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| 2. |
- Bakhtadze, Ekaterine, et al.
(författare)
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Common variants in the TCF7L2 gene help to differentiate autoimmune from non-autoimmune diabetes in young (15-34 years) but not in middle-aged (40-59 years) diabetic patients
- 2008
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 51:12, s. 2224-2232
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Tidskriftsartikel (refereegranskat)abstract
- Type 1 diabetes in children is characterised by autoimmune destruction of pancreatic beta cells and the presence of certain risk genotypes. In adults the same situation is often referred to as latent autoimmune diabetes in adults (LADA). We tested whether genetic markers associated with type 1 or type 2 diabetes could help to discriminate between autoimmune and non-autoimmune diabetes in young (15-34 years) and middle-aged (40-59 years) diabetic patients. In 1,642 young and 1,619 middle-aged patients we determined: (1) HLA-DQB1 genotypes; (2) PTPN22 and INS variable-number tandem repeat (VNTR) polymorphisms; (3) two single nucleotide polymorphisms (rs7903146 and rs10885406) in the TCF7L2 gene; (4) glutamic acid decarboxylase (GAD) and IA-2-protein tyrosine phosphatase-like protein (IA-2) antibodies; and (5) fasting plasma C-peptide. Frequency of risk genotypes HLA-DQB1 (60% vs 25%, p =9.4x10(-34); 45% vs 18%, p= 1.4x10(-16)), PTPN22 CT/TT (34% vs 26%, p=0.0023; 31% vs 23%, p=0.034), INS VNTR class I/I (69% vs 53%, p=1.3x10(-8); 69% vs 51%, p=8.5x10(-5)) and INS VNTR class IIIA/IIIA (75% vs 63%, p=4.3x10(-6); 73% vs 60%, p=0.008) was increased in young and middle-aged GAD antibodies (GADA)-positive compared with GADA-negative patients. The type 2 diabetes-associated genotypes of TCF7L2 CT/TT of rs7903146 were significantly more common in young GADA-negative than in GADA-positive patients (53% vs 43%; p=0.0004). No such difference was seen in middle-aged patients, in whom the frequency of the CT/TT genotypes of TCF7L2 was similarly increased in GADA-negative and GADA-positive groups (55% vs 56%). Common variants in the TCF7L2 gene help to differentiate young but not middle-aged GADA-positive and GADA-negative diabetic patients, suggesting that young GADA-negative patients have type 2 diabetes and that middle-aged GADA-positive patients are different from their young GADA-positive counterparts and share genetic features with type 2 diabetes.
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| 3. |
- Bakhtadze, Ekaterine
(författare)
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Exploring the Grey Zone between Type 1 and Type 2 Diabetes
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- T1D is most common in children and young adults and is characterized by autoimmune destruction of insulin producing pancreatic beta cells, presence of certain risk genotypes such as HLA-DQB1, INS VNTR, PTPN22 and need of insulin for survival. In adults the same situation is often referred to as Latent Autoimmune Diabetes in Adults (LADA), with age at onset after 35 years and non-insulin requiring at least for 6 month after diagnosis. On the other hand, T2D is characterized by impaired insulin secretion and/or insulin resistance, which coexists with excessive hepatic glucose production and abnormal fat metabolism. Environmental factors causing insulin resistance are puberty, pregnancy, weight gain (central obesity “apple type”) and sedentary lifestyle. Usually T2D is diagnosed after 40 years of age and in some cases is diagnosed when patients develop vascular and neuropathic complications. TCF7L2 is by far the strongest T2D-associated gene. Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes inherited in an autosomal dominant fashion (individual has one copy of a mutant gene and one normal gene on a pair of autosomal chromosomes) characterized by nonketotic diabetes, age at onset before 25 years and primarily defect in beta-cell function. Until now, mutations in six genes have been identified as the cause of different forms of MODY, i.e. HNF-4 (MODY 1), glucokinase (GCK) (MODY 2), HNF-1 (MODY 3), IPF1 (MODY 4), HNF-1ß, formerly TCF2 (MODY 5) and NeuroD1 (MODY6). The goal of this thesis was to genetically dissect autoimmune (T1D and LADA) and non-autoimmune (T2D and MODY) diabetes in young (15-34 years old)and middle-aged (40-59 years old) Swedish diabetic patients for proper diagnosis and treatment of the disease in the future. To fulfill our goals we have selected 1642 young (15-34 years old) adult diabetic patients from Diabetes Incidence Study in Sweden (DISS) and 1619 middle-aged (40-59 years old) diabetic patients from Diabetes Registry in Southern Sweden. We determined genetic markers: HLA-DQB1 (study I and II), PTPN22, Ins VNTR, TCF7L2 (study II), PPARG, KCNJ11, IGF2BP2, WFS1, CDKAL1, JAZF1, CDKN2A/2B, HHEX, SLC30A8 and FTO (study III) and MODY genes- HNF-4 , GCK, HNF-1 and HNF-1ß, formerly TCF2 (study IV), measured islet antibodies (ICA, IA-2A and GADA) and C-peptide (marker of beta-cell function instead of insulin). In Study I we evaluated whether HLA-DQB1 genotypes facilitates the classification of diabetes as compared with islet antibodies among young (15-34 years) adult diabetic patients. Islet antibodies were found among 83% clinically considered to have T1D, 23% with T2D and 45% with unclassifiable diabetes.fpC-peptide concentrations after diagnosis were markedly lower in patients with than in those without islet antibodies. Irrespective of clinical classification, patients with islet antibodies showed increased frequencies of at least one risk HLA-DQB1 genotypes compared with patients without. Antibody negative patients with risk HLA-DQB1 genotypes had significantly lower fasting fpC-peptide concentrations than those without risk genotypes. We concluded that Assessment of islet antibodies is necessary for an etiological classification of diabetic patients. HLA-DQB1 genotyping does not improve the classification in patients with islet antibodies. However, in patients without islet antibodies, HLA-DQB1 genotyping together with fpC-peptide measurement may be of value in the differentiation between idiopathic T1D versus T2D. In Study II we evaluated whether genetic markers associated with T1D (HLADQB1,INS VNTR and PTPN22) and T2D (TCF7L2) could help to discriminate between autoimmune and non-autoimmune diabetes in young (15-34 years) and middle-aged (40-59 years) diabetic patients. Frequency of risk genotypes HLADQB1, PTPN22 CT/TT, INS VNTR class I/I and INS VNTR class IIIA/IIIA was increased in young and middle-aged GADA+ compared with GADA- patients. T2D-associated genotypes of TCF7L2 CT/TT of rs7903146 were significantly more common in young GADA- than in GADA+ patients. No such difference was seen in middle-aged patients, in whom the frequency of the CT/TT genotypes of TCF7L2 was similarly increased in GADA- and GADA+ groups. We concluded that common variants in the TCF7L2 gene help to differentiate young but not middle aged GADA+ and GADA- diabetic patients, suggesting that young GADA- patients have T2D and that middle-aged GADA+ patients (LADA) are different from their young GADA-positive (T1D) counterparts and share genetic features with T2D. In Study III we genotyped a panel of 10 novel T2D-associated risk genotypes in young (15-34 years) and middle-aged (40-59 years) GADA+ and GADA- diabetic patients and evaluated how they would modify the clinical phenotype. Young GADA- patients had increased frequency of risk variants in the PPARG, IGF2BP2, WFS1, JAZF1 and CDKN2A/2B genes compared with an elderly nondiabetic control group. Also risk variants in JAZF1 (AA) and CDKN2A/2B (TT) were more common in GADA- than in GADA + young diabetic patients. As expected middle-aged GADA- patients had increased prevalence of risk variants in the PPARG, IGF2BP2, WFS1, CDKAL1, JAZF1, SLC30A8, CDKN2A/2B, KCNJ11 and FTO genes compared with non-diabetic controls with no significant difference