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. 2024 Sep 2;15(4):688–698. doi: 10.1007/s13340-024-00754-1

Genetics of type-1 diabetes

Hiroshi Ikegami 1,2,✉, Shinsuke Noso 3
PMCID: PMC11512969  PMID: 39469551

Abstract

Type-1 diabetes is a multifactorial disease characterized by genetic and environmental factors that contribute to its development and progression. Despite progress in the management of type-1 diabetes, the final goal of curing the disease is yet to be achieved. To establish effective methods for the prevention, intervention, and cure of the disease, the molecular mechanisms and pathways involved in its development and progression should be clarified. One effective approach is to identify genes responsible for disease susceptibility and apply information obtained from the function of genes in disease etiology for the protection, intervention, and cure of type-1 diabetes. In this review, we discuss the genetic basis of type-1 diabetes, along with prospects for its prevention, intervention, and cure for type-1 diabetes.

Introduction

Type-1 diabetes is caused by immune-mediated destruction of pancreatic beta cells in genetically susceptible individuals. Type-1 diabetes is divided into two subtypes: autoimmune and idiopathic [1]. Clinically, three subtypes are defined based on the mode of onset: acute, fulminant, and slowly progressive [2–4]. Acute-onset type-1 diabetes is a typical form of type-1 diabetes, but its incidence and prevalence are markedly different among different populations, with a high incidence in populations of European ancestry and a low incidence in East Asian populations, including the Japanese [5]. Fulminant type-1 diabetes, in contrast, is prevalent in Japan and East Asian countries, but very rare in populations of European ancestry [6]. Marked differences in the incidence of type-1 diabetes among different populations suggest that genetic factors contribute to the development of the disease. In this review, the genetic basis of type-1 diabetes is discussed, along with prospects for its prevention, intervention, and cure for type-1 diabetes.

Genetic basis for type-1 diabetes

Although multiple susceptibility genes for type-1 diabetes have been reported, whether genetic factors contribute to type-1 diabetes should be discussed first. The marked difference in the incidence of type-1 diabetes among different populations suggests that genetic factors contribute to the etiology of type-1 diabetes. Familial clustering of the disease is also reported with a much higher incidence of type-1 diabetes in siblings of probands with type-1 diabetes than in the general population [7, 8]. Familial clustering of type-1 diabetes is evident even in low-incidence countries such as Japan (Fig. 1) [7, 8]. Familial clustering can be caused by sharing of not only genetic, but also environmental factors among family members. Twin studies have been conducted to clarify the contributions of genetic factors to familial clustering. Monozygotic and dizygotic twins share similar environmental factors, but the sharing of genetic factors is different. Monozygotic twins share the whole genome, whereas dizygotic twins share a partial genome, as in the case of siblings. The higher concordance rate of type-1 diabetes in monozygotic twins than in dizygotic twins indicates the contribution of genetic factors to type-1 diabetes susceptibility [9, 10].

Fig. 1.

Fig. 1

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Familial clustering of type 1 diabetes. The frequency of type 1 diabetes in the siblings of probands with type 1 diabetes is much higher than that in the general population, even in Japan, which has one of the lowest incidence populations in the world. (1) Data from Ikegami H et al. Endocrine J 1996 [7]. (2) Data based on survey on family history of type 1 diabetes at summer camps for childhood diabetes in 1998: Ikegami H et al. Diab Res Clin Prac 2007 [8]

Further evidence comes from animal models of the spontaneous development of type-1 diabetes. Inbred, which means genetically homogeneous, animal models of type-1 diabetes, such as non-obese diabetic (NOD) mice [11] and Komeda diabetes-prone (KDP) rats [12], by themselves indicate the contribution of genetic factor to the development of type-1 diabetes. When NOD mice were crossed with non-diabetic control mice, none of the F1 hybrid mice developed type-1 diabetes, indicating a recessive inheritance [13, 14]. When F1 mice were backcrossed with NOD mice, a certain percentage of them developed type-1 diabetes. When NOD mice were crossed with control non-obese non-diabetic (NON) mice, a sister strain of NOD mice, approximately 10% of the backcrossed mice developed type-1 diabetes [13], suggesting that at least three recessive genes contribute to the development of type-1 diabetes. When NOD mice were crossed with a different control strain, C57BL/6, the frequency of type-1 diabetes in backcross generations was 3%, suggesting the contribution of at least five recessive genes [14]. The difference in the number of susceptibility genes suggested by breeding studies with different strain combinations [14–18] can be explained by the fact that multiple susceptibility genes contribute to type-1 diabetes, and some susceptibility variants are shared between the NOD and control strains [14, 17, 18]. Susceptibility genes for type-1 diabetes are not mutations limited to NOD mice, but are variants that also exist in some control strains; therefore, the frequency of diabetes in breeding studies is affected by the number of susceptibility genes that are shared or not shared between NOD and control strains of mice. The larger the number of different variants, the lower the frequency of type-1 diabetes in the backcross generations. Only gene variants that are not shared between the NOD and control mice can be detected in breeding studies.

