ORCID Profile
0000-0003-4322-6942
Current Organisations
University of Helsinki
,
Folkhälsan Research Center
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Publisher: American Diabetes Association
Date: 12-01-2022
DOI: 10.2337/DC21-0974
Abstract: In iduals with type 1 diabetes are at a high lifetime risk of coronary artery disease (CAD), calling for early interventions. This study explores the use of a genetic risk score (GRS) for CAD risk prediction, compares it to established clinical markers, and investigates its performance according to the age and pharmacological treatment. This study in 3,295 in iduals with type 1 diabetes from the Finnish Diabetic Nephropathy Study (467 incident CAD, 14.8 years follow-up) used three risk scores: a GRS, a validated clinical score, and their combined score. Hazard ratios (HR) were calculated with Cox regression, and model performances were compared with the Harrell C-index (C-index). A HR of 6.7 for CAD was observed between the highest and the lowest 5th percentile of the GRS (P = 1.8 × 10−6). The performance of GRS (C-index = 0.562) was similar to HbA1c (C-index = 0.563, P = 0.96 for difference), HDL (C-index = 0.571, P = 0.6), and total cholesterol (C-index = 0.594, P = 0.1). The GRS was not correlated with the clinical score (r = −0.013, P = 0.5). The combined score outperformed the clinical score (C-index = 0.813 vs. C-index = 0.820, P = 0.003). The GRS performed better in in iduals below the median age (38.6 years) compared with those above (C-index = 0.637 vs. C-index = 0.546). A GRS identified in iduals at high risk of CAD and worked better in younger in iduals. GRS was also an independent risk factor for CAD, with a predictive power comparable to that of HbA1c and HDL and total cholesterol, and when incorporated into a clinical model, modestly improved the predictions. The GRS promises early risk stratification in clinical practice by enhancing the prediction of CAD.
Publisher: Cold Spring Harbor Laboratory
Date: 31-07-2020
DOI: 10.1101/2020.07.30.228734
Abstract: A subset of in iduals with type 1 diabetes mellitus (T1DM) are predisposed to developing diabetic kidney disease (DKD), which is the most common cause globally of end-stage kidney disease (ESKD). Emerging evidence suggests epigenetic changes in DNA methylation may have a causal role in both T1DM and DKD. The aim of this investigation was to assess differences in blood-derived DNA methylation patterns between in iduals with T1DM-ESKD and in iduals with long-duration T1DM but no evidence of kidney disease upon repeated testing. Blood-derived DNA from in iduals (107 cases, 253 controls and 14 experimental controls) were bisulphite treated before DNA methylation patterns from both groups were generated and analysed using Illumina's Infinium MethylationEPIC BeadChip arrays (n=862,927 sites). Differentially methylated CpG sites (dmCpGs) were identified (false discovery rate adjusted p≤x10-8 and fold change ±2) by comparing methylation levels between ESKD cases and T1DM controls at single site resolution. Gene annotation and functionality was investigated to enrich and rank methylated regions associated with ESKD in T1DM. Top-ranked genes within which several dmCpGs were located and supported by in silico functional data, and replication where possible, include AFF3, ARID5B, CUX1, ELMO1, FKBP5, HDAC4, ITGAL, LY9, PIM1, RUNX3, SEPTIN9, and UPF3A. Top-ranked enrichment pathways included pathways in cancer, TGF-β signalling and Th17 cell differentiation. Epigenetic alterations provide a dynamic link between an in idual's genetic background and their environmental exposures. This robust evaluation of DNA methylation in carefully phenotyped in iduals, has identified biomarkers associated with ESKD, revealing several genes and implicated key pathways associated with ESKD in in iduals with T1DM.
