Special Issue "Genetics and Functional Genomics of Diabetes Mellitus"

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (31 January 2017).

Special Issue Editors

Guest Editor
Prof. Dr. Bernhard O. Boehm, M.D., FRCP

Professor of Metabolic Disease, LKC School of Medicine, A Joined Medical School by Imperial College London and Nanyang Technological University, Singapore; Genome Institute of Singapore, A*STAR, Singapore
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Guest Editor
Dr. Rajkumar Dorajoo

Genome Institute of Singapore, A*STAR, Singapore
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Special Issue Information

Dear Colleagues,

Diabetes mellitus is a heterogeneous clinical entity, characterized by high blood sugar levels. Diabetes is a major public health problem that is approaching epidemic proportions globally. Since 1980, age-standardized diabetes prevalence in adults has increased. Together with population growth and ageing, this rise has led to a near quadrupling of the number of adults with diabetes, affecting around 400 million people worldwide 1.

Once considered “Diabetes Mellitus: A Geneticist’s Nightmare” 2, technologies have greatly enabled the resolution of disease-relevant genomic regions, and ultimately defined disease causing variants describing specific, i.e., monogenic disease variants.

The combination of genomic studies with functional assays is now providing the rationale for dissecting diabetes mellitus into various subtypes. Still lacking is a full translation of already existing knowledge into clinical practice. There is an unmet need in view of the substantial health burden to translate genetic and functional information into stratified treatment and monitoring approaches. However, the identification of informative mutations has provided proof of principle of this kind of approach 3.

Herein, we will summarize current knowledge on genetics and functional genomics of diabetes mellitus, covering common and rare variants, from autoimmunity to insulin resistance and impaired glucose-induced insulin secretion disease phenotypes.

  1. NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in diabetes since 1980: A pooled analysis of 751 population-based studies with 4.4 million participants. Lancet 2016, doi:10.1016/S0140-6736(16)00618-8.
  2. Neel, J. Diabetes mellitus: A geneticist’s nightmare. In The Genetics of Diabetes Mellitus; Creutzfeldt, W., Kobberling, J., Neel, J.V., Eds.; Springer-Verlag: Berlin, Germany, 1976; pp. 1–11.
  3. Pearson, E.R. Personalized medicine in diabetes: The role of “omics” and biomarkers. Diabetic Med. 2016, in press.

Prof. Dr. Bernhard O. Boehm
Dr. Rajkumar Dorajoo
Guest Editors

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Published Papers (10 papers)

