Genetics of Diabetes

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 May 2015) | Viewed by 109334

Special Issue Editor

Inserm UMR-S-958 "Genetics of diabetes", University Paris Diderot - Paris 7, School of Medicine, Site Villemin, 10 avenue de Verdun, 75010 Paris, France
Interests: immunogenetics; MHC; autoimmunity; type 1 diabetes; eQTL mapping; multifactorial genetics

Special Issue Information

Dear Colleagues,

Genetic studies, including genome-wide linkage and association studies, have been a main component of research strategies aiming at understanding the pathogenesis of various forms of diabetes. Type 1 and type 2 diabetes benefited from consortia screening large cohorts using various polymorphisms (microsatellites, SNPs and CNVs), from common to rare. For other “specific” forms of diabetes (neonatal, syndromic or atypical), characterization of homogeneous phenotypes through linkage was crucial. However, despite intensive studies, the identification of the causative variants or mutations remains challenging and the molecular mechanisms are still rarely characterized. The achievement of next-generation-sequencing technologies applied to the search for DNA variants or aiming at characterizing functional elements, as examplified by the recent ENCODE project, opens a promising era to decipher the genetic bases of diabetes, to help better understand pathogenetic mechanisms, hopefully leading to personalized medicine.
This Special Issue of “Genes” welcomes reviews and original papers covering recent genetic research on any type of diabetes, either multifactorial or monogenic, both in man and in animal models, using high-throughput omic approaches. Special interest will be given to integrative biology studies.

Dr. Claire Vandiedonck
Guest Editor

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Keywords

  • diabetes
  • genetics
  • genomics
  • metagenomics
  • next-generation sequencing
  • chromatin studies
  • epigenomics
  • proteomics
  • metabolomics
  • integrative biology
  • molecular function

Published Papers (8 papers)

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Research

Jump to: Review

542 KiB  
Article
Alu Elements as Novel Regulators of Gene Expression in Type 1 Diabetes Susceptibility Genes?
by Simranjeet Kaur and Flemming Pociot
Genes 2015, 6(3), 577-591; https://doi.org/10.3390/genes6030577 - 13 Jul 2015
Cited by 6 | Viewed by 6260
Abstract
Despite numerous studies implicating Alu repeat elements in various diseases, there is sparse information available with respect to the potential functional and biological roles of the repeat elements in Type 1 diabetes (T1D). Therefore, we performed a genome-wide sequence analysis of T1D candidate [...] Read more.
Despite numerous studies implicating Alu repeat elements in various diseases, there is sparse information available with respect to the potential functional and biological roles of the repeat elements in Type 1 diabetes (T1D). Therefore, we performed a genome-wide sequence analysis of T1D candidate genes to identify embedded Alu elements within these genes. We observed significant enrichment of Alu elements within the T1D genes (p-value < 10e−16), which highlights their importance in T1D. Functional annotation of T1D genes harboring Alus revealed significant enrichment for immune-mediated processes (p-value < 10e−6). We also identified eight T1D genes harboring inverted Alus (IRAlus) within their 3' untranslated regions (UTRs) that are known to regulate the expression of host mRNAs by generating double stranded RNA duplexes. Our in silico analysis predicted the formation of duplex structures by IRAlus within the 3'UTRs of T1D genes. We propose that IRAlus might be involved in regulating the expression levels of the host T1D genes. Full article
(This article belongs to the Special Issue Genetics of Diabetes)
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221 KiB  
Article
MicroRNA-224 is Readily Detectable in Urine of Individuals with Diabetes Mellitus and is a Potential Indicator of Beta-Cell Demise
by Siobhán Bacon, Britta Engelbrecht, Jasmin Schmid, Shona Pfeiffer, Ross Gallagher, Ailbhe McCarthy, Marie Burke, Caoimhín Concannon, Jochen H. M. Prehn and Maria M. Byrne
Genes 2015, 6(2), 399-416; https://doi.org/10.3390/genes6020399 - 23 Jun 2015
Cited by 32 | Viewed by 7688