compared with GADA+ patients. Middle-aged GADA diabetic patients with more risk alleles (≥12) had decreased C-peptide concentrations than patients with less risk alleles (≤9). Also, GADA+ patients with more risk alleles had an earlier age at onset than GADA+ patients with less risk alleles. Distribution of T2D-associated risk alleles was quite similar inmiddle-aged patients regardless of presence of GADA. T2D- associated risk genotypes modify the disease phenotype (age at onset and C-peptide) in middleaged but not in young diabetic patients. In Study IV we evaluated whether common variants in MODY genes can discriminate between autoimmune and non-autoimmune diabetes in young adult diabetic patients and screened antibody negative diabetic patients with 3 members with diabetes in the family for HNF-4 , GCK and HNF-1 mutations. No significant difference in frequency of common variants in MODY genes was seen between Ab+ and Ab- individuals. In Ab+ diabetic patients carriers of the T2D-associated T allele of the HNF-1 gene had higher age at onset of diabetes, but severe symptoms of diabetes (weight reduction and/or polyuria) than G allele carriers. Finally, in Ab- diabetic patients carriers of the T2D-associated G allele of HNF-1ß gene had less frequent weight reduction and/or polyuria and ketonuria at diagnosis than A allele careers. One patient had frameshift mutation in exon 4 designated “Pro291fsinsC” in the HNF-1 gene. Common variants in MODY genes do not discriminate between young patients with autoimmune and non-autoimmune diabetes but they do influence onset and presentation of the disease. Our studies show that genetic markers clearly improve the classification of diabetes and together with islet antibodies they might be of help for diagnosis and treatment of different diabetic subgroups.
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| 5. |
- Cervin, Camilla, et al.
(författare)
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Genetic similarities between latent autoimmune diabetes in adults, type 1 diabetes, and type 2 diabetes
- 2008
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 57:5, s. 1433-1437
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE-Latent autoimmune diabetes in adults (LADA) is often considered a slowly progressing subtype of type 1 diabetes, although the clinical picture more resembles type 2 diabetes. One way to improve classification is to study whether LADA shares genetic features with type 1 and/or type 2 diabetes. RESEARCH DESIGN AND METHODS-To accomplish this we studied whether LADA shares variation in the HLA locus or INS VNTR and PTPN22 genes with type I diabetes or the TCF7L2 gene with type 2 diabetes in 361 LADA, 718 type 1 diabetic, and 1,676 type 2 diabetic patients, as well as 1,704 healthy control subjects from Sweden and Finland. RESULTS-LADA subjects showed, compared with type 2 diabetic patients, increased frequency of risk for the HLA-DQB1 *0201/*0302 genotype (27 vs. 6.9%; P < 1 X 10(-6)), with similar frequency as with type I diabetes (36%). In addition, LADA subjects showed higher frequencies of protective HLA-DQB1 *0602(3)/X than type I diabetic patients (8.1 vs. 3.2%, P = 0.003). The AA genotype of rs689, referring to the class I allele in the INS VNTR, as well as the CT/TT genotypes of rs2476601 in the PTPN22 gene, were increased both in type 1 diabetic (P = 3 X 10(-14) and P = 1 X 10(-10), respectively) and LADA (P = 0.001 and P = 0.002) subjects compared with control subjects. Notably, the frequency of the type 2 diabetes-associated CT/TT genotypes of rs7903146 in the TCF7L2 were increased in LADA subjects (52.8%; P = 0.03), to the same extent as in type 2 diabetic subjects (54.1%, P = 3 X 10(-7)), compared with control subjects (44.8%) and type I diabetic subjects (43.39%). CONCLUSIONS-LADA shares genetic features with both type I (HLA, INS VNTR, and PTPN22) and type 2 (TCF7L2) diabetes, which justifies considering LADA as an admixture of the two major types of diabetes.
