ESPE Yearbook of Paediatric Endocrinology

Brief summary: This review article discusses the influence of genetics on type 1 diabetes (T1D), particularly with regard to differences across diverse genetic ancestries, and the development of validated genetic risk scores (GRS) for use various populations. These may contribute to disease prevention and treatment.

The autoimmune destruction of pancreatic beta cells is triggered by the interaction of genetic predisposition and environmental factors. T1D has a major genetic risk factor, the human MHC on chromosome 6p21.3 with HLA class I and class II genes contributing 33–50% of genetic risk. As a result, there is an increased interest in developing genetic risk scores (GRS) for non-European individuals by improving methodology and mapping for global populations. By review of published literature, including the Type 1 Diabetes Genetics Consortium (T1DGC), a study examining the genetics of T1D includes African ancestry and multi-ethnic samples, shows that the primary risk allele in Asian individuals is HLA-DR3 with HLA-DR4 conferring lower risk, the opposite of that seen in Europeans. The findings are similar in India. A protective African-specific HLA-DR3 haplotype has been identified in non-Hispanic Black individuals and despite conferring protection in European populations, HLA-DR7 confers risk in this population. Hispanic individuals in the US have a stronger association with HLA-DR3 than non-Hispanic individuals, but the complexity of this demographic makes it difficult to describe as a single population.

The goal of GRS is to predict future disease and is dependent on the amount of heritable risk captured by association with genetic variants. GRS-1 and GRS-2 perform well in European populations. In a US sample, GRS-1 performed well in Hispanic and non-Hispanic While individuals, but not in non-Hispanic Black individuals. Other GRS have been developed in Japan and included non-HLA variants to improve differentiation. A GRS developing using information from African ancestry risk alleles show strong performance in individuals of African ancestry and outperformed a larger GRS of European ancestry. Overall, the development of a cross-population GRS for T1D remains an ongoing challenge with an ideal solution being a unified model that performs well regardless of ancestry. Improved knowledge of genetic factors in T1D will enable more detailed evaluation of currently unknown factors that initiate T1D and allow for improved and equitable care.