Susceptibility gene identification methods

To identify the genes responsible for diseases with genetic component, such as type-1 diabetes, two major approaches have been used: linkage and association studies. The former is applied for families with multiple members with the disease, searching for shared genetic regions between affected members. This approach is effective in the case of diseases with strong genetic components, such as maturity-onset diabetes of the young (MODY) with families comprising multiple affected members. In the case of type-1 diabetes, such families are very rare. Therefore, this approach is practically challenging to implement. Instead, affected sib pairs have been studied in which two or more siblings (brothers and sisters) are affected by the same disease.

In contrast, association studies are conducted in sporadic cases, meaning non-familial cases in the general population. Genetic marker frequencies were compared between the cases, i.e., those affected with the diseases, and non-affected controls, searching for markers more frequently observed in the disease cases than in the control.

Concerning genes and genetic markers, two approaches have been used: candidate gene and random marker approaches. The former allows for studying suspected gene candidates based on disease etiology and pathogenesis. The candidate gene approach is based on the assumption that candidate genes are more likely to be responsible for disease susceptibility due to their functional relationship with the disease. In contrast, the random marker approach uses a significant number of markers spanning the genome to identify the chromosomal position of the disease susceptibility. Recent progress in genotyping and data analysis technology made it possible to conduct genome-wide association study (GWAS), i.e., large-scale association studies involving dense panels of genetic markers across the genome and a markedly high number of cases and controls. An example of GWAS will be discussed later. More recently, progress in sequencing technology, i.e., the establishment of next generation sequencing, enabled researchers to conduct whole-exome or even whole-genome sequencing, which will also be discussed later.

Candidate genes for type-1 diabetes

Initially, genes for type-1 diabetes were studied using a candidate gene approach. As type-1 diabetes is an organ-specific autoimmune disease affecting pancreatic beta cells, genes responsible for immune regulation and organ specificity are candidates. The former is the major histocompatibility complex (MHC) and the latter is insulin, a beta cell-specific antigen. Both are now proven to be associated with type-1 diabetes [19, 20].

The contribution of the MHC to the inheritance of type-1 diabetes has been demonstrated in breeding studies of NOD mice. All diabetic mice in the backcross generations were homozygotes for NOD-derived MHC regardless of strain combinations [14–18], indicating that homozygosity of NOD MHC is necessary for the development of type-1 diabetes. The contribution of the MHC to the development of type-1 diabetes was further confirmed in studies using congenic strains. A congenic strain refers to a strain in which the locus of interest in the recipient strain is replaced by that of the donor strain. For example, the congenic strain NOD.NON-H2 is a NOD strain in which H2 (mouse MHC, corresponding to human HLA) is replaced by H2 of a control NON strain. None of the NOD mice congenic for the MHC from control strains, such as NON and C57BL/10 mice, developed type-1 diabetes [17, 18], indicating that NOD MHC is necessary for type-1 diabetes. However, none of the control strains congenic to MHC from NOD mice developed type-1 diabetes [17], indicating that NOD MHC are not sufficient for the development of type-1 diabetes. This is explained by the fact that multiple susceptibility genes are necessary for the development of type-1 diabetes, and NOD MHC in combination with other susceptibility genes of NOD mice constitutes full susceptibility to type-1 diabetes.