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| 6. |
- Lindholm, Eero, et al.
(författare)
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Association between LTA, TNF and AGER polymorphisms and late diabetic complications.
- 2008
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 3:6
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Several candidate genes on the short arm of chromosome 6 including the HLA locus, TNF, LTA and AGER could be associated with late diabetic complications. The aim of our study was therefore to explore whether polymorphisms (TNF -308 G-->A, LTA T60N C-->A and AGER -374 T-->A) in these genes alone or together (as haplotypes) increased the risk for diabetic complications. METHODOLOGY/PRINCIPAL FINDINGS: The studied polymorphisms were genotyped in 742 type 1 and 2957 type 2 diabetic patients as well as in 206 non-diabetic control subjects. The Haploview program was used to analyze putative linkage disequilibrium between studied polymorphisms. The TNF, LTA and AGER polymorphisms were associated with the HLA-DQB1 risk genotypes. The AGER -374 A allele was more common in type 1 diabetic patients with than without diabetic nephropathy (31.2 vs. 28.4%, p = 0.007). In a logistic regression analysis, the LTA but not the AGER polymorphism was associated with diabetic nephropathy (OR 2.55[1.11-5.86], p = 0.03). The AGER -374 A allele was associated with increased risk of sight threatening retinopathy in type 2 diabetic patients (1.65[1.11-2.45], p = 0.01) and also with increased risk for macrovascular disease in type 1 diabetic patients (OR 2.05[1.19-3.54], p = 0.01), but with decreased risk for macrovascular disease in type 2 diabetic patients (OR 0.66[0.49-0.90], p = 0.009). The TNF A allele was associated with increased risk for macrovascular complications in type 2 (OR 1.53 [1.04-2.25], p = 0.03, but not in type 1 diabetic patients. CONCLUSIONS/SIGNIFICANCE: The association between diabetic complications and LTA, TNF and AGER polymorphisms is complex, with partly different alleles conferring susceptibility in type 1 and type 2 diabetic patients. We can not exclude the possibility that the genes are part of a large haplotype block that also includes HLA-DQB1 risk genotypes.
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| 7. |
- Lindholm, Eero, et al.
(författare)
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The -374 T/A polymorphism in the gene encoding RAGE is associated with diabetic nephropathy and retinopathy in type 1 diabetic patients.
- 2006
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 49:Sep 13, s. 2745-2755
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis The receptor for AGE (RAGE) is considered to be mainly an intracellular signal-transducer or pro-inflammatory peptide of possible importance for inflammation and autoimmune diseases. Our aim was to study whether the -374 T/A polymorphism in the gene encoding RAGE (AGER) is associated with diabetes type and presence of diabetic complications. Methods The AGER -374 T/A polymorphism was genotyped in 867 type 1 diabetic patients, 2,467 type 2 diabetic patients and 205 non-diabetic control subjects of Scandinavian origin. Results AGER polymorphism was related to different HLA-DQB1 genotypes and the presence of diabetic complications. Type 1 diabetic patients had a higher frequency of the AGER -374 A/A or T/A genotypes than type 2 diabetic patients (51.1 vs 44.9%, p=0.002) and control subjects (51.1 vs 47.6%, p=0.0006). The RAGE -374 T/A polymorphism was associated with HLA-DQB1 genotypes; patients with HLA risk genotypes had a higher frequency of the A/A or T/A genotypes than patients with other HLA-DQB1 genotypes (60.3 vs 40.3%, p < 0.000001). In type 1 diabetic patients, the frequency of the A/A or T/A genotypes was higher in patients with diabetic nephropathy than without (61.1 vs 46.8%, p=0.006) and with sight-threatening retinopathy than without (56.1 vs 47.6%, p=0.03). In type 2 diabetic patients with HbA(1c) values below the median, the T/T genotype was more frequent in patients with diabetic nephropathy than without (54.3 vs 38.2%, p=0.02). Conclusions/interpretation Our results show an association between the AGER -374 T/A polymorphism and type 1 diabetes. This association was HLA-DQB1-dependent. The polymorphism was associated with diabetic nephropathy in both type 1 and type 2 diabetes, in an HbA(1c)-dependent manner in the latter group, and also with sight-threatening retinopathy in type 1 diabetic patients.
