Type 1 diabetes (T1D), additionally referred to as insulin-dependent diabetes, is a disorder or a chronic situation characterized by substantially high blood sugar levels due to little or lack of insulin manufacturing by the pancreas. Insulin hormone is necessary for the absorption of sugar into the cells for strength production. A broad range of factors, together with some viruses and genetics, may contribute to an individual’s T1D condition. Although T1D typically occurs during adolescence, it may additionally also develop in adult. The preliminary symptoms or signs of T1D end result from high blood sugar levels and might also include excessive thirst (polydipsia), time-honored urination (polyuria), blurred vision, fatigue, tingling in the hands and feet, and loss of weight (Ikegami, Babaya, & Kawabata, 2011). This paper gives a summary of how type 1 diabetes relates to genetics.
Type I diabetes (T1D) can be described as a complex, multigenetic condition or disease. The initial reports of T1D’s association with genetics emerged from the human leukocyte antigen (HLA) region. About four decades since that discovery, biologists have made significant steps in determining the HLA-encoding genes and alleles responsible for T1D’s genetic association, as well as other genetic loci that contribute to T1D risk (Bluestone, Atkinson, & Arvan, 2012). One of such studies relates to the type 1 Diabetes Genetics Consortium. The T1DGC may be defined as a global collaboration intended to create diversity and sufficient size repository for identifying all the genetic loci responsible for T1D risk. The T1DGC involved the collection and genotyping of more than 14,000 samples. However, the HLA association remained the strongest of all the T1D associated genes and gene regions identified by all the studies (Bluestone, Atkinson, & Arvan, 2012).
The second strongest T1D genetic association, after HLA, comes from polymorphism located in the insulin gene’s promoter region (OR = 2.38). Apart from HLA and polymorphism, only two other loci, IL2RA and PTPN22, have ORs higher than 1.5 (Hemminki, 2012). Most of the loci identified have ORs ranging between 1.1 and I.3, which makes the HLA region the most important for associating T1D with genetics. Therefore, all studies relating to T1D’s genetic susceptibility have to consider HLA when interpreting any form of T1D genetic association data. Due to that reason, this paper focuses mainly on HLA-encoding genes in summerizing the relationship between type 1 diabetes and genetics (Hemminki, 2012).
The HLA’s function in guiding the immune response indicates a role for HLA in both autoimmune disease and the immune response to environmental pathogens (Hemminki, 2012). The significance of HLA typing in studies relating to disease association got identified during the 1970s and HLA has been involved in the etiology of over 100 diseases, including various complex autoimmune conditions, such as rheumatoid arthritis, type 1 diabetes, and a broad range of infectious diseases, including malaria (Hemminki, 2012).
Determining HLA associations with T1D tend to be complicated due to the extremely high reported number of alleles at the HLA genetic loci, as well as the variations in frequencies and haplotypic combinations of allele among populations (Ikegami, Babaya, & Kawabata, 2011). The complication may also result from the HLA’s interactions with other susceptibility factors and the HLA susceptibility loci’s incomplete penetrance. Research into the HLA association with T1D has been in progress for about forty years, and most of such studies have been using Caucasian subjects to link HLA with type 1 diabetes. Although researchers have made great advancement, there is still more to explore, particularly regarding the non-Caucasian populations (Ikegami, Babaya, & Kawabata, 2011).
Studies have made significant discoveries about the influence of some HLA alleles on the risk of type 1 diabetes. However, the HLA loci’s extreme polymorphism, coupled with the revelations of new alleles and the HLA region’s LD (linkage disequilibrium), makes the association analysis a complicated process (Hemminki, 2012). Besides, the actual biological process of HLA-conferred susceptibility remains indefinable. The greatest genetic risk of type 1 diabetes in Caucasians is described by the DR/DR4 heterogenous genotypes, where the DR4 haplotype has DQB1*03:02 allele and the DR4 is not DRB1*04:03. That may be due to the DQ heterodimers encoded in the genotype, or it may be as a result of various ununderstood factors (Hemminki, 2012). However, the risk of type 1 diabetes exhibited by the DR3/DR4 genotype is so great that other susceptibility loci tend to have minimal or no effect. Moreover, the separation of the DR3/DR4 high-risk group from non-DR3/DR4 individuals has made significant contributions to identifying additional susceptibility loci (Hemminki, 2012).
Any genetic susceptibility to type 1 diabetes that does not relate to HLA, PTPN22, and INS genes tend to be conferred by several loci, each having little effect (OR 1.1-1.3). The identification of all the loci has been through the process of liking disequilibrium with common Single nucleotide polymorphisms (SNPs) (Bluestone, Atkinson, & Arvan, 2012). New sequencing technologies are therefore expected to allow for the determination of rare variants that may combine to identify additional type 1 diabetes (T1D) susceptibility loci. Besides, phase-specific sequencing information will provide better analysis of the biological basis of various identified or observed T1D genetic associations. Despite the discovery of much information regarding the relationship between type 1 diabetes and genetics, more data is still necessary for the creation of a better understanding of the relationship (Bluestone, Atkinson, & Arvan, 2012).
In overall, about forty years have passed since the first reporting of type 1 diabetes’ association with genetics. After such a long period of research and several other reports, HLA significantly remains the highest predictor of the risk to type 1 diabetes. However, the genetics surrounding type 1 diabetes is more complex than the first reporters might have imagined. That is because “HLA” does not imply one genetic locus but a genome region that consists of different genes that encode HLA’s three classical class I and three classical class II antigens, as well as several other genes whose reactions may also influence T1D susceptibility. The susceptibility to T1D is also affected by Polymorphisms in various genes found outside the HLA region, such as PTPN22 and insulin genes, though to a lower degree compared to the classical HLA loci. Besides, the various genes that influence T1D susceptibility can be categorized into three primary groups, which include insulin expression, immune function, and beta-cell function. Several T1D susceptibility loci take part in encoding products that contribute to immune response, and the insulin gene (where promoter polymorphisms affect the levels of insulin expression) is the strongest T1D susceptibility locus after HLA.
Bluestone, J., Atkinson, M., & Arvan, P. (2012). Type 1 diabetes. Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory Press.
Hemminki, K. (2012). Familial risks in understanding type 1 diabetes genetics. Nature Reviews Genetics. http://dx.doi.org/10.1038/nrg3069-c1
Ikegami, H., Noso, S., Babaya, N., & Kawabata, Y. (2011). Genetics and pathogenesis of type 1 diabetes: prospects for prevention and intervention. Journal of Diabetes Investigation, 2(6), 415-420. http://dx.doi.org/10.1111/j.2040-1124.2011.00176.x