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- Ahlqvist, Emma, et al.
(författare)
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Novel subgroups of adult-onset diabetes and their association with outcomes : a data-driven cluster analysis of six variables
- 2018
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Ingår i: The Lancet Diabetes and Endocrinology. - 2213-8587 .- 2213-8595. ; 6:5, s. 361-369
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundDiabetes is presently classified into two main forms, type 1 and type 2 diabetes, but type 2 diabetes in particular is highly heterogeneous. A refined classification could provide a powerful tool to individualise treatment regimens and identify individuals with increased risk of complications at diagnosis.MethodsWe did data-driven cluster analysis (k-means and hierarchical clustering) in patients with newly diagnosed diabetes (n=8980) from the Swedish All New Diabetics in Scania cohort. Clusters were based on six variables (glutamate decarboxylase antibodies, age at diagnosis, BMI, HbA1c, and homoeostatic model assessment 2 estimates of β-cell function and insulin resistance), and were related to prospective data from patient records on development of complications and prescription of medication. Replication was done in three independent cohorts: the Scania Diabetes Registry (n=1466), All New Diabetics in Uppsala (n=844), and Diabetes Registry Vaasa (n=3485). Cox regression and logistic regression were used to compare time to medication, time to reaching the treatment goal, and risk of diabetic complications and genetic associations.FindingsWe identified five replicable clusters of patients with diabetes, which had significantly different patient characteristics and risk of diabetic complications. In particular, individuals in cluster 3 (most resistant to insulin) had significantly higher risk of diabetic kidney disease than individuals in clusters 4 and 5, but had been prescribed similar diabetes treatment. Cluster 2 (insulin deficient) had the highest risk of retinopathy. In support of the clustering, genetic associations in the clusters differed from those seen in traditional type 2 diabetes.InterpretationWe stratified patients into five subgroups with differing disease progression and risk of diabetic complications. This new substratification might eventually help to tailor and target early treatment to patients who would benefit most, thereby representing a first step towards precision medicine in diabetes.
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| 2. |
- Ahluwalia, Tarunveer S, et al.
(författare)
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Uromodulin gene variant is associated with type 2 diabetic nephropathy.
- 2011
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Ingår i: Journal of Hypertension. - 1473-5598. ; 29, s. 1731-1734
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Tidskriftsartikel (refereegranskat)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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| 4. |
- Enhörning, Sofia, et al.
(författare)
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Plasma copeptin and the risk of diabetes mellitus.
- 2010
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Ingår i: Circulation. - 1524-4539. ; 121:19, s. 51-2102
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Tidskriftsartikel (refereegranskat)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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| 5. |
- Gaulton, Kyle J, et al.
(författare)
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Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.
- 2015
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 47:12, s. 1415-1415
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Tidskriftsartikel (refereegranskat)abstract
- We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.
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| 6. |
- Guey, Lin T., et al.
(författare)
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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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Ingår i: Genetic Epidemiology. - : Wiley. - 0741-0395. ; 35:4, s. 236-246
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Tidskriftsartikel (refereegranskat)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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| 7. |
- Lindholm, Eero, et al.
(författare)
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Polymorphism in the MHC2TA gene is associated with features of the metabolic syndrome and cardiovascular mortality.
- 2006
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 1:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Recently, a -168A-->G polymorphism in the MHC class II transactivator gene (MHC2TA) was shown to be associated with increased susceptibility to myocardial infarction (MI). AIM: To confirm the association between the MHC2TA -168A-->G polymorphism and MI and to study its putative role for microalbuminuria, the metabolic syndrome (MetS) and cardiovascular mortality. MATERIALS AND METHODS: Using an allelic discrimination method we genotyped 11,064 individuals from three study populations: 1) 4,432 individuals from the Botnia type 2 diabetes (T2D) study, 2) 1,222 patients with MI and 2,345 control subjects participating in the Malmo Diet and Cancer study and comprising an MI case-control sample, and 3) 3,065 T2D patients from the Local Swedish Diabetes registry. RESULTS: No association between the -168A-->G polymorphism in MHC2TA and MI was observed. However, in the Botnia cohort the AG/GG genotypes were associated with cardiovascular mortality after MI (1.78 [1.09-2.92], p = 0.02). In addition, the AG/GG genotypes were more common in subjects with MetS (40.1% vs. 36.9%, p = 0.03) and in non-diabetic subjects with microalbuminuria (45.4% vs. 36.5%, p = 0.003) compared to control subjects. CONCLUSIONS: A polymorphism in MHC2TA was associated with cardiovascular mortality and predictors of cardiovascular mortality, microalbuminuria and MetS.
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| 9. |
- Orho-Melander, Marju, et al.
(författare)
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Common Missense Variant in the Glucokinase Regulatory Protein Gene Is Associated With Increased Plasma Triglyceride and C-Reactive Protein but Lower Fasting Glucose Concentrations
- 2008
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 57:11, s. 3112-3121
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE-Using the genome-wide association approach, we recently identified the glucokinase regulatory protein gene (GCKR, rs780094) region as a novel quantitative trait locus for plasma triglyceride concentration in Europeans. Here, we sought to study the association of GCKR variants with metabolic phenotypes, including measures of glucose homeostasis, to evaluate the GCYR locus in samples of non-European ancestry and to fine-map across the associated genomic interval. RESEARCH DESIGN AND METHODS-We performed association studies in 12 independent cohorts comprising >45,000 individuals representing several ancestral groups (whites from Northern and Southern Europe, whites from the U.S., African Americans from the U.S., Hispanics of Caribbean origin, and Chinese, Malays, and Asian Indians from Singapore). We conducted genetic fine-mapping across the similar to 417-kb region of linkage disequilibrium. spanning GCKR and 16 other genes on chromosome 2p23 by imputing untyped HapMap single nucleotide polymorphisms (SNPs) and genotyping 104 SNPs across the associated genomic interval. RESULTS-We provide comprehensive evidence that GCYR rs780094 is associated with opposite effects on fasting plasma triglyceride (P-meta = 3 x 10(-56)) and glucose (P-meta = 1 x 10(-13)) concentrations. In addition, we confirmed recent reports that the same SNP is associated with C-reactive protein (CRP) level (P = 5 x 10(-5)). Both fine-mapping approaches revealed a common missense GCKR variant (rs1260326, Pro446Leu, 34% frequency, r(2) = 0.93 with rs780094) as the strongest association signal in the region. CONCLUSIONS-These findings point to a molecular mechanism in humans by which higher triglycerides and CRP can be coupled with lower plasma glucose concentrations and position GCKR in central pathways regulating both hepatic triglyceride and glucose metabolism. Diabetes 57:3112-3121, 2008
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