**2.2 Genetics**

Relatives of patients with T1D are at increased risk of developing T1D compared to the general population [21]. Human leukocyte antigen (HLA) has been shown to be a major genetic determinant in the development of T1D, accounting for approximately 50% of genetic risk [22, 23]. HLA class II alleles DR04, DR03, and homozygous DR04/DR03 genotypes increase the risk of T1D, while DR02 is highly protective against the disease [23]. Currently, genetic risk screening for T1D is performed by HLA-genotyping. However high-risk HLA genotypes are only present in 30–40% of T1D patients. Suggesting that HLA genotyping is too insufficient in sensitivity and specificity to be a useful T1D marker [6, 7]. While the HLA locus encodes for the strongest genetic susceptibility genes for T1D, there are five other non-HLA gene regions also associated with the disease: INS, CTLA-4, PTPN22, SUMO4, IL2RA, and IFIH1 (**Table 2**) [21, 27, 29].

Individually, non-HLA genes only weakly contribute to the assessment of risk for T1D. However, when used in combination, non-HLA genes may prove to have more predictive value [2]. Among the non-HLA genes, the INS VNTR has the strongest association with T1D [21]. The working theory is polymorphisms in the INS gene may lead to immune tolerance to insulin by changing the amount of insulin mRNA in the thymus during fetal development and childhood [30]. Similar polymorphisms


*HLA: human leukocyte antigen, VNTR: variable number of tandem repeats, CTLA4: cytotoxic T-lymphocyte associated protein 4, PTPN22: protein tyrosine phosphatase 22, SUMO: small ubiquitin-like modifier, GRS: genetic risk score, AUC: area under the curve*