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Research

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Open AccessArticle
Juvenile-Onset Diabetes and Congenital Cataract: “Double-Gene” Mutations Mimicking a Syndromic Diabetes Presentation
Genes 2017, 8(11), 309; https://doi.org/10.3390/genes8110309
Received: 19 July 2017 / Revised: 24 October 2017 / Accepted: 24 October 2017 / Published: 7 November 2017
Cited by 1 | PDF Full-text (1058 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Monogenic forms of diabetes may account for 1–5% of all cases of diabetes, and may occur in the context of syndromic presentations. We investigated the case of a girl affected by insulin-dependent diabetes, diagnosed at 6 years old, associated with congenital cataract. Her [...] Read more.
Monogenic forms of diabetes may account for 1–5% of all cases of diabetes, and may occur in the context of syndromic presentations. We investigated the case of a girl affected by insulin-dependent diabetes, diagnosed at 6 years old, associated with congenital cataract. Her consanguineous parents and her four other siblings did not have diabetes or cataract, suggesting a recessive syndrome. Using whole exome sequencing of the affected proband, we identified a heterozygous p.R825Q ABCC8 mutation, located at the exact same amino-acid position as the p.R825W recurring diabetes mutation, hence likely responsible for the diabetes condition, and a homozygous p.G71S mutation in CRYBB1, a gene known to be responsible for congenital cataract. Both mutations were predicted to be damaging and were absent or extremely rare in public databases. Unexpectedly, we found that the mother was also homozygous for the CRYBB1 mutation, and both the mother and one unaffected sibling were heterozygous for the ABCC8 mutation, suggesting incomplete penetrance of both mutations. Incomplete penetrance of ABCC8 mutations is well documented, but this is the first report of an incomplete penetrance of a CRYBB1 mutation, manifesting between susceptible subjects (unaffected mother vs. affected child) and to some extent within the patient herself, who had distinct cataract severities in both eyes. Our finding illustrates the importance of family studies to unmask the role of confounding factors such as double-gene mutations and incomplete penetrance that may mimic monogenic syndromes including in the case of strongly evocative family structure with consanguinity. Full article
(This article belongs to the Special Issue Genetics and Functional Genomics of Diabetes Mellitus)
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Open AccessArticle
The Clinical Course of Patients with Preschool Manifestation of Type 1 Diabetes Is Independent of the HLA DR-DQ Genotype
Received: 30 January 2017 / Revised: 3 May 2017 / Accepted: 16 May 2017 / Published: 19 May 2017
Cited by 2 | PDF Full-text (1164 KB) | HTML Full-text | XML Full-text | Correction
Abstract
Introduction: Major histocompatibility complex class II genes are considered major genetic risk factors for autoimmune diabetes. We analysed Human Leukocyte Antigen (HLA) DR and DQ haplotypes in a cohort with early-onset (age < 5 years), long term type 1 diabetes (T1D) and explored [...] Read more.
Introduction: Major histocompatibility complex class II genes are considered major genetic risk factors for autoimmune diabetes. We analysed Human Leukocyte Antigen (HLA) DR and DQ haplotypes in a cohort with early-onset (age < 5 years), long term type 1 diabetes (T1D) and explored their influence on clinical and laboratory parameters. Methods: Intermediate resolution HLA-DRB1, DQA1 and DQB1 typing was performed in 233 samples from the German Paediatric Diabetes Biobank and compared with a local control cohort of 19,544 cases. Clinical follow-up data of 195 patients (diabetes duration 14.2 ± 2.9 years) and residual C-peptide levels were compared between three HLA risk groups using multiple linear regression analysis. Results: Genetic variability was low, 44.6% (104/233) of early-onset T1D patients carried the highest-risk genotype HLA-DRB1*03:01-DQA1*05:01-DQB1*02:01/DRB1*04-DQA1*03:01-DQB1*03:02 (HLA-DRB1*04 denoting 04:01/02/04/05), and 231 of 233 individuals carried at least one of six risk haplotypes. Comparing clinical data between the highest (n = 83), moderate (n = 106) and low risk (n = 6) genotypes, we found no difference in age at diagnosis (mean age 2.8 ± 1.1 vs. 2.8 ± 1.2 vs. 3.2 ± 1.5 years), metabolic control, or frequency of associated autoimmune diseases between HLA risk groups (each p > 0.05). Residual C-peptide was detectable in 23.5% and C-peptide levels in the highest-risk group were comparable to levels in moderate to high risk genotypes. Conclusion: In this study, we saw no evidence for a different clinical course of early-onset T1D based on the HLA genotype within the first ten years after manifestation. Full article
