Genetic polymorphisms in susceptibility to Type 1 Diabetes

doi:10.1016/j.cca.2007.09.021

Clinica Chimica Acta

Volume 387, Issues 1–2, January 2008, Pages 9-17

https://doi.org/10.1016/j.cca.2007.09.021 Get rights and content

Abstract

Type 1 Diabetes is a serious complex disease caused by several environmental and genetic factors. It is one of most common childhood diseases, requires life-long treatment, and is associated with increased mortality, mainly due to complications that occur later in life. More than three decades of genetic studies have identified several genetic disease variants and a longer list of putative associated genetic loci. These findings have greatly increased our understanding of the genetic background of T1D and have encouraged the development of genetic tools for mapping complex diseases. Here we review the wealth of data on T1D and discuss the major genetic polymorphisms involved in the disease. We place some putative genetic risk factors in perspective and look at those still to be detected.

Introduction

Diabetes is a disease caused by the body's incapacity to either produce insulin (Type 1 Diabetes, T1D) or make use of it properly (Type 2 Diabetes, T2D). Much attention is being given to obesity-related T2D, partly because of the threats posed by the current epidemic of T2D, which may have a serious impact on the provision and costs of health care. T1D may only account for 5–10% of all diabetes cases, but it remains a serious, life-long disease [1]. It is the third most common disorder of childhood, affecting between 1 and 4 in 10,000 individuals before the age of 30 [2], [3]. T1D is an autoimmune disease that is characterized by autoimmune destruction of the insulin-producing pancreatic β-cells, resulting in a lack or absence of insulin production and disturbed glucose homeostasis [4]. Without replacement therapy by exogenous insulin, this condition will lead to hyperglycemia, ketosis and diabetic ketoacidosis, and will ultimately have fatal consequences.

T1D is considered to be a complex disease caused by multiple environmental and genetic risk factors [5]. Evidence for the influence of environmental factors is the global increase in incidence of 3% per year, and dietary factors that influence the susceptibility for T1D, such as early exposure to cow's milk and gluten [6], [7], [8]. It is also evident that genetic factors play an important role in determining the risk for T1D, since it shows a strong clustering in some families, with a sibling recurrence rate of 6%, and a monozygotic twin concordance rate of 30–50% [5], [9], [10], [11]. More direct evidence is seen in the strong association between several genetic variants and T1D. The first major genetic risk locus was detected as early as 1974 by Nerup et al. followed by Cudworth and Woodrow, who detected an association with the HLA system [12], [13]. Since then 30 years of genetic studies have significantly advanced our knowledge of genetic susceptibility factors for T1D, making it one of the most studied complex genetic diseases to date. Here we review the major findings from this large body of data and consider possible developments in the future.

Section snippets

HLA

The HLA complex (or Major Histocompatibility Complex (MHC)) was the first genetic region found to be associated with T1D (the IDDM1 locus). The HLA complex extends over 4 Mb and contains at least 128 genes, of which the majority is involved in immunity [14]. The HLA complex is divided into three main regions: classes I, II and III. HLA class I and II genes encode for surface molecules that present intracellular peptide fragments to T lymphocytes (Fig. 1). HLA class I genes are primarily

Established common variants

Many candidate genes have been studied in T1D in the past decades, but few have been found to be associated to T1D. Many of the initially significant associations failed to be confirmed by independent studies, some have been inconsistently confirmed, and only three have shown association consistently over many different studies and are now well established as risk factors for T1D. These three T1D loci are the Variable Number of Tandem Repeats (VNTR) near the Insulin gene (INS), the Cytotoxic

Refuted variants

The methods used in the genetic studies that identified the genetic risk factors for T1D have changed dramatically in recent years but these results have shaped our understanding of the genetic basis of common disease and the methods needed to elucidate them [81]. The established genetic risk factors are estimated to explain ∼ 60% of the genetic variability, and are probably those that confer a higher risk for disease and were therefore relatively easy to detect. Furthermore, all the established

Prospects of genome-wide studies

With the problems of initial reports of associations not being confirmed and from some theoretical considerations, it is now believed that genome-wide association studies will be able to detect the remaining important genetic risk factors for T1D [116]. Genome-wide association studies will scan the entire genome for association with disease, by testing up to 500,000 SNPs distributed evenly across the genome. Such studies require large samples of more than 1000 patients and controls to retain

Conclusions

Genetic studies of Type 1 Diabetes (T1D) have now spanned more than 30 years and have identified several undisputed genetic risk polymorphisms with a relatively modest risk for disease. These genetic risk variants are good examples of complex disease genes, and the methods by which they have been detected in T1D are serving as a standard for other complex diseases. In addition, the genetic polymorphisms found to be involved in T1D have significantly increased our understanding of which immune

Acknowledgments

This work was supported by the Dutch Diabetes Research Foundation, the Netherlands Organization for Health Research and Development, and the Juvenile Diabetes Research Foundation International (JDRF) (2001.10.004). We acknowledge Jorien van der Voort for graphic design.