Abstract
MicroRNA (miRNA) are a class of non-coding, 19–25 nucleotide RNA critical for network-level regulation of gene expression. miRNA serve as paracrine signaling molecules. Using an unbiased array approach, we previously identified elevated levels of miR-224 and miR-103 to be associated with a monogenic [...] Read more.
MicroRNA (miRNA) are a class of non-coding, 19–25 nucleotide RNA critical for network-level regulation of gene expression. miRNA serve as paracrine signaling molecules. Using an unbiased array approach, we previously identified elevated levels of miR-224 and miR-103 to be associated with a monogenic form of diabetes; HNF1A-MODY. miR-224 is a novel miRNA in the field of diabetes. We sought to explore the role of miR-224 as a potential biomarker in diabetes, and whether such diabetes-associated-miRNA can also be detected in the urine of patients. Absolute levels of miR-224 and miR-103 were determined in the urine of n = 144 individuals including carriers of a HNF1A mutation, participants with type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM) and normal controls. Expression levels were correlated with clinical and biochemical parameters. miR-224 was significantly elevated in the urine of carriers of a HNF1A mutation and participants with T1DM. miR-103 was highly expressed in urine across all diabetes cohorts when compared to controls. For both miR-224 and-103, we found a significant correlation between serum and urine levels (p < 0.01). We demonstrate that miRNA can be readily detected in the urine independent of clinical indices of renal dysfunction. We surmise that the differential expression levels of miR-224 in both HNF1A-MODY mutation carriers and T1DM may be an attempt to compensate for beta-cell demise. Full article
(This article belongs to the Special Issue Genetics of Diabetes)
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186 KiB  
Article
Polymorphisms in Fatty Acid Desaturase (FADS) Gene Cluster: Effects on Glycemic Controls Following an Omega-3 Polyunsaturated Fatty Acids (PUFA) Supplementation
by Hubert Cormier, Iwona Rudkowska, Elisabeth Thifault, Simone Lemieux, Patrick Couture and Marie-Claude Vohl
Genes 2013, 4(3), 485-498; https://doi.org/10.3390/genes4030485 - 10 Sep 2013
Cited by 21 | Viewed by 7764
Abstract
Changes in desaturase activity are associated with insulin sensitivity and may be associated with type 2 diabetes mellitus (T2DM). Polymorphisms (SNPs) in the fatty acid desaturase (FADS) gene cluster have been associated with the homeostasis model assessment of insulin sensitivity (HOMA-IS) [...] Read more.
Changes in desaturase activity are associated with insulin sensitivity and may be associated with type 2 diabetes mellitus (T2DM). Polymorphisms (SNPs) in the fatty acid desaturase (FADS) gene cluster have been associated with the homeostasis model assessment of insulin sensitivity (HOMA-IS) and serum fatty acid composition. Objective: To investigate whether common genetic variations in the FADS gene cluster influence fasting glucose (FG) and fasting insulin (FI) responses following a 6-week n-3 polyunsaturated fatty acids (PUFA) supplementation. Methods: 210 subjects completed a 2-week run-in period followed by a 6-week supplementation with 5 g/d of fish oil (providing 1.9 g–2.2 g of EPA + 1.1 g of DHA). Genotyping of 18 SNPs of the FADS gene cluster covering 90% of all common genetic variations (minor allele frequency ≥ 0.03) was performed. Results: Carriers of the minor allele for rs482548 (FADS2) had increased plasma FG levels after the n-3 PUFA supplementation in a model adjusted for FG levels at baseline, age, sex, and BMI. A significant genotype*supplementation interaction effect on FG levels was observed for rs482548 (p = 0.008). For FI levels, a genotype effect was observed with one SNP (rs174456). For HOMA-IS, several genotype*supplementation interaction effects were observed for rs7394871, rs174602, rs174570, rs7482316 and rs482548 (p = 0.03, p = 0.01, p = 0.03, p = 0.05 and p = 0.07; respectively). Conclusion: Results suggest that SNPs in the FADS gene cluster may modulate plasma FG, FI and HOMA-IS levels in response to n-3 PUFA supplementation. Full article
(This article belongs to the Special Issue Genetics of Diabetes)
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Review

