS We compared T1D genetic risk scores (GRSs) of patients with KPD across subgroups, race/ethnicity, β-cell function, and glycemia. RESULTS Among 426 patients with KPD (54% Hispanic, 31% African American, 11% White), rank order of GRS was A+β− > A+β+ = A−β− > A−β+. GRS of A+β− KPD was lower than that of a T1D cohort, and GRS of A−β+ KPD was higher than that of a type 2 diabetes cohort. GRS was lowest among African American patients, with a similar distribution across KPD subgroups. CONCLUSIONS T1D genetic risk delineates etiologic differences among KPD subgroups. Patients with A+β− KPD have the highest and those with A−β+ KPD the lowest GRS.

Atypical Diabetes: What Have We Learned and What Does the Future Hold?

“…A−β− KPD also resembles T1D, but does not have detectable islet autoantibodies. Additionally, A−β− KPD harbors a lower frequency of T1D-associated HLA susceptibility alleles ( 51 , 52 ), and demonstrates a lower T1D genetic risk score ( 53 ). Importantly, many patients with A−β− KPD either harbor pathogenic variants in essential β-cell transcription factors or demonstrate occult (T cell–mediated) islet autoimmunity ( 54 , 55 ).…”