Identity of susceptibility genes in the MHC

Based on the necessity of NOD MHC in the development of type-1 diabetes, the next question was which MHC gene is responsible for type-1 diabetes. The MHC consists of multiple genes related to immune regulation, such as class I MHC genes, K and D in mice, and A, B, and C in humans; class II genes, such as A and E in mice; and DP, DQ, and DR in humans. All these genes are important for immune regulation and are therefore candidate susceptibility genes for type-1 diabetes. Class II genes are particularly strong candidates because they are necessary for the initiation of immune reactions against target antigens, and a strong association has been reported between class II HLA and human type-1 diabetes [19]. Based on these results, the DNA sequence of the Ab gene encoding the class II A beta chain of the NOD mouse was determined and found to be unique compared to known Ab sequences of the control strains [21]. In particular, the amino acid at position 57 of the A beta chain, which is conserved to be aspartic acid in all known strains of mice, was substituted with serine [21]. Since this substitution was observed only in the NOD mouse, but not in other strains of mice at that time, and position 57 of A-beta molecule is critical for antigen binding and presentation, this variant in Ab gene was suspected to be a mutation responsible for type-1 diabetes in the NOD mouse [21]. However, when we investigated class II MHC in the NOD mouse and its related strains derived from the same original outbred colony, Jcl:ICR mice, the same Ab sequence as in the NOD mouse was observed in a sister strain, the CTS mouse, and some mice in the original colony, Jcl:ICR mice [13, 22], indicating that the reported variant is not unique to the NOD mouse, but is also observed in non-diabetic mice. To prove that the NOD mouse Ab gene is responsible for type-1 diabetes, it is necessary to demonstrate that the same variant identified in non-diabetic NOD-related strains confers susceptibility to type-1 diabetes. To this end, we established a congenic strain, NOD.CTS-H2, by introgressing CTS MHC, whose Ab sequence is identical to that of the NOD mouse [22], into the NOD genetic background. In contrast to the complete resistance observed in NOD mice congenic to MHC from non-diabetic control strains [18], NOD.CTS-H2 congenic mice developed type-1 diabetes [23], indicating that CTS MHC confers susceptibility to type-1 diabetes. Since class II MHC of the CTS mouse is identical to that of the NOD mouse, but class I MHC is different from that of the NOD mouse [13, 22], the development of type-1 diabetes in NOD.CTS-H2 indicated that class II MHC, Ab sequence in particular, of the NOD mouse, is responsible for type-1 diabetes.

Although CTS MHC conferred susceptibility to type-1 diabetes, it was not as strong as NOD MHC, as shown by the lower incidence and later onset of type-1 diabetes in NOD.CTS-H2 mice than in NOD mice [11, 23]. The difference in the phenotype despite the same class II MHC and background genes suggests that susceptibility genes for type-1 diabetes in the MHC consist of multiple components and that genes adjacent to but distinct from class II MHC are necessary in addition to class II MHC to confer full susceptibility to type-1 diabetes. Because the class I MHC of the CTS mouse is different from that of the NOD mouse, class I MHC is a strong candidate for the second component of susceptibility genes in the MHC. This was later proven to be a class I K gene in two independent studies [24, 25].

The association between class II HLA and type-1 diabetes in humans is well appreciated [26–28]. Based on the finding that class I MHC, in addition to class II MHC, contribute to type-1 diabetes in NOD mice, the contribution of class I HLA has been investigated in humans. As in the case of NOD mice, the contribution of class I HLA in addition to class II HLA has been suggested in human type-1 diabetes [29–31]. These data illustrate the importance of comparative studies between humans and animal models. Observations in humans should be proven by functional studies in animal models, and the observations in animal models should be fed back to and translated into humans.

Insulin gene-related pathway

Insulin gene (INS) is associated with type-1 diabetes, and the variable number of tandem repeats (VNTR) located in the 5′ upstream region was suggested to be responsible for type-1 diabetes susceptibility [20, 32–34]. Insulin is specifically expressed in the beta cells of the pancreas but only exception is the thymus, where a panel of autoantigens is expressed to educate T-cells not to attack the self by eliminating autoreactive T-cells to self-antigens (negative selection), such as insulin. INS-VNTR affects the expression of insulin in the thymus. A susceptible variant of INS-VNTR has been reported to reduce the expression of insulin in the thymus and impair the negative selection of autoreactive T-cells to insulin, leading to an autoimmune attack against insulin-producing beta cells of the pancreas [35, 36].