Publisher: American Diabetes Association
Date: 17-10-2011
DOI: 10.2337/DB11-0073
Abstract: Hyperglycemia plays a pivotal role in the development and progression of vascular complications, which are the major sources of morbidity and mortality in diabetes. Furthermore, these vascular complications often persist and progress despite improved glucose control, possibly as a result of prior episodes of hyperglycemia. Epigenetic modifications mediated by histone methyltransferases are associated with gene-activating events that promote enhanced expression of key proinflammatory molecules implicated in vascular injury. In this study, we investigated genetic polymorphisms of the SETD7, SUV39H1, and SUV39H2 methyltransferases as predictors of risk for micro- and macrovascular complications in type 1 diabetes. In the Finnish Diabetic Nephropathy Study (FinnDiane) cohort, 37 tagging single nucleotide polymorphisms (SNPs) were genotyped in 2,991 in iduals with type 1 diabetes and diabetic retinopathy, diabetic nephropathy, and cardiovascular disease. Seven SNPs were genotyped in the replication cohorts from the Steno Diabetes Center and All Ireland/Warren 3/Genetics of Kidneys in Diabetes (GoKinD) U.K. study. In a meta-analysis, the minor T allele of the exonic SNP rs17353856 in the SUV39H2 was associated with diabetic retinopathy (genotypic odds ratio 0.75, P = 1.2 × 10−4). The same SNP showed a trend toward an association with diabetic nephropathy as well as cardiovascular disease in the FinnDiane cohort. Our findings propose that a genetic variation in a gene coding for a histone methyltransferase is protective for a diabetic microvascular complication. The pathophysiological implications of this polymorphism or other genetic variation nearby for the vascular complications of type 1 diabetes remain to be investigated.
Publisher: American Diabetes Association
Date: 17-07-2012
DOI: 10.2337/DB11-0751
Abstract: We formed the GEnetics of Nephropathy–an International Effort (GENIE) consortium to examine previously reported genetic associations with diabetic nephropathy (DN) in type 1 diabetes. GENIE consists of 6,366 similarly ascertained participants of European ancestry with type 1 diabetes, with and without DN, from the All Ireland-Warren 3-Genetics of Kidneys in Diabetes U.K. and Republic of Ireland (U.K.-R.O.I.) collection and the Finnish Diabetic Nephropathy Study (FinnDiane), combined with reanalyzed data from the Genetics of Kidneys in Diabetes U.S. Study (U.S. GoKinD). We found little evidence for the association of the EPO promoter polymorphism, rs161740, with the combined phenotype of proliferative retinopathy and end-stage renal disease in U.K.-R.O.I. (odds ratio [OR] 1.14, P = 0.19) or FinnDiane (OR 1.06, P = 0.60). However, a fixed-effects meta-analysis that included the previously reported cohorts retained a genome-wide significant association with that phenotype (OR 1.31, P = 2 × 10−9). An expanded investigation of the ELMO1 locus and genetic regions reported to be associated with DN in the U.S. GoKinD yielded only nominal statistical significance for these loci. Finally, top candidates identified in a recent meta-analysis failed to reach genome-wide significance. In conclusion, we were unable to replicate most of the previously reported genetic associations for DN, and significance for the EPO promoter association was attenuated.