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107 KiB  
Review
Genetics of Type 2 Diabetes and Clinical Utility
by Rajkumar Dorajoo, Jianjun Liu and Bernhard O. Boehm
Genes 2015, 6(2), 372-384; https://doi.org/10.3390/genes6020372 - 23 Jun 2015
Cited by 29 | Viewed by 6518
Abstract
A large proportion of heritability of type 2 diabetes (T2D) has been attributed to inherent genetics. Recent genetic studies, especially genome-wide association studies (GWAS), have identified a multitude of variants associated with T2D. It is thus reasonable to question if these findings may [...] Read more.
A large proportion of heritability of type 2 diabetes (T2D) has been attributed to inherent genetics. Recent genetic studies, especially genome-wide association studies (GWAS), have identified a multitude of variants associated with T2D. It is thus reasonable to question if these findings may be utilized in a clinical setting. Here we briefly review the identification of risk loci for T2D and discuss recent efforts and propose future work to utilize these loci in clinical setting—for the identification of individuals who are at particularly high risks of developing T2D and for the stratification of specific health-care approaches for those who would benefit most from such interventions. Full article
(This article belongs to the Special Issue Genetics of Diabetes)
4249 KiB  
Review
Genetics of Type 2 Diabetes—Pitfalls and Possibilities
by Rashmi B. Prasad and Leif Groop
Genes 2015, 6(1), 87-123; https://doi.org/10.3390/genes6010087 - 12 Mar 2015
Cited by 309 | Viewed by 41554
Abstract
Type 2 diabetes (T2D) is a complex disease that is caused by a complex interplay between genetic, epigenetic and environmental factors. While the major environmental factors, diet and activity level, are well known, identification of the genetic factors has been a challenge. However, [...] Read more.
Type 2 diabetes (T2D) is a complex disease that is caused by a complex interplay between genetic, epigenetic and environmental factors. While the major environmental factors, diet and activity level, are well known, identification of the genetic factors has been a challenge. However, recent years have seen an explosion of genetic variants in risk and protection of T2D due to the technical development that has allowed genome-wide association studies and next-generation sequencing. Today, more than 120 variants have been convincingly replicated for association with T2D and many more with diabetes-related traits. Still, these variants only explain a small proportion of the total heritability of T2D. In this review, we address the possibilities to elucidate the genetic landscape of T2D as well as discuss pitfalls with current strategies to identify the elusive unknown heritability including the possibility that our definition of diabetes and its subgroups is imprecise and thereby makes the identification of genetic causes difficult. Full article
(This article belongs to the Special Issue Genetics of Diabetes)
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415 KiB  
Review
The Genetics of Diabetic Nephropathy
by Eoin Brennan, Caitríona McEvoy, Denise Sadlier, Catherine Godson and Finian Martin
Genes 2013, 4(4), 596-619; https://doi.org/10.3390/genes4040596 - 05 Nov 2013
Cited by 31 | Viewed by 11404
Abstract
Up to 40% of patients with type 1 and type 2 diabetes will develop diabetic nephropathy (DN), resulting in chronic kidney disease and potential organ failure. There is evidence for a heritable genetic susceptibility to DN, but despite intensive research efforts the causative [...] Read more.
Up to 40% of patients with type 1 and type 2 diabetes will develop diabetic nephropathy (DN), resulting in chronic kidney disease and potential organ failure. There is evidence for a heritable genetic susceptibility to DN, but despite intensive research efforts the causative genes remain elusive. Recently, genome-wide association studies have discovered several novel genetic variants associated with DN. The identification of such variants may potentially allow for early identification of at risk patients. Here we review the current understanding of the key molecular mechanisms and genetic architecture of DN, and discuss the merits of employing an integrative approach to incorporate datasets from multiple sources (genetics, transcriptomics, epigenetic, proteomic) in order to fully elucidate the genetic elements contributing to this serious complication of diabetes. Full article
(This article belongs to the Special Issue Genetics of Diabetes)
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823 KiB  
Review
Monogenic Diabetes: A Diagnostic Algorithm for Clinicians
by Richard W. Carroll and Rinki Murphy
Genes 2013, 4(4), 522-535; https://doi.org/10.3390/genes4040522 - 26 Sep 2013
Cited by 24 | Viewed by 14026
Abstract
Monogenic forms of beta cell diabetes account for approximately 1%–2% of all cases of diabetes, yet remain underdiagnosed. Overlapping clinical features with common forms of diabetes, make diagnosis challenging. A genetic diagnosis of monogenic diabetes in many cases alters therapy, affects prognosis, enables [...] Read more.
Monogenic forms of beta cell diabetes account for approximately 1%–2% of all cases of diabetes, yet remain underdiagnosed. Overlapping clinical features with common forms of diabetes, make diagnosis challenging. A genetic diagnosis of monogenic diabetes in many cases alters therapy, affects prognosis, enables genetic counseling, and has implications for cascade screening of extended family members. We describe those types of monogenic beta cell diabetes which are recognisable by distinct clinical features and have implications for altered management; the cost effectiveness of making a genetic diagnosis in this setting; the use of complementary diagnostic tests to increase the yield among the vast majority of patients who will have commoner types of diabetes which are summarised in a clinical algorithm; and the vital role of cascade genetic testing to enhance case finding. Full article
(This article belongs to the Special Issue Genetics of Diabetes)
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1195 KiB  
Review
Genes Involved in Type 1 Diabetes: An Update
by Marina Bakay, Rahul Pandey and Hakon Hakonarson
Genes 2013, 4(3), 499-521; https://doi.org/10.3390/genes4030499 - 16 Sep 2013
Cited by 58 | Viewed by 12682
Abstract
Type 1 Diabetes (T1D) is a chronic multifactorial disease with a strong genetic component, which, through interactions with specific environmental factors, triggers disease onset. T1D typically manifests in early to mid childhood through the autoimmune destruction of pancreatic β cells resulting in a [...] Read more.
Type 1 Diabetes (T1D) is a chronic multifactorial disease with a strong genetic component, which, through interactions with specific environmental factors, triggers disease onset. T1D typically manifests in early to mid childhood through the autoimmune destruction of pancreatic β cells resulting in a lack of insulin production. Historically, prior to genome-wide association studies (GWAS), six loci in the genome were fully established to be associated with T1D. With the advent of high-throughput single nucleotide polymorphism (SNP) genotyping array technologies, enabling investigators to perform high-density GWAS, many additional T1D susceptibility genes have been discovered. Indeed, recent meta-analyses of multiple datasets from independent investigators have brought the tally of well-validated T1D disease genes to almost 60. In this mini-review, we address recent advances in the genetics of T1D and provide an update on the latest susceptibility loci added to the list of genes involved in the pathogenesis of T1D. Full article
(This article belongs to the Special Issue Genetics of Diabetes)
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