The susceptibility genes for type-1 diabetes in NOD mice have not been mapped to insulin loci, but insulin is a target antigen for type-1 diabetes in NOD mice [37]. The insulin gene was confirmed to be expressed in the thymus of NOD mice; however, its expression level was significantly lower than that in the control mice [38]. NOD was found to have multiple variants in the promoter region of Mafa, a gene encoding insulin-specific transcription factor MafA, and promoter with these variants showed reduced promoter activity, leading to the reduced expression of MafA and its downstream target, insulin, in the thymus [38]. Thus, in both humans and NOD mice, the expression level of insulin in the thymus appears to be critical for susceptibility to type-1 diabetes, but the genetic basis is different in that the cis regulatory region of insulin (INS-VNTR) in humans and the trans-activator of insulin gene (MafA) are responsible for the reduced expression of insulin in the thymus, leading to increased susceptibility to type-1 diabetes (Fig. 2) [35, 36, 38]. These data indicate the importance of comparative studies between humans and animal models in that different genes, INS-VNTR and Mafa, affect the same pathway, reduce insulin expression in the thymus, and contribute to type-1 diabetes in humans and NOD mice, respectively. Further studies have suggested that MAFA in humans, which is syntenic to Mafa in mice, is associated with type-1 diabetes, in addition to INS-VNTR [38, 39]. The identified variant in the coding region was found to affect the transactivation function of MAFA, and variants in the promoter region were found to cause quantitative changes in MAFA expression, both of which lead to altered expression of insulin in the thymus [38, 39]. The same pathway, insulin gene expression in the thymus, identified through variants in different genes, Mafa in NOD mice, and INS-VNTR in humans, is an important target for the prevention, intervention, and eventual cure of type-1 diabetes.

Fig. 2.

Fig. 2

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Insulin expression in the thymus and autoimmunity against beta cells. Low insulin expression in the thymus leads to the escape of autoreactive T-cells against insulin, resulting in autoimmunity against insulin-producing pancreatic beta cells

Similarities and differences between European and Japanese populations.

In addition to HLA and INS, several candidate genes, such as PTPN22, CTLA4, IL2RA, are associated with type-1 diabetes; however, most studies have been conducted in populations of European ancestry [40–42]. Studies in Japanese and East Asian populations have been hampered by the low incidence of type-1 diabetes and difficulty in collecting a large number of samples to study non-HLA genes, whose effects are generally weak. Therefore, large-scale studies with sufficient statistical power are necessary to prove their contribution. To overcome this limitation, a collaborative study group, the Japanese Study Group on Type-1 Diabetes Genetics, was established [43], making it possible to conduct large-scale studies in Japan. Through these studies, similarities and differences in the contributions of candidate genes to type-1 diabetes have been clarified between Japanese and populations of European ancestry. Most genes reported in populations of European ancestry appear to contribute to type-1 diabetes in the Japanese population [20, 43–47], but substantial differences have also been observed [8, 48], such as associated phenotypes [43] and risk-allele frequencies [20, 44, 46], demonstrating the importance of genetic association studies across different populations. Recent studies on the genetic basis of human diseases have increasingly focused on individuals of diverse ancestries [49, 50].

Genome-wide approach

Following the candidate gene approach, a random marker approach with a large number of polymorphic markers throughout the genome termed a genome-wide association study (GWAS), has been used in a large number of cases and controls to identify disease-associated loci. Because a GWAS requires a large number of samples, most studies on type-1 diabetes have been conducted in high-incidence countries with populations of European ancestry. GWAS have contributed to the identification of a large number of new susceptibility loci for type-1 diabetes [51–55]. However, most of them are loci and chromosomal positions where susceptibility genes are likely to exist, and not the genes themselves responsible for disease susceptibility. Identifying responsible genes and disease-causing variants is a formidable challenge. Almost all GWAS on type-1 diabetes have been conducted in populations of European ancestry in which a combination of variants of nearby genes, termed haplotypes, is fixed, making it difficult to dissect the effect of disease-causing variants from those of variants in nearby genes. In contrast, the combination of variants in nearby genes is different in populations of diverse ancestry, such as Japanese and East Asian populations, making it possible to highlight disease-causing variants by comparing disease association results among diverse populations [55–57]. Therefore, we conducted a GWAS in the Japanese population to identify specific variants that are beneficial for understanding type-1 diabetes in the Japanese population, but also contribute to global efforts to identify disease-causing variants through trans-ancestral studies.