Publisher: Springer Science and Business Media LLC
Date: 28-06-2022
DOI: 10.1007/S00125-022-05735-0
Abstract: Diabetic kidney disease (DKD) is the leading cause of kidney failure and has a substantial genetic component. Our aim was to identify novel genetic factors and genes contributing to DKD by performing meta-analysis of previous genome-wide association studies (GWAS) on DKD and by integrating the results with renal transcriptomics datasets. We performed GWAS meta-analyses using ten phenotypic definitions of DKD, including nearly 27,000 in iduals with diabetes. Meta-analysis results were integrated with estimated quantitative trait locus data from human glomerular ( N =119) and tubular ( N =121) s les to perform transcriptome-wide association study. We also performed gene aggregate tests to jointly test all available common genetic markers within a gene, and combined the results with various kidney omics datasets. The meta-analysis identified a novel intronic variant (rs72831309) in the TENM2 gene associated with a lower risk of the combined chronic kidney disease (eGFR ml/min per 1.73 m 2 ) and DKD (microalbuminuria or worse) phenotype ( p =9.8×10 −9 although not withstanding correction for multiple testing, p .3×10 −9 ). Gene-level analysis identified ten genes associated with DKD ( COL20A1 , DCLK1 , EIF4E , PTPRN–RESP18 , GPR158 , INIP–SNX30 , LSM14A and MFF p .7×10 −6 ). Integration of GWAS with human glomerular and tubular expression data demonstrated higher tubular AKIRIN2 gene expression in in iduals with vs without DKD ( p =1.1×10 −6 ). The lead SNPs within six loci significantly altered DNA methylation of a nearby CpG site in kidneys ( p .5×10 −11 ). Expression of lead genes in kidney tubules or glomeruli correlated with relevant pathological phenotypes (e.g. TENM2 expression correlated positively with eGFR [ p =1.6×10 −8 ] and negatively with tubulointerstitial fibrosis [ p =2.0×10 −9 ], tubular DCLK1 expression correlated positively with fibrosis [ p =7.4×10 −16 ], and SNX30 expression correlated positively with eGFR [ p =5.8×10 −14 ] and negatively with fibrosis [ p .0×10 −16 ]). Altogether, the results point to novel genes contributing to the pathogenesis of DKD. The GWAS meta-analysis results can be accessed via the type 1 and type 2 diabetes (T1D and T2D, respectively) and Common Metabolic Diseases (CMD) Knowledge Portals, and downloaded on their respective download pages ( ownloads.html ownloads.html ownloads.html ).
Publisher: Wiley
Date: 24-02-2017
DOI: 10.1111/ENE.13244
Publisher: Cold Spring Harbor Laboratory
Date: 25-10-2020
DOI: 10.1101/2020.10.21.20215921
Abstract: This study examines associations between 51 urinary metabolites and risk of progression of diabetic nephropathy in in iduals with type 1 diabetes by employing an automated nuclear magnetic resonance (NMR) metabolomics technique suitable for large-scale urine s le collections. For 2,670 in iduals with type 1 diabetes from the FinnDiane Study, we collected 24-hour urine s les and measured metabolite concentrations by NMR. In iduals were followed for 9.0 ± 5.0 years until their first sign of progression of diabetic nephropathy, end-stage kidney disease or study end. Cox regression analyses were performed on the entire study population (overall progression), on 1,999 in iduals with normoalbuminuria and 347 in iduals with macroalbuminuria at baseline. Seven urinary metabolites were associated with overall progression after adjustment for baseline albuminuria and chronic kidney disease stage (p 8 × 10 -4 ): Leucine (hazard ratio 1.47, 95% confidence interval [1.30, 1.66] per 1-SD creatinine-scaled metabolite concentration), valine (1.38 [1.22, 1.56]), isoleucine (1.33 [1.18, 1.50]), pseudouridine (1.25 [1.11, 1.42]), threonine (1.27 [1.11, 1.46]) and citrate (0.84 [0.75, 0.93]). 2-hydroxyisobutyrate was associated with overall (1.30 [1.16, 1.45]) and also progression from normoalbuminuria (1.56 [1.25, 1.95]). Six amino acids and pyroglutamate were associated with progression from macroalbuminuria. Branched-amino acids and other urinary metabolites were associated with the progression of diabetic nephropathy on top of baseline albuminuria and chronic kidney disease. We found differences in associations for overall progression and progression from normo- and macroalbuminuria. These novel biomarker discoveries illustrate the utility of analysing urinary metabolites in entire population cohorts. In iduals with type 1 diabetes are vulnerable to diabetic nephropathy and would benefit from earlier detection of disease progression. Urinary metabolites as a direct read-out of kidney function are potential progression markers. However, analytical tools to quantify a broad panel of urinary metabolites at large scale and low cost are lacking. Recent developments in nuclear magnetic resonance address this need. This study in 2,670 in iduals with type 1 diabetes identified ten urinary metabolites associated with progression of diabetic nephropathy. Importantly, different albuminuria categories had different urinary profiles: 2-hydroxyisobutyrate was associated with progression from normoalbuminuria and branched-chain amino acids with progression from macroalbuminuria. These results provide new potential biomarkers and highlight the potential of analysing urinary metabolites on a larger scale.