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The onset of the disease usually occurs at a young age but also may occur at any age (Chiang et al., 2014; Fatehi-Hassanabad and Chan, 2005). T1D which accounts for 5–10% of diabetic cases, results from autoimmune-mediated destruction of pancreatic β cells (Accili, 2000; Behrooz and Bobby, 2007; Fatehi-Hassanabad and Chen, 2005). Type 2 diabetes mellitus (T2D), also known as non-insulin dependent diabetes (NIDDM) affects approximately between 2 and 6% of the adult population mostly in Western countries (Bailey, 2000) and estimated to be 8.3% in the whole world in 2011 to 2030 (Whiting et al., 2011).
Pyruvate dehydrogenase kinase 4 (PDK4), a mammalian mitochondrial serine kinase has emerged as an interesting candidate for diabetes therapy. Due to the high prevalence of this disease especially type 2 diabetes (T2D) and the health complications associated with it, there is extensive effort to find the appropriate treatment. Understanding the regulation of PDK4 activity would therefore contribute significantly to the development of therapeutic agents. This research outlines the utilization of bioinformatics tools such as Interweaver, ClustalW and Protein Structure Visualizer, in order to predict proteins that potentially interact with PDK4 and possibly regulate its activity. Interweaver database identified 96 proteins that have possible interaction sites for PDK4. Protein p100/p49, containing a death domain that is known to have a role in suppressing apoptosis, was identified as a potential partner for PDK4. The alignment between p100/p49 primary sequence and that of PDK4 using ClustalW demonstrated sequence similarity between the two proteins. Swiss PDB Viewer then located the positions of the amino acids that are in the hypothetical protein binding motif of p100/p49 within the 3D structure of hPDK4. These amino acids were found to be located in the region of PDK4 which is known to bind protein substrates of PDK4 and may be accessible to other proteins as well. These findings were very interesting as PDK4 has not previously been associated with apoptosis and this could be the link between apoptosis and insulin resistance. Cell biology studies were then performed to verify the relationship between PDK4 and apoptosis. In this regard, HeLa and HepG2 cells were treated with apoptosis-inducing agents such as TNFα, C2-ceramide, and linoleic acid. These cells were then monitored for apoptosis and PDK4 mRNA expression using a DNA laddering assay as well as Real Time PCR. The results showed that these factors induced apoptosis in a concentration dependent manner and suppressed PDK4 mRNA levels. These findings suggested a relationship between PDK4 and apoptosis.
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High concentrations of anti-caspase-8 antibodies in Chilean patients with type 1 diabetes
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Deregulation of apoptosis across the Fas–FasL pathway is an increasingly relevant phenomenon in the pathogenic mechanisms associated with autoimmune diseases. Caspase-8 initiates the activation of the apoptotic process and interacts directly with Fas in the membrane of the T lymphocyte.
To standardize an Elisa essay to measure the concentration of anti-caspase-8 antibodies in plasma of Type 1 Diabetes (T1D) patients and analyze their possible distribution and association with characteristics of the disease.
124 patients newly diagnosed with T1D and 132 controls: children and youngsters. ELISA test was standardized to detect anti-caspase-8 antibodies in plasma. It correlated the concentration of this antibody with classical markers of autoimmunity as anti-IA-2 and anti-GAD65, and the clinical characteristics at onset of diabetes mellitus. The statistical analysis was performed using logistic regression.
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This is the first report in the literature of levels of anti-caspase-8 antibodies in T1D through ELISA. The high concentration in patients with T1D, and its strong correlation with anti-GAD65 auto-antibodies, suggests a potential role of anti-caspase-8 auto-antibodies as surrogate marker autoimmunity in T1D patients.
The flavoheme reductase Ncb5or protects cells against endoplasmic reticulum stress-induced lipotoxicity
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NCB5OR is a novel flavoheme reductase with a cytochrome b5-like domain at the N-terminus and a cytochrome b5 reductase-like domain at the C terminus. Ncb5or knock-out mice develop insulin deficient diabetes and loss of white adipose tissue. Ncb5or^−/− mice have impairment of Δ9 fatty acid desaturation with elevated ratios of palmitate to palmitoleate and stearate to oleate. In this study we assess the role of the endoplasmic reticulum (ER) stress response in mediating lipotoxicity in Ncb5or^−/− mice. The ER stress response was assessed by induction of BiP, ATF3, ATF6, XBP-1, and C/EBP homologous protein (CHOP). Exposure to palmitate, but not oleate or mixtures of oleate and palmitate induced these markers of ER stress to a much greater extent in Ncb5or^−/− hepatocytes than in wild-type cells. In contrast, Ncb5or^−/− and Ncb5or^+/+ hepatocytes were equally sensitive to ER stress imposed by increasing concentrations of tunicamycin. In order to assess the role of ER stress in vivo, we prepared mice that lack both NCB5OR and CHOP, a proapoptotic transcription factor important in the ER stress response. Onset of hyperglycemia in the Chop^−/−;Ncb5or^−/− mice was delayed two weeks beyond that observed in Chop^+/+;Ncb5or^−/− mice. Taken together these results suggest that ER stress plays a critical role in palmitate-induced lipotoxicity both in vitro and in vivo.