GWAS in fulminant type-1 diabetes

All Japan collaborative efforts by the Committee of Type-1 Diabetes of the Japan Diabetes Society made it possible to conduct a GWAS of type-1 diabetes in the Japanese population [58]. Fulminant type-1 diabetes was selected because this subtype is prevalent in the Japanese population but very rare in European populations [6, 59]; therefore, a GWAS is only possible in the Japanese population. A novel susceptibility locus with genome-wide significance was identified on chromosome 12q13.13 [58, 59] (Fig. 3A). Fine mapping revealed a stronger signal at marker rs3782151, which is located in CSAD, a gene encoding cysteine sulfinic acid decarboxylase (CSAD) (Fig. 3B). CSAD is a key enzyme in taurine biosynthesis (Fig. 4). Taurine plays an important role in anti-inflammatory and cytoprotective effects through membrane stabilization, osmoregulation, and anti-oxidative and anti-apoptotic activities (Fig. 4), suggesting that CSAD variants contribute to fulminant type-1 diabetes by impairing the protection of pancreatic beta cells. Taurine has been reported to protect beta cells from destruction in type-1 diabetes in NOD mice [60] and streptozotocin-induced diabetes [61, 62]. An independent metabolome analysis of human type-1 diabetes indicated that hypotaurine, an intermediate metabolite in taurine biosynthesis, is a marker of active beta cell destruction in type-1 diabetes (Fig. 4) [63]. The fact that independent studies from genetic [58, 59], interventional [60–62], and functional [63] points of view indicated the contribution of the same taurine synthesis pathway to beta cell destruction and failure suggests that this pathway is an important target for beta cell protection and curing type-1 diabetes.

Fig. 3.

Fig. 3

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Susceptibility loci for fulminant type 1 diabetes identified by GWAS in Japanese population. A. Manhattan plot of GWAS showing a novel susceptibility locus on chromosome 12q13.13 with genome-wide significance, in addition to the previously known locus HLA-DR. B. Fine-mapping of the region on chromosome 12q13.13. The top hit marker, rs3782151, was located in the gene encoding cysteine sulfinic acid decarboxylase (CSAD) and in another gene, lnc-ITGB7-1, encoding long-noncoding RNA located in the same region, but with different transcription. lnc-ITGB7-1 affects the transcription of the nearby gene ITGB7 with risk allele increase the expression of ITGB7, a molecule involved in the migration, entry, and adhesion of lymphocytes to inflamed organs. Data based on Kawabata et al. Diabetes 2019 [58]

Fig. 4.

Fig. 4

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Taurine biosynthesis pathway and its relation to type 1 diabetes. CSAD, a key enzyme in taurine synthesis, has been identified as a susceptibility gene for fulminant type 1 diabetes using genome-wide association studies (1). Hypotaurine, an intermediate metabolite of this pathway, has been identified through metabolome analysis as a biomarker of acute autoimmunity in type 1 diabetes (2). Taurine, the final product of this pathway, has been reported to exert anti-inflammatory and cytoprotective effects through membrane stabilization, osmoregulation, anti-oxidative, and anti-apoptotic activities. Taurine supplementation protects beta cells from destruction (3–5). (1) Kawabata Y et al. Diabetes 2019 [58]. (2) Noso S et al. J Diabetes Investig 2023 [63]. (3) Arany E et al. Diabetologia 2004 [60]. (4) Lin S et al. Adv Exp Med Biol 2013 [61]. (5) Nakatsuru Y et al. Diabetol Int 2018 [62]

In addition to CSAD, the top-hit marker, rs3782151, was located within a gene encoding a long non-coding (lnc) RNA, termed lnc-ITGB7-1 (Fig. 3B). lnc-ITGB7-1 is a cis expression quantitative trait locus for ITGB7 that affects the expression of this gene. ITGB7 encodes integrin β subunit 7 (ITGB7), which is involved in the migration, entry, and adhesion of lymphocytes to inflamed organs [58, 59]. These data suggest that variants identified through GWAS in fulminant diabetes affect the fulminant phenotype through the acceleration of destruction (lnc-ITGB7-1) and impaired protection (CSAD) of beta cells (Fig. 3B).