Publisher: Springer Science and Business Media LLC
Date: 22-12-2022
DOI: 10.1038/S41467-022-34963-6
Abstract: Type 1 diabetes affects over nine million in iduals globally, with approximately 40% developing diabetic kidney disease. Emerging evidence suggests that epigenetic alterations, such as DNA methylation, are involved in diabetic kidney disease. Here we assess differences in blood-derived genome-wide DNA methylation associated with diabetic kidney disease in 1304 carefully characterised in iduals with type 1 diabetes and known renal status from two cohorts in the United Kingdom-Republic of Ireland and Finland. In the meta-analysis, we identify 32 differentially methylated CpGs in diabetic kidney disease in type 1 diabetes, 18 of which are located within genes differentially expressed in kidneys or correlated with pathological traits in diabetic kidney disease. We show that methylation at 21 of the 32 CpGs predict the development of kidney failure, extending the knowledge and potentially identifying in iduals at greater risk for diabetic kidney disease in type 1 diabetes.
Publisher: Springer Science and Business Media LLC
Date: 22-10-2021
DOI: 10.1007/S00125-021-05584-3
Abstract: This prospective, observational study examines associations between 51 urinary metabolites and risk of progression of diabetic nephropathy in in iduals with type 1 diabetes by employing an automated NMR metabolomics technique suitable for large-scale urine s le collections. We collected 24-h urine s les for 2670 in iduals with type 1 diabetes from the Finnish Diabetic Nephropathy study and measured metabolite concentrations by NMR. In iduals were followed up for 9.0 ± 5.0 years until their first sign of progression of diabetic nephropathy, end-stage kidney disease or study end. Cox regressions were performed on the entire study population (overall progression), on 1999 in iduals with normoalbuminuria and 347 in iduals with macroalbuminuria at baseline. Seven urinary metabolites were associated with overall progression after adjustment for baseline albuminuria and chronic kidney disease stage ( p 8 × 10 −4 ): leucine (HR 1.47 [95% CI 1.30, 1.66] per 1-SD creatinine-scaled metabolite concentration), valine (1.38 [1.22, 1.56]), isoleucine (1.33 [1.18, 1.50]), pseudouridine (1.25 [1.11, 1.42]), threonine (1.27 [1.11, 1.46]) and citrate (0.84 [0.75, 0.93]). 2-Hydroxyisobutyrate was associated with overall progression (1.30 [1.16, 1.45]) and also progression from normoalbuminuria (1.56 [1.25, 1.95]). Six amino acids and pyroglutamate were associated with progression from macroalbuminuria. Branched-chain amino acids and other urinary metabolites were associated with the progression of diabetic nephropathy on top of baseline albuminuria and chronic kidney disease. We found differences in associations for overall progression and progression from normo- and macroalbuminuria. These novel discoveries illustrate the utility of analysing urinary metabolites in entire population cohorts.