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| 8. |
- Stenström, Gunnar, et al.
(författare)
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Latent Autoimmune Diabetes in Adults: Definition, Prevalence, {beta}-Cell Function, and Treatment.
- 2005
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Ingår i: Diabetes. - 1939-327X. ; 54:Suppl 2, s. 68-72
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Tidskriftsartikel (refereegranskat)abstract
- Latent autoimmune diabetes in adults (LADA) is a disorder in which, despite the presence of islet antibodies at diagnosis of diabetes, the progression of autoimmune ß-cell failure is slow. LADA patients are therefore not insulin requiring, at least during the first 6 months after diagnosis of diabetes. Among patients with phenotypic type 2 diabetes, LADA occurs in 10% of individuals older than 35 years and in 25% below that age. Prospective studies of ß-cell function show that LADA patients with multiple islet antibodies develop ß-cell failure within 5 years, whereas those with only GAD antibodies (GADAs) or only islet cell antibodies (ICAs) mostly develop ß-cell failure after 5 years. Even though it may take up to 12 years until ß-cell failure occurs in some patients, impairments in the ß-cell response to intravenous glucose and glucagon can be detected at diagnosis of diabetes. Consequently, LADA is not a latent disease; therefore, autoimmune diabetes in adults with slowly progressive ß-cell failure might be a more adequate concept. In agreement with proved impaired ß-cell function at diagnosis of diabetes, insulin is the treatment of choice. In 1986, Groop et al. (1) reported a subgroup of type 2 diabetic patients who, despite having islet autoantibodies, showed preserved ß-cell function. The type of diabetes in these patients was referred to as latent type 1 diabetes, showing clearly different features from classic type 1 and classic type 2 diabetes. Later, Tuomi et al. (2) and Zimmet et al. (3) launched the eponym LADA (latent autoimmune diabetes in adults) for this slowly progressive form of autoimmune diabetes initially managed with diet and oral hypoglycemic agents before becoming insulin requiring. However, it is now clear that classic autoimmune type 1 diabetes (4) is frequent among patients older than 30 years at diagnosis of diabetes. Whether LADA is a separate entity from conventional autoimmune type 1 diabetes among adults may therefore be challenged. In this article, we review LADA with regard to definitions and our experience with ß-cell function and discuss treatment. The question as to whether the eponym LADA still should be used will also be considered.
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| 9. |
- Thrainsdottir, Soley, et al.
(författare)
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Sural nerve biopsy may predict future nerve dysfunction.
- 2009
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Ingår i: Acta Neurologica Scandinavica. - : Hindawi Limited. - 1600-0404 .- 0001-6314. ; 120, s. 38-46
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Tidskriftsartikel (refereegranskat)abstract
- Thrainsdottir S, Malik RA, Rosén I, Jakobsson F, Bakhtadze E, Petersson J, Sundkvist G, Dahlin LB. Sural nerve biopsy may predict future nerve dysfunction. Acta Neurol Scand: DOI: 10.1111/j.1600-0404.2008.01118.x. (c) 2008 The Authors Journal compilation (c) 2008 Blackwell Munksgaard.Objective - Sural nerve pathology in peripheral neuropathy shows correlation with clinical findings and neurophysiological tests. The aim was to investigate progression of nerve dysfunction over time in relation to a baseline nerve biopsy. Methods - Baseline myelinated nerve fiber density (MNFD) was assessed in sural nerve biopsies from 10 men with type 2 diabetes, 10 with impaired and 10 with normal glucose tolerance. Nerve conduction and quantitative perception thresholds were estimated at baseline and follow-up (7-10 years later). Results - Subjects with low MNFD (
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