Whole-exome and whole-genome sequencing

Advances in sequencing technologies have made it possible to sequence whole exons and whole genomes of several subjects to identify genetic variants associated with diseases [64, 65]. Although technically possible, the number of variants identified through such an approach is large, making it difficult to identify meaningful signals associated with the disease from the large amount of noise. One way to overcome this limitation is to study clustered families with type-1 diabetes. As mentioned previously, the incidence of type-1 diabetes is very low in the general Japanese population but is as high in siblings of type-1 diabetic probands as in populations of European ancestry [7, 8]. Consequently, the degree of familial clustering in the Japanese population is much higher than in populations of European ancestry [48, 57], suggesting that a rare variant with a strong genetic effect is clustered in such families. Although the number of multiplex families with type-1 diabetes is very limited in Japan, we accumulated 32 affected members from 16 families, including six families with more than three members with type-1 diabetes, through a nationwide collaboration (Fig. 5) [66–69], and applied whole-exome sequencing technologies to identify rare variants [69]. Several rare variants of known [67] and previously unknown [69] genes have been identified using this approach.

Fig. 5.

Fig. 5

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Multiplex families with type 1 diabetes in Japanese population. A total of 32 affected members from 16 families, including six families with more than three members with type 1 diabetes, were identified through nationwide collaboration. Closed box and circle: subjects with type 1 diabetes

Protection of beta cells: a step toward cure of diabetes

Identification of the taurine pathway as an important molecular target of type-1 diabetes opened the door for prevention, intervention, and cure of type-1 diabetes from a different aspect, that is, protection of beta cells from outside attack [70], in addition to previously appreciated aspects, calming down outside attack [71, 72]. This is particularly important in the Japanese population because beta cells are more fragile than those of European ancestry [70]. The Japanese population is more prone to complete depletion of endogenous insulin in type-1 diabetes [70, 73], whereas residual beta cell function is often detected after a long duration in populations of European ancestry [74]. Beta-cell fragility is not limited to type-1 diabetes but is also evident in type 2 and other types of diabetes, in that beta-cell failure can easily develop in the face of mild obesity and mild insulin resistance in type 2 diabetes [70], and in the face of decreased pancreatic volume after partial pancreatectomy [75–77]. In any case, residual beta cells are under strong stress to secrete larger amounts of insulin than before, but in Japan, beta cells cannot compensate for increased demand, and beta cell failure manifests [70]. Final molecular mechanisms of beta-cell failure appear to be common, such as oxidative stress, endoplasmic reticulum stress, and apoptosis, among different types of diabetes [70, 78, 79]. When protection of beta cells are strengthened by over-expression of anti-oxidative molecule, thioredoxin, specifically in beta cells, beta-cell failure is protected in not only type-1 diabetes (NOD mice) [80] but also obese type 2 diabetes (db/db mice) [81] and other types of diabetes (STZ-induced diabetes) [80], suggesting that oxidative stress is one of the common mechanisms of beta-cell failure [70, 78, 82] and that beta-cell protection can be an effective method for protection of beta-cell failure regardless of types of diabetes [70, 82, 83].

Conclusion

Regardless of the approaches and methods used for type-1 diabetes research, the ultimate goal is to cure the disease. The identification of genes for type-1 diabetes provides important information on pathways and molecules critical for beta cell destruction and failure, leading to the establishment of effective methods for the prevention, intervention, and cure of type-1 diabetes. Even if the effect of each gene variant is small, the information obtained from these studies provides targets for the prevention and intervention of the onset and progression of type-1 diabetes. The larger the number of genes, molecules, and pathways identified, the higher the possibility of preventing and curing the disease. In addition to large-scale association studies such as GWAS, family-based studies are also important for identifying genes with large effect [66–69], [84, 85]. All possible efforts should be made to clarify the genetic basis of type 1 diabetes to achieve the final goal of curing the disease.

Declarations

Conflict of interest

Hiroshi Ikegami: lecture fees (Novo Nordisk Pharma, Sanofi, Sumitomo Pharma), scholarship donations (LifeScan Japan, Sumitomo Pharma).

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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