Publisher: Public Library of Science (PLoS)
Date: 20-09-2012
Publisher: American Diabetes Association
Date: 28-12-2021
DOI: 10.2337/DCI21-0045
Publisher: Springer Science and Business Media LLC
Date: 05-2021
DOI: 10.1186/S13148-021-01081-X
Abstract: A subset of in iduals with type 1 diabetes mellitus (T1DM) are predisposed to developing diabetic kidney disease (DKD), the most common cause globally of end-stage kidney disease (ESKD). Emerging evidence suggests epigenetic changes in DNA methylation may have a causal role in both T1DM and DKD. The aim of this exploratory investigation was to assess differences in blood-derived DNA methylation patterns between in iduals with T1DM-ESKD and in iduals with long-duration T1DM but no evidence of kidney disease upon repeated testing to identify potential blood-based biomarkers. Blood-derived DNA from in iduals (107 cases, 253 controls and 14 experimental controls) were bisulphite treated before DNA methylation patterns from both groups were generated and analysed using Illumina’s Infinium MethylationEPIC BeadChip arrays ( n = 862,927 sites). Differentially methylated CpG sites (dmCpGs) were identified (false discovery rate adjusted p ≤ × 10 –8 and fold change ± 2) by comparing methylation levels between ESKD cases and T1DM controls at single site resolution. Gene annotation and functionality was investigated to enrich and rank methylated regions associated with ESKD in T1DM. Top-ranked genes within which several dmCpGs were located and supported by functional data with methylation look-ups in other cohorts include: AFF3, ARID5B, CUX1, ELMO1 , FKBP5 , HDAC4, ITGAL, LY9 , PIM1, RUNX3, SEPTIN9 and UPF3A . Top-ranked enrichment pathways included pathways in cancer, TGF-β signalling and Th17 cell differentiation. Epigenetic alterations provide a dynamic link between an in idual’s genetic background and their environmental exposures. This robust evaluation of DNA methylation in carefully phenotyped in iduals has identified biomarkers associated with ESKD, revealing several genes and implicated key pathways associated with ESKD in in iduals with T1DM.
Publisher: Wiley
Date: 04-09-2018
DOI: 10.1111/AOS.13769
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2013
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 19-09-2019
Abstract: Although studies show that diabetic kidney disease has a heritable component, searches for the genetic determinants of this complication of diabetes have had limited success. In this study, a new international genomics consortium, the JDRF funded Diabetic Nephropathy Collaborative Research Initiative, assembled nearly 20,000 s les from participants with type 1 diabetes, with and without kidney disease. The authors found 16 new diabetic kidney disease–associated loci at genome-wide significance. The strongest signal centers on a protective missense coding variant at COL4A3 , a gene that encodes a component of the glomerular basement membrane that, when mutated, causes the progressive inherited nephropathy Alport syndrome. These GWAS-identified risk loci may provide insights into the pathogenesis of diabetic kidney disease and help identify potential biologic targets for prevention and treatment. Although diabetic kidney disease demonstrates both familial clustering and single nucleotide polymorphism heritability, the specific genetic factors influencing risk remain largely unknown. To identify genetic variants predisposing to diabetic kidney disease, we performed genome-wide association study (GWAS) analyses. Through collaboration with the Diabetes Nephropathy Collaborative Research Initiative, we assembled a large collection of type 1 diabetes cohorts with harmonized diabetic kidney disease phenotypes. We used a spectrum of ten diabetic kidney disease definitions based on albuminuria and renal function. Our GWAS meta-analysis included association results for up to 19,406 in iduals of European descent with type 1 diabetes. We identified 16 genome-wide significant risk loci. The variant with the strongest association (rs55703767) is a common missense mutation in the collagen type IV alpha 3 chain ( COL4A3) gene, which encodes a major structural component of the glomerular basement membrane (GBM). Mutations in COL4A3 are implicated in heritable nephropathies, including the progressive inherited nephropathy Alport syndrome. The rs55703767 minor allele (Asp326Tyr) is protective against several definitions of diabetic kidney disease, including albuminuria and ESKD, and demonstrated a significant association with GBM width protective allele carriers had thinner GBM before any signs of kidney disease, and its effect was dependent on glycemia. Three other loci are in or near genes with known or suggestive involvement in this condition ( BMP7) or renal biology ( COLEC11 and DDR1 ). The 16 diabetic kidney disease–associated loci may provide novel insights into the pathogenesis of this condition and help identify potential biologic targets for prevention and treatment.
