| 1. |
- Bakhtadze, Ekaterine, et al.
(author)
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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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In: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 51:12, s. 2224-2232
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Journal article (peer-reviewed)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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| 2. |
- Jansson, Henrik, et al.
(author)
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Type 2 diabetes and risk for periodontal disease: a role for dental health awareness
- 2006
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In: Journal of Clinical Periodontology. - 1600-051X .- 0303-6979. ; 33:6, s. 408-414
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Journal article (peer-reviewed)abstract
- Background: Several studies have found correlations between diabetes and an increased prevalence of periodontitis. Objective: To analyse, in a group of subjects with type 2 diabetes (T2D), (i) the association between medical characteristics and severe periodontal disease and (ii) dental care habits and knowledge of oral health. Methods: One hundred and ninety-one subjects with T2D were examined. Based on assessment of marginal bone height in panoramic radiographs, two periodontal subgroups were identified: one periodontally diseased (PD+) and one periodontally healthy (PD-) group. All subjects completed a questionnaire about their medical and oral health. Results: Twenty per cent of the subjects were classified as PD+. This was verified by clinical parameters. PD+ individuals had higher haemoglobin A1c (HbA1c) levels (p=0.033) and higher prevalences of cardiovascular complications (p=0.012). They were also less likely to be of Scandinavian origin (p=0.028) and more likely to smoke (p < 0.001) than the PD- group. The PD+ group rated their oral health as poor (p < 0.0001) and believed that T2D had an influence on their oral status (p < 0.0001). Conclusion: The best predictor for severe periodontal disease in subjects with T2D is smoking followed by HbA1c levels. T2D subjects should be informed about the increased risk for periodontal disease when suffering from T2D.
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| 3. |
- Ahluwalia, Tarun, et al.
(author)
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Common variants in CNDP1 and CNDP2, and risk of nephropathy in type 2 diabetes.
- 2011
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In: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 54, s. 2295-2302
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Journal article (peer-reviewed)abstract
- AIMS/HYPOTHESIS: Several genome-wide linkage studies have shown an association between diabetic nephropathy and a locus on chromosome 18q harbouring two carnosinase genes, CNDP1 and CNDP2. Carnosinase degrades carnosine (β-alanyl-L-: histidine), which has been ascribed a renal protective effect as a scavenger of reactive oxygen species. We investigated the putative associations of genetic variants in CNDP1 and CNDP2 with diabetic nephropathy (defined either as micro- or macroalbuminuria) and estimated GFR in type 2 diabetic patients from Sweden. METHODS: We genotyped nine single nucleotide polymorphisms (SNPs) and one trinucleotide repeat polymorphism (D18S880, five to seven leucine repeats) in CNDP1 and CNDP2 in a case-control set-up including 4,888 unrelated type 2 diabetic patients (with and without nephropathy) from Sweden (Scania Diabetes Registry). RESULTS: Two SNPs, rs2346061 in CNDP1 and rs7577 in CNDP2, were associated with an increased risk of diabetic nephropathy (rs2346061 p = 5.07 × 10(-4); rs7577 p = 0.021). The latter was also associated with estimated GFR (β = -0.037, p = 0.014), particularly in women. A haplotype including these SNPs (C-C-G) was associated with a threefold increased risk of diabetic nephropathy (OR 2.98, 95% CI 2.43-3.67, p < 0.0001). CONCLUSIONS/INTERPRETATION: These data suggest that common variants in CNDP1 and CNDP2 play a role in susceptibility to kidney disease in patients with type 2 diabetes.
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| 4. |
- Ahluwalia, Tarunveer S, et al.
(author)
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Uromodulin gene variant is associated with type 2 diabetic nephropathy.