(This article belongs to the Special Issue Genetics and Functional Genomics of Diabetes Mellitus)
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Open AccessArticle
Tissue Non-Specific Genes and Pathways Associated with Diabetes: An Expression Meta-Analysis
Received: 21 November 2016 / Revised: 3 January 2017 / Accepted: 13 January 2017 / Published: 21 January 2017
Cited by 5 | PDF Full-text (908 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
We performed expression studies to identify tissue non-specific genes and pathways of diabetes by meta-analysis. We searched curated datasets of the Gene Expression Omnibus (GEO) database and identified 13 and five expression studies of diabetes and insulin responses at various tissues, respectively. We [...] Read more.
We performed expression studies to identify tissue non-specific genes and pathways of diabetes by meta-analysis. We searched curated datasets of the Gene Expression Omnibus (GEO) database and identified 13 and five expression studies of diabetes and insulin responses at various tissues, respectively. We tested differential gene expression by empirical Bayes-based linear method and investigated gene set expression association by knowledge-based enrichment analysis. Meta-analysis by different methods was applied to identify tissue non-specific genes and gene sets. We also proposed pathway mapping analysis to infer functions of the identified gene sets, and correlation and independent analysis to evaluate expression association profile of genes and gene sets between studies and tissues. Our analysis showed that PGRMC1 and HADH genes were significant over diabetes studies, while IRS1 and MPST genes were significant over insulin response studies, and joint analysis showed that HADH and MPST genes were significant over all combined data sets. The pathway analysis identified six significant gene sets over all studies. The KEGG pathway mapping indicated that the significant gene sets are related to diabetes pathogenesis. The results also presented that 12.8% and 59.0% pairwise studies had significantly correlated expression association for genes and gene sets, respectively; moreover, 12.8% pairwise studies had independent expression association for genes, but no studies were observed significantly different for expression association of gene sets. Our analysis indicated that there are both tissue specific and non-specific genes and pathways associated with diabetes pathogenesis. Compared to the gene expression, pathway association tends to be tissue non-specific, and a common pathway influencing diabetes development is activated through different genes at different tissues. Full article
(This article belongs to the Special Issue Genetics and Functional Genomics of Diabetes Mellitus)
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Open AccessArticle
Type 2 Diabetes Susceptibility in the Greek-Cypriot Population: Replication of Associations with TCF7L2, FTO, HHEX, SLC30A8 and IGF2BP2 Polymorphisms
Received: 26 September 2016 / Revised: 13 December 2016 / Accepted: 30 December 2016 / Published: 6 January 2017
Cited by 8 | PDF Full-text (250 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Type 2 diabetes (T2D) has been the subject of numerous genetic studies in recent years which revealed associations of the disease with a large number of susceptibility loci. We hereby initiate the evaluation of T2D susceptibility loci in the Greek-Cypriot population by performing [...] Read more.
Type 2 diabetes (T2D) has been the subject of numerous genetic studies in recent years which revealed associations of the disease with a large number of susceptibility loci. We hereby initiate the evaluation of T2D susceptibility loci in the Greek-Cypriot population by performing a replication case-control study. One thousand and eighteen individuals (528 T2D patients, 490 controls) were genotyped at 21 T2D susceptibility loci, using the allelic discrimination method. Statistically significant associations of T2D with five of the tested single nucleotide polymorphisms (SNPs) (TCF7L2 rs7901695, FTO rs8050136, HHEX rs5015480, SLC30A8 rs13266634 and IGF2BP2 rs4402960) were observed in this study population. Furthermore, 14 of the tested SNPs had odds ratios (ORs) in the same direction as the previously published studies, suggesting that these variants can potentially be used in the Greek-Cypriot population for predictive testing of T2D. In conclusion, our findings expand the genetic assessment of T2D susceptibility loci and reconfirm five of the worldwide established loci in a distinct, relatively small, newly investigated population. Full article
(This article belongs to the Special Issue Genetics and Functional Genomics of Diabetes Mellitus)