Publisher: Cold Spring Harbor Laboratory
Date: 19-12-2018
DOI: 10.1101/499616
Abstract: Diabetic kidney disease (DKD) is a heritable but poorly understood complication of diabetes. To identify genetic variants predisposing to DKD, we performed genome-wide association analyses in 19,406 in iduals with type 1 diabetes (T1D) using a spectrum of DKD definitions basedon albuminuria and renal function. We identified 16 genome-wide significant loci. The variant with the strongest association (rs55703767) is a common missense mutation in the collagen type IV alpha 3 chain (COL4A3) gene, which encodes a major structural component of the glomerular basement membrane (GBM) implicated in heritable nephropathies. The rs55703767 minor allele (Asp326Tyr) is protective against several definitions of DKD, including albuminuria and end-stage renal disease. Three other loci are in or near genes with known or suggestive involvement in DKD (BMP7) or renal biology ( COLEC11 and DDR1 ). The 16 DKD-associated loci provide novel insights into the pathogenesis of DKD, identifying potential biological targets for prevention and treatment.
Publisher: American Diabetes Association
Date: 25-08-2015
DOI: 10.2337/DB15-0254
Abstract: Obesity has been posited as an independent risk factor for diabetic kidney disease (DKD), but establishing causality from observational data is problematic. We aimed to test whether obesity is causally related to DKD using Mendelian randomization, which exploits the random assortment of genes during meiosis. In 6,049 subjects with type 1 diabetes, we used a weighted genetic risk score (GRS) comprised of 32 validated BMI loci as an instrument to test the relationship of BMI with macroalbuminuria, end-stage renal disease (ESRD), or DKD defined as presence of macroalbuminuria or ESRD. We compared these results with cross-sectional and longitudinal observational associations. Longitudinal analysis demonstrated a U-shaped relationship of BMI with development of macroalbuminuria, ESRD, or DKD over time. Cross-sectional observational analysis showed no association with overall DKD, higher odds of macroalbuminuria (for every 1 kg/m2 higher BMI, odds ratio [OR] 1.05, 95% CI 1.03–1.07, P & 0.001), and lower odds of ESRD (OR 0.95, 95% CI 0.93–0.97, P & 0.001). Mendelian randomization analysis showed a 1 kg/m2 higher BMI conferring an increased risk in macroalbuminuria (OR 1.28, 95% CI 1.11–1.45, P = 0.001), ESRD (OR 1.43, 95% CI 1.20–1.72, P & 0.001), and DKD (OR 1.33, 95% CI 1.17–1.51, P & 0.001). Our results provide genetic evidence for a causal link between obesity and DKD in type 1 diabetes. As obesity prevalence rises, this finding predicts an increase in DKD prevalence unless intervention should occur.
Publisher: American Diabetes Association
Date: 27-04-2018
DOI: 10.2337/DB17-0914
Abstract: Identification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication s les, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 × 10−8) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased s le sizes will continue to provide more robust inference regarding risk variant discovery for DKD.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2012
Publisher: American Diabetes Association
Date: 24-05-2021
DOI: 10.2337/DC20-3175
Abstract: Obesity, which is associated with nonalcoholic fatty liver (NAFL), has increased among people with type 1 diabetes. Therefore, we explored the associations between body fat distribution and NAFL in this population. This study included 121 adults with type 1 diabetes from the Finnish Diabetic Nephropathy (FinnDiane) Study for whom NAFL was determined by magnetic resonance imaging. Body composition was assessed by dual-energy X-ray absorptiometry. Genetic data concerning PNPLA3 rs738409 and TM6SF2 rs58542926 were available as a directly genotyped polymorphism. Associations between body fat distribution, waist-to-height ratio (WHtR), BMI, and NAFL were explored using logistic regression. A receiver operating characteristic (ROC) curve was used to determine the WHtR and BMI thresholds with the highest sensitivity and specificity to detect NAFL. Median age was 38.5 (33–43.7) years, duration of diabetes was 21.2 (17.9–28.4) years, 52.1% were women, and the prevalence of NAFL was 11.6%. After adjusting for sex, age, duration of diabetes, and PNPLA3 rs738409, the volume (P = 0.03) and percentage (P = 0.02) of visceral adipose tissue were associated with NAFL, whereas gynoid, appendicular, and total adipose tissues were not. The area under the curve between WHtR and NAFL was larger than BMI and NAFL (P = 0.04). The WHtR cutoff of 0.5 showed the highest sensitivity (86%) and specificity (55%), whereas the BMI of 26.6 kg/m2 showed 79% sensitivity and 57% specificity. Visceral adipose tissue is associated with NAFL in adults with type 1 diabetes, and WHtR may be considered when screening for NAFL in this population.