An insight into the genetics of type 1 Diabetes
2009, Inmunologia
Citation Excerpt :
These data point to the regulation of self-tolerance in the thymus as a milestone in the development of T1D pathology. By inducing higher levels of insulin expression in the thymus, class III alleles would allow a stronger negative selection and deletion of insulin-reactive T lymphocyte clones, preventing their escape from the thymus and trigger of the autoimmune reaction(19-21). Reactivity to insulin alone is not enough to develop T1D, but it has been observed that individuals with the susceptibility polymorphisms have a higher rate of insulin autoantibodies(22).
La diabetes tipo 1 (T1D) es una enfermedad compleja causada por la destrucción autoinmune de las células beta del páncreas, fruto de la interacción entre factores genéticos y ambientales. A pesar de los enormes avances en el estudio de la T1D, los mecanismos etiológicos de la enfermedad y los factores genéticos y ambientales implicados en la misma siguen siendo en parte desconocidos.
La investigación en el campo de la genética de la T1D abarca más de treinta años y se han descubierto hasta 40 regiones cromosómicas relacionadas con la susceptibilidad a T1D. Algunas de ellas, como la correspondiente al HLA o al gen de la insulina, se han establecido claramente como factores de riesgo, mientras que en otras se necesita confirmar resultados preliminares. En este texto revisaremos algunos de estos genes de susceptibilidad: los alelos del MHC de clase II, el gen de la insulina, CTLA4, PTPN22, IL2 y la subunidad de su receptor IL2RA, la helicasa IFIH1/MDA5, el bloque CAPSL-IL7R, la lectina CLEC16A, el factor de transcripción de la respuesta Th1 STAT4 y la tirosin-fosfatasa PTPN2.
Type 1 Diabetes (T1D) is a complex trait caused by T-cell mediated autoimmune destruction of islet beta cells in the pancreas, resulting of the interaction between genetic and environmental factors. Despite enormous advances in the study of T1D, the aethiologic mechanisms of this disease and the genetic and environmental factors involved remain not fully determined.
Research in the field of T1D genetics spans now for more than thirty years and up to 40 chromosomic regions associated with T1D susceptibility have been reported. Some of these, namely the HLA region or the insulin gene, are clearly established as risk factors while others need more study to confirm preliminary results. In this text we will review some of the main susceptibility genes currently accepted for T1D: the MHC class II alleles, the insulin gene, CTLA4, PTPN22, IL2 and its receptor subunit IL2RA, the helicase IFIH1/MDA5, the CAPSL-IL7R block, the lectin CLEC16A, the Th1 transcription factor STAT4, and the tyrosine phosphatase PTPN2.
Interactions between programmed death 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) gene polymorphisms in type 1 diabetes
2009, Diabetes Research and Clinical Practice
Citation Excerpt :
T1D is a T cell-mediated autoimmune disease characterized by the self-destruction of the insulin secreting (β) cells in the pancreas by means of interactions between genes and environmental factors [1–5].
To explore the contribution of the PD-1 gene polymorphisms involved in T1D as well as the relationship between the PD-1/CTLA-4 genes and soluble CTLA-4 concentrations.
261 incident cases of T1D and 280 healthy children less 15 years old were included in this study. Haplotypes for polymorphisms of the PD-1 and CTLA-4 genes were determined by PCR and RFLP methods. Screening for soluble CTLA-4 was done using an ELISA assay. Statistical analysis was performed using the online SHESIS package.
Our results show that sCTLA-4 levels were higher in T1D than in controls (2.99 ± 1.7 ng/ml versus 1.43 ± 0.31 ng/ml, p < 0.001). The allele dosage of CTLA-4 on PD-1 haplotypes, showing a significant modified effect of G carriers over AA genotype on the sCTLA-4 concentrations (5.48 ± 2.09 ng/ml versus 3.27 ± 1.30 ng/ml, p < 0.03 in T–C haplotype) and (1.92 ± 0.79 ng/ml versus 3.41 ± 1.10 ng/ml, p < 0.02 in C–T haplotype).
Consistent with the higher serum sCTLA-4 levels observed in other autoimmune diseases, our results suggest that sCTLA-4 is elevated in T1D. Our data suggest a possible gene dosage effect of “G” CTLA-4 carriers on sCTLA-4 over the possible protective or susceptible effect conferred by PD-1 haplotypes.