Review

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Open AccessReview
The Genetic Architecture of Type 1 Diabetes
Received: 12 May 2017 / Revised: 7 August 2017 / Accepted: 16 August 2017 / Published: 22 August 2017
Cited by 6 | PDF Full-text (1546 KB) | HTML Full-text | XML Full-text
Abstract
Type 1 diabetes (T1D) is classically characterised by the clinical need for insulin, the presence of disease-associated serum autoantibodies, and an onset in childhood. The disease, as with other autoimmune diseases, is due to the interaction of genetic and non-genetic effects, which induce [...] Read more.
Type 1 diabetes (T1D) is classically characterised by the clinical need for insulin, the presence of disease-associated serum autoantibodies, and an onset in childhood. The disease, as with other autoimmune diseases, is due to the interaction of genetic and non-genetic effects, which induce a destructive process damaging insulin-secreting cells. In this review, we focus on the nature of this interaction, and how our understanding of that gene–environment interaction has changed our understanding of the nature of the disease. We discuss the early onset of the disease, the development of distinct immunogenotypes, and the declining heritability with increasing age at diagnosis. Whilst Human Leukocyte Antigens (HLA) have a major role in causing T1D, we note that some of these HLA genes have a protective role, especially in children, whilst other non-HLA genes are also important. In adult-onset T1D, the disease is often not insulin-dependent at diagnosis, and has a dissimilar immunogenotype with reduced genetic predisposition. Finally, we discuss the putative nature of the non-genetic factors and how they might interact with genetic susceptibility, including preliminary studies of the epigenome associated with T1D. Full article
(This article belongs to the Special Issue Genetics and Functional Genomics of Diabetes Mellitus)
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Open AccessReview
Effects of Type 1 Diabetes Risk Alleles on Immune Cell Gene Expression
Received: 2 March 2017 / Revised: 17 May 2017 / Accepted: 14 June 2017 / Published: 21 June 2017
Cited by 5 | PDF Full-text (1245 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Genetic studies have identified 61 variants associated with the risk of developing Type 1 Diabetes (T1D). The functions of most of the non-HLA (Human Leukocyte Antigen) genetic variants remain unknown. We found that only 16 of these risk variants could potentially be linked [...] Read more.
Genetic studies have identified 61 variants associated with the risk of developing Type 1 Diabetes (T1D). The functions of most of the non-HLA (Human Leukocyte Antigen) genetic variants remain unknown. We found that only 16 of these risk variants could potentially be linked to a protein-coding change. Therefore, we investigated whether these variants affected susceptibility by regulating changes in gene expression. To do so, we examined whole transcriptome profiles of 600 samples from the Type 1 Diabetes Genetics Consortium (T1DGC). These comprised four different immune cell types (Epstein-Barr virus (EBV)-transformed B cells, either basal or after stimulation; and cluster of differentiation (CD)4+ and CD8+ T cells). Many of the T1D-associated risk variants regulated expression of either neighboring (cis-) or distant (trans-) genes. In brief, 24 of the non-HLA T1D variants affected the expression of 31 nearby genes (cis) while 25 affected 38 distant genes (trans). The effects were highly significant (False Discovery Rate p < 0.001). In addition, we searched in public databases for expression effects of T1D single nucleotide polymorphisms (SNPs) in other immune cell types such as CD14+ monocytes, lipopolysaccharide (LPS) stimulated monocytes, and CD19+ B cells. In this paper, we review the (expression quantitative trait loci (eQTLs) associated with each of the 60 T1D variants and provide a summary of the genes impacted by T1D risk alleles in various immune cells. We then review the methodological steps involved in analyzing the function of genome wide association studies (GWAS)-identified variants, with emphasis on those affecting gene expression. We also discuss recent advancements in the methodologies and their advantages. We conclude by suggesting future study designs that will aid in the study of T1D risk variants. Full article
(This article belongs to the Special Issue Genetics and Functional Genomics of Diabetes Mellitus)
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Open AccessReview
Inherited Variation in Vitamin D Genes and Type 1 Diabetes Predisposition
Received: 7 February 2017 / Revised: 11 April 2017 / Accepted: 12 April 2017 / Published: 20 April 2017
Cited by 8 | PDF Full-text (505 KB) | HTML Full-text | XML Full-text
Abstract
The etiology and pathophysiology of type 1 diabetes remain largely elusive with no established concepts for a causal therapy. Efforts to clarify genetic susceptibility and screening for environmental factors have identified the vitamin D system as a contributory pathway that is potentially correctable. [...] Read more.