Publisher: American Diabetes Association
Date: 28-11-2018
DOI: 10.2337/DB18-0567
Abstract: To identify genetic variants associated with diabetic retinopathy (DR), we performed a large multiethnic genome-wide association study. Discovery included eight European cohorts (n = 3,246) and seven African American cohorts (n = 2,611). We meta-analyzed across cohorts using inverse-variance weighting, with and without liability threshold modeling of glycemic control and duration of diabetes. Variants with a P value & × 10−5 were investigated in replication cohorts that included 18,545 European, 16,453 Asian, and 2,710 Hispanic subjects. After correction for multiple testing, the C allele of rs142293996 in an intron of nuclear VCP-like (NVL) was associated with DR in European discovery cohorts (P = 2.1 × 10−9), but did not reach genome-wide significance after meta-analysis with replication cohorts. We applied the Disease Association Protein-Protein Link Evaluator (DAPPLE) to our discovery results to test for evidence of risk being spread across underlying molecular pathways. One protein–protein interaction network built from genes in regions associated with proliferative DR was found to have significant connectivity (P = 0.0009) and corroborated with gene set enrichment analyses. These findings suggest that genetic variation in NVL, as well as variation within a protein–protein interaction network that includes genes implicated in inflammation, may influence risk for DR.
Publisher: Springer Science and Business Media LLC
Date: 11-02-2015
DOI: 10.1038/NATURE14177
Publisher: American Diabetes Association
Date: 07-08-2014
DOI: 10.2337/DC14-0065
Abstract: Osteopontin (OPN) is a multifunctional protein suggested to be a player in the arterial disease of patients with type 2 diabetes. However, its role for complications in patients with type 1 diabetes (T1D) is unknown. We therefore investigated the associations between OPN and diabetic vascular complications and all-cause mortality in patients with T1D. Serum OPN was measured in 2,145 adults with T1D without end-stage renal disease (ESRD dialysis or transplantation) as part of the Finnish Diabetic Nephropathy (FinnDiane) Study. Data on renal status, cardiovascular disease (CVD), and all-cause mortality during follow-up were verified from medical files, hospital discharge registries, and the Finnish National Death Registry, respectively. The median follow-up time was 10.5 (interquartile range 8.9–11.8) years. Serum OPN was higher at baseline in patients who developed incident microalbuminuria (16.0 ± 0.9 vs. 14.1 ± 0.2 µg/L P = 0.04), progressed to ESRD (28.3 ± 1.7 vs. 15.4 ± 0.2 µg/L P & 0.001), suffered an incident CVD event (20.2 ± 1.2 vs. 15.5 ± 0.2 µg/L P & 0.001), or died (23.3 ± 1.4 vs. 15.8 ± 0.2 µg/L P & 0.001) during follow-up. In multivariate Cox regression analysis, OPN was independently associated with the development of incident microalbuminuria, an incident CVD event, and death, after adjustments for associated risk factors. Even after calculating reclassification indexes, OPN was predictive of CVD and all-cause mortality beyond the Framingham risk score covariates and hs-CRP. Serum OPN is a strong predictor of incipient diabetic nephropathy, a first-ever CVD event, and all-cause mortality in patients with T1D. Serum OPN may be of clinical significance for the risk prediction of CVD events in patients with T1D.
Publisher: Springer Science and Business Media LLC
Date: 11-02-2015
DOI: 10.1038/NATURE14132
No related grants have been discovered for Niina Sandholm.