- 2011
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In: Journal of Hypertension. - 1473-5598. ; 29, s. 1731-1734
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Journal article (peer-reviewed)abstract
- AIMS/HYPOTHESIS: About 35% of individuals with type 2 diabetes develop persistent albuminuria, lose renal function, and are at increased risk for microvascular complications like diabetic nephropathy. Recent genome-wide association studies have identified the uromodulin locus (UMOD), encoding the most common protein in human urine to be associated with hypertension and also with chronic kidney disease (CKD). In the present study we examined the association of the common variant of the uromodulin (UMOD) gene with type 2 diabetic nephropathy and kidney function. METHODS: UMOD variant rs13333226 was genotyped in a case-control material including 4888 unrelated type 2 diabetic individuals (n = 880 with and n = 4008 without nephropathy) from Sweden (Scania Diabetes Registry) using the ABI Real time TaqMan allelic discrimination assay. RESULTS: The G allele of rs13333226 was associated with a decreased risk of nephropathy [odds ratio (OR) 0.80, 95% confidence interval (CI) 0.69-0.91, P = 0.001] after correction for confounding factors like age, sex, body mass index (BMI), blood pressure, kidney function, smoking and duration of diabetes. The same allele was also associated with a better kidney function [estimated glomerular filtration rate (eGFR), β = 0.117, P < 0.0001] and lower systolic blood pressure (β = -0.048, P = 0.013) in the overall study cohort. CONCLUSION/INTERPRETATION: The present study highlights that the common variant of the UMOD gene is protective against diabetic nephropathy susceptibility and also affects kidney function and blood pressure in patients with type 2 diabetes. However, the association with diabetic nephropathy was independent of blood pressure and kidney function.
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| 5. |
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| 6. |
- Cervin, Camilla, et al.
(author)
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Genetic similarities between latent autoimmune diabetes in adults, type 1 diabetes, and type 2 diabetes
- 2008
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In: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 57:5, s. 1433-1437
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Journal article (peer-reviewed)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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| 7. |
- Enhörning, Sofia, et al.
(author)
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Plasma copeptin and the risk of diabetes mellitus.
- 2010
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In: Circulation. - 1524-4539. ; 121:19, s. 51-2102
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Journal article (peer-reviewed)abstract
- BACKGROUND: Animal studies suggest that the arginine vasopressin system may play a role in glucose metabolism, but data from humans are limited. METHODS AND RESULTS: We analyzed plasma copeptin (copeptin), a stable C-terminal fragment of the arginine vasopressin prohormone. Using baseline and longitudinal data from a Swedish population-based sample (n=4742; mean age, 58 years; 60% women) and multivariable logistic regression, we examined the association of increasing quartiles of copeptin (lowest quartile as reference) with prevalent diabetes mellitus at baseline, insulin resistance (top quartile of fasting plasma insulin among nondiabetic subjects), and incident diabetes mellitus on long-term follow-up. New-onset diabetes mellitus was ascertained through 3 national and regional registers. All models were adjusted for clinical and anthropometric risk factors, cystatin C, and C-reactive protein. In cross-sectional analyses, increasing copeptin was associated with prevalent diabetes mellitus (P=0.04) and insulin resistance (P<0.001). During 12.6 years of follow-up, 174 subjects (4%) developed new-onset diabetes mellitus. The odds of developing diabetes mellitus increased across increasing quartiles of copeptin, even after additional adjustment for baseline fasting glucose and insulin (adjusted odds ratios, 1.0, 1.37, 1.79, and 2.09; P for trend=0.004). The association with incident diabetes mellitus remained significant in analyses restricted to subjects with fasting whole blood glucose <5.4 mmol/L at baseline (adjusted odds ratios, 1.0, 1.80, 1.92, and 3.48; P=0.001). CONCLUSIONS: Elevated copeptin predicts increased risk for diabetes mellitus independently of established clinical risk factors, including fasting glucose and insulin. These findings could have implications for risk assessment, novel antidiabetic treatments, and metabolic side effects from arginine vasopressin system modulation.
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| 8. |
- Glans, Forouzan, et al.
(author)
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Immigrants from the Middle-East have a different form of Type 2 diabetes compared with Swedish patients.
- 2008
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In: Diabetic Medicine: A journal of the British Diabetic Association. - : Wiley. - 1464-5491. ; 25:3, s. 303-307
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Journal article (peer-reviewed)abstract
- AIMS: To compare the clinical characteristics of Type 2 diabetes (T2DM) between immigrants from the Middle-East and Swedish patients. METHODS: The study group included 450 consecutive patients with T2DM, 379 Swedish-born aged 61 +/- 12 years and 71 patients originally from the Middle-East aged 50 +/- 11 years from the diabetes clinic of Malmo University Hospital. RESULTS: Onset of diabetes had occurred 12 years earlier in the Middle-East immigrants compared with the Swedish-born patients (43 +/- 10 vs. 55 +/- 12 years, P < 0.001). Immigrants had lower fasting serum C-peptide [0.7 (0.1-2.6) vs. 0.9 (0.1-4.0) nmol/l, P = 0.013], lower homeostasis model assessment (HOMA)-beta[1.7 (0.1-9.1) vs. 2.7 (0.1-59.0), P = 0.010], lower HOMA-IR [0.4 (0.02-1.19) vs. 0.4 (0.01-2.8), P = 0.005] than the Swedish group. A first-degree family history of diabetes was reported in 61% of immigrants, compared with 47% of Swedish-born (P = 0.022). CONCLUSIONS: Immigrants from the Middle-East have an earlier onset, stronger family history and more rapid decline of pancreatic B-cell function than Swedish patients, suggesting that they have a different form of T2DM compared with Swedish patients.