The etiology and pathophysiology of type 1 diabetes remain largely elusive with no established concepts for a causal therapy. Efforts to clarify genetic susceptibility and screening for environmental factors have identified the vitamin D system as a contributory pathway that is potentially correctable. This review aims at compiling all genetic studies addressing the vitamin D system in type 1 diabetes. Herein, association studies with case control cohorts are presented as well as family investigations with transmission tests, meta-analyses and intervention trials. Additionally, rare examples of inborn errors of vitamin D metabolism manifesting with type 1 diabetes and their immune status are discussed. We find a majority of association studies confirming a predisposing role for vitamin D receptor (VDR) polymorphisms and those of the vitamin D metabolism, particularly the CYP27B1 gene encoding the main enzyme for vitamin D activation. Associations, however, are tenuous in relation to the ethnic background of the studied populations. Intervention trials identify the specific requirements of adequate vitamin D doses to achieve vitamin D sufficiency. Preliminary evidence suggests that doses may need to be individualized in order to achieve target effects due to pharmacogenomic variation. Full article
(This article belongs to the Special Issue Genetics and Functional Genomics of Diabetes Mellitus)
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Open AccessReview
The Diabetes-Linked Transcription Factor PAX4: From Gene to Functional Consequences
Received: 30 January 2017 / Revised: 24 February 2017 / Accepted: 3 March 2017 / Published: 9 March 2017
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Abstract
Paired box 4 (PAX4) is a key factor in the generation of insulin producing β-cells during embryonic development. In adult islets, PAX4 expression is sequestered to a subset of β-cells that are prone to proliferation and more resistant to stress-induced apoptosis. The importance [...] Read more.
Paired box 4 (PAX4) is a key factor in the generation of insulin producing β-cells during embryonic development. In adult islets, PAX4 expression is sequestered to a subset of β-cells that are prone to proliferation and more resistant to stress-induced apoptosis. The importance of this transcription factor for adequate pancreatic islets functionality has been manifested by the association of mutations in PAX4 with the development of diabetes, independently of its etiology. Overexpression of this factor in adult islets stimulates β-cell proliferation and increases their resistance to apoptosis. Additionally, in an experimental model of autoimmune diabetes, a novel immunomodulatory function for this factor has been suggested. Altogether these data pinpoint at PAX4 as an important target for novel regenerative therapies for diabetes treatment, aiming at the preservation of the remaining β-cells in parallel to the stimulation of their proliferation to replenish the β-cell mass lost during the progression of the disease. However, the adequate development of such therapies requires the knowledge of the molecular mechanisms controlling the expression of PAX4 as well as the downstream effectors that could account for PAX4 action. Full article
(This article belongs to the Special Issue Genetics and Functional Genomics of Diabetes Mellitus)
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Open AccessReview
Type 1 Diabetes Candidate Genes Linked to Pancreatic Islet Cell Inflammation and Beta-Cell Apoptosis
Received: 8 January 2017 / Revised: 7 February 2017 / Accepted: 10 February 2017 / Published: 16 February 2017
Cited by 19 | PDF Full-text (562 KB) | HTML Full-text | XML Full-text
Abstract
Type 1 diabetes (T1D) is a chronic immune-mediated disease resulting from the selective destruction of the insulin-producing pancreatic islet β-cells. Susceptibility to the disease is the result of complex interactions between environmental and genetic risk factors. Genome-wide association studies (GWAS) have identified more [...] Read more.
Type 1 diabetes (T1D) is a chronic immune-mediated disease resulting from the selective destruction of the insulin-producing pancreatic islet β-cells. Susceptibility to the disease is the result of complex interactions between environmental and genetic risk factors. Genome-wide association studies (GWAS) have identified more than 50 genetic regions that affect the risk of developing T1D. Most of these susceptibility loci, however, harbor several genes, and the causal variant(s) and gene(s) for most of the loci remain to be established. A significant part of the genes located in the T1D susceptibility loci are expressed in human islets and β cells and mounting evidence suggests that some of these genes modulate the β-cell response to the immune system and viral infection and regulate apoptotic β-cell death. Here, we discuss the current status of T1D susceptibility loci and candidate genes with focus on pancreatic islet cell inflammation and β-cell apoptosis. Full article
(This article belongs to the Special Issue Genetics and Functional Genomics of Diabetes Mellitus)
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Other

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Open AccessCorrection
Correction: Reinauer et al., The Clinical Course of Patients with Preschool Manifestation of Type 1 Diabetes Is Independent of the HLA DR-DQ Genotype. Genes 2017, 8, 146
Received: 13 December 2017 / Revised: 20 December 2017 / Accepted: 20 December 2017 / Published: 3 January 2018
PDF Full-text (163 KB) | HTML Full-text | XML Full-text
Abstract
The article entitled “The Clinical Course of Patients with Preschool Manifestation of Type 1 Diabetes is Independent of the HLA DR-DQ Genotype” contained a calculation error in Table 2 and the statistical methods used were not completely described.[...]
Full article
(This article belongs to the Special Issue Genetics and Functional Genomics of Diabetes Mellitus)
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