Genetic risk in extremely early onset type 1 diabetes

Area of Science:

• Immunogenetics
• Pediatric Endocrinology
• Genetic Epidemiology

Background:

• Early identification of type 1 diabetes (T1D) risk, particularly for very early onset (<2 years), is vital to prevent severe diabetic ketoacidosis (DKA).
• Genetic variations, especially within the Human Leukocyte Antigen (HLA) complex, are known contributors to T1D susceptibility.
• Heterogeneity in T1D onset age suggests underlying genetic influences that warrant further investigation.

Purpose of the Study:

• To investigate the contribution of genetic variation to the heterogeneity of T1D onset age.
• To specifically analyze genetic associations in individuals diagnosed with T1D before the age of 2 years.
• To evaluate the utility of a 67 single nucleotide polymorphism (SNP) T1D genetic risk score (T1D-GRS) for screening very early onset T1D.

Main Methods:

• Association testing was performed on 6773 individuals with T1D, stratifying by age of onset (<2, 2-7, 7-13, 13+ years).
• Heterogeneity in HLA variants was analyzed across these age groups.
• A 67 SNP T1D-GRS was calculated for each individual to quantify aggregated genetic risk.

Main Results:

• Higher T1D-GRS values were observed with decreasing age of T1D onset.
• DR3-DQ2 homozygosity showed the strongest association with T1D onset <2 years (log-OR=4.27).
• The T1D-GRS demonstrated high discriminative ability for T1D onset <2 years (AUC=0.94), identifying 88% of cases at the 85th population centile.

Conclusions:

• Increased genetic risk is associated with very early onset T1D.
• T1D-GRS shows significant potential for screening newborns, particularly for identifying those at risk of younger T1D onset.
• Genetic risk stratification may improve early detection and management of T1D.