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| 9. |
- Guey, Lin T., et al.
(author)
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Power in the Phenotypic Extremes: A Simulation Study of Power in Discovery and Replication of Rare Variants
- 2011
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In: Genetic Epidemiology. - : Wiley. - 0741-0395. ; 35:4, s. 236-246
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Journal article (peer-reviewed)abstract
- Next-generation sequencing technologies are making it possible to study the role of rare variants in human disease. Many studies balance statistical power with cost-effectiveness by (a) sampling from phenotypic extremes and (b) utilizing a two-stage design. Two-stage designs include a broad-based discovery phase and selection of a subset of potential causal genes/variants to be further examined in independent samples. We evaluate three parameters: first, the gain in statistical power due to extreme sampling to discover causal variants; second, the informativeness of initial (Phase I) association statistics to select genes/variants for follow-up; third, the impact of extreme and random sampling in (Phase 2) replication. We present a quantitative method to select individuals from the phenotypic extremes of a binary trait, and simulate disease association studies under a variety of sample sizes and sampling schemes. First, we find that while studies sampling from extremes have excellent power to discover rare variants, they have limited power to associate them to phenotype-suggesting high false-negative rates for upcoming studies. Second, consistent with previous studies, we find that the effect sizes estimated in these studies are expected to be systematically larger compared with the overall population effect size; in a well-cited lipids study, we estimate the reported effect to be twofold larger. Third, replication studies require large samples from the general population to have sufficient power; extreme sampling could reduce the required sample size as much as fourfold. Our observations offer practical guidance for the design and interpretation of studies that utilize extreme sampling. Genet. Epidemiol. 35: 236-246, 2011. (c) 2011 Wiley-Liss, Inc.
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| 10. |
- Li, Haiyan, et al.
(author)
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Possible human leukocyte antigen-mediated genetic interaction between type 1 and type 2 Diabetes
- 2001
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In: Journal of Clinical Endocrinology and Metabolism. - 1945-7197. ; 86:2, s. 574-582
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Journal article (peer-reviewed)abstract
- We assessed the prevalence of families with both type 1 and type 2 diabetes in Finland; and we studied, in patients with type 2 diabetes, the association between a family history of type 1 diabetes, glutamic acid decarboxylase (GAD) antibodies (GADab), and type 1 diabetes-associated human leukocyte antigen (HLA) DQB1-genotypes. Further, in mixed type 1/type 2 diabetes families, we investigated whether sharing an HLA haplotype with a family member with type 1 diabetes influenced the manifestation of type 2 diabetes. Among 695 families ascertained through the presence of more than 1 patient with type 2 diabetes, 100 (14%) also had members with type 1 diabetes. Type 2 diabetic patients from the mixed families had, more often, GADab (18% vs. 8%, P < 0.0001) and DQB1*0302/X genotype (25% vs. 12%, P = 0.005) than patients from families with only type 2 diabetes; but they had a lower frequency of DQB1*02/0302 genotype, compared with adult-onset type 1 patients (4% vs. 27%, P < 0.0001). In the mixed families, the insulin response to oral glucose load was impaired in patients who had HLA class II risk haplotypes, either DR3(17)-DQA1*0501-DQB1*02 or DR4*0401/4-DQA1*0301-DQB1*0302, compared with patients without such haplotypes (P = 0.016). This finding was independent of the presence of GADab. We conclude that type 1 and type 2 diabetes cluster in the same families. A shared genetic background with a patient with type 1 diabetes predisposes type 2 diabetic patients both to autoantibody positivity and, irrespective of antibody positivity, to impaired insulin secretion. The findings support a possible genetic interaction between type 1 and type 2 diabetes mediated by the HLA locus.
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