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Invited critical reviewGenetic polymorphisms in susceptibility to Type 1 Diabetes

Abstract

Introduction

Section snippets

HLA

Established common variants

Refuted variants

Prospects of genome-wide studies

Conclusions

Acknowledgments

Immunol Today

J Autoimmun

Lancet

Hum Immunol

Hum Immunol

Immunol Today

Hum Immunol

Am J Hum Genet

Am J Hum Genet

Curr Opin Immunol

J Autoimmun

Blood

Am J Hum Genet

Am J Hum Genet

Hum Immunol

Am J Hum Genet

Lancet

Diabetes Res Clin Pract

J Mol Diagn

J Autoimmun

Prevalence and incidence rate of diabetes mellitus in a Swedish community during 30 years of follow-up

Diabetologia

Geographical variation of presentation at diagnosis of type I diabetes in children: the EURODIAB study. European and Diabetes

Diabetologia

Incidence of childhood type 1 diabetes worldwide. Diabetes Mondiale (DiaMond) Project Group

Diabetes Care

Immunopathogenesis and immunotherapeutic approaches to type 1A diabetes

Expert Opin Biol Ther

Increased levels of cow's milk and beta-lactoglobulin antibodies in young children with newly diagnosed IDDM. The Childhood Diabetes in Finland Study Group

Diabetes Care

Relationship between cows' milk consumption and incidence of IDDM in childhood

Diabetes Care

Is it dietary insulin?

Ann N Y Acad Sci

Concordance rates of insulin dependent diabetes mellitus: a population based study of young Danish twins

Bmj

Genetic liability of type 1 diabetes and the onset age among 22,650 young Finnish twin pairs: a nationwide follow-up study

Diabetes

HL-A system and diabetes mellitus

Diabetes

Gene map of the extended human MHC

Nat Rev Genet

HLA-D region beta-chain DNA endonuclease fragments differ between HLA-DR identical healthy and insulin-dependent diabetic individuals

Nature

HLA-DQ beta gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus

Nature

A diabetes-susceptible HLA haplotype is best defined by a combination of HLA-DR and -DQ alleles

J Clin Invest

HLA-encoded genetic predisposition in IDDM: DR4 subtypes may be associated with different degrees of protection

Diabetes

A correlation between the relative predisposition of MHC class II alleles to type 1 diabetes and the structure of their proteins

Hum Mol Genet

HLA class II alleles and susceptibility and resistance to insulin dependent diabetes mellitus in Mexican–American families

Nat Genet

Genotype effects and epistasis in type 1 diabetes and HLA-DQ trans dimer associations with disease

Genes Immun

HLA-DQA1 and -DQB1 alleles associated with genetic susceptibility to IDDM in a black population

Diabetes

The role of HLA class II genes in insulin-dependent diabetes mellitus: molecular analysis of 180 Caucasian, multiplex families

Am J Hum Genet

Distribution of HLA-DRB1, -DQA1 and -DQB1 alleles and DQA1-DQB1 genotypes among Norwegian patients with insulin-dependent diabetes mellitus

Tissue Antigens

HLA class II associations with Type 1 diabetes mellitus: a multivariate approach

Tissue Antigens

The HLA associated predisposition to type 1 diabetes and other autoimmune diseases

J Pediatr Endocrinol Metab

Relative predispositional effects of HLA class II DRB1-DQB1 haplotypes and genotypes on type 1 diabetes: a meta-analysis

Tissue Antigens

Transcomplementation of HLA genes in IDDM. HLA-DQ alpha- and beta-chains produce hybrid molecules in DR3/4 heterozygotes

Diabetes

Invited critical review
Genetic polymorphisms in susceptibility to Type 1 Diabetes

Impaired binding of a DQ2 and DQ8-binding HSV VP16 peptide to a DQA1^⁎0501/DQB1^⁎0302 trans class II heterodimer