Publications by authors named "Emma H Dahlström"

11 Publications

  • Page 1 of 1

Apolipoprotein C-III predicts cardiovascular events and mortality in individuals with type 1 diabetes and albuminuria.

J Intern Med 2021 Nov 24. Epub 2021 Nov 24.

Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.

Objectives: We studied apolipoprotein C-III (apoC-III) in relation to diabetic kidney disease (DKD), cardiovascular outcomes, and mortality in type 1 diabetes.

Methods: The cohort comprised 3966 participants from the prospective observational Finnish Diabetic Nephropathy Study. Progression of DKD was determined from medical records. A major adverse cardiac event (MACE) was defined as acute myocardial infarction, coronary revascularization, stroke, or cardiovascular mortality through 2017. Cardiovascular and mortality data were retrieved from national registries.

Results: ApoC-III predicted DKD progression independent of sex, diabetes duration, blood pressure, HbA , smoking, LDL-cholesterol, lipid-lowering medication, DKD category, and remnant cholesterol (hazard ratio [HR] 1.43 [95% confidence interval 1.05-1.94], p = 0.02). ApoC-III also predicted the MACE in a multivariable regression analysis; however, it was not independent of remnant cholesterol (HR 1.05 [0.81-1.36, p = 0.71] with remnant cholesterol; 1.30 [1.03-1.64, p = 0.03] without). DKD-specific analyses revealed that the association was driven by individuals with albuminuria, as no link between apoC-III and the outcome was observed in the normal albumin excretion or kidney failure categories. The same was observed for mortality: Individuals with albuminuria had an adjusted HR of 1.49 (1.03-2.16, p = 0.03) for premature death, while no association was found in the other groups. The highest apoC-III quartile displayed a markedly higher risk of MACE and death than the lower quartiles; however, this nonlinear relationship flattened after adjustment.

Conclusions: The impact of apoC-III on MACE risk and mortality is restricted to those with albuminuria among individuals with type 1 diabetes. This study also revealed that apoC-III predicts DKD progression, independent of the initial DKD category.
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http://dx.doi.org/10.1111/joim.13412DOI Listing
November 2021

Genome-Wide Association Study of Peripheral Artery Disease.

Circ Genom Precis Med 2021 10 4;14(5):e002862. Epub 2021 Oct 4.

Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health (A.S., J.C.H.), University of Oxford, United Kingdom.

Background: Peripheral artery disease (PAD) affects >200 million people worldwide and is associated with high mortality and morbidity. We sought to identify genomic variants associated with PAD overall and in the contexts of diabetes and smoking status.

Methods: We identified genetic variants associated with PAD and then meta-analyzed with published summary statistics from the Million Veterans Program and UK Biobank to replicate their findings. Next, we ran stratified genome-wide association analysis in ever smokers, never smokers, individuals with diabetes, and individuals with no history of diabetes and corresponding interaction analyses, to identify variants that modify the risk of PAD by diabetic or smoking status.

Results: We identified 5 genome-wide significant ( ≤5×10) associations with PAD in 449 548 (N=12 086) individuals of European ancestry near ) loci (which overlapped previously reported associations). Meta-analysis with variants previously associated with PAD showed that 18 of 19 published variants remained genome-wide significant. In individuals with diabetes, rs116405693 at the ) locus was associated with PAD (odds ratio [95% CI], 1.51 [1.32-1.74], =2.5×10, =5.3×10). Furthermore, in smokers, rs12910984 at the locus was associated with PAD (odds ratio [95% CI], 1.15 [1.11-1.19], =9.3×10, =3.9×10).

Conclusions: Our analyses confirm the published genetic associations with PAD and identify novel variants that may influence susceptibility to PAD in the context of diabetes or smoking status.
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http://dx.doi.org/10.1161/CIRCGEN.119.002862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8542067PMC
October 2021

The Low-Expression Variant of Is Associated With Cardiovascular Disease in Type 1 Diabetes.

Diabetes 2021 10 9;70(10):2391-2401. Epub 2021 Jul 9.

Folkhälsan Research Center, Helsinki, Finland.

Fatty acid binding protein 4 (FABP4) is implicated in the pathogenesis of cardiometabolic disorders. Pharmacological inhibition or genetic deletion of FABP4 improves cardiometabolic health and protects against atherosclerosis in preclinical models. As cardiovascular disease (CVD) is common in type 1 diabetes, we examined the role of FABP4 in the development of complications in type 1 diabetes, focusing on a functional, low-expression variant (rs77878271) in the promoter of the gene. For this, we assessed the risk of CVD, stroke, coronary artery disease (CAD), end-stage kidney disease, and mortality using Cox proportional hazards models for the rs77878271 in 5,077 Finnish individuals with type 1 diabetes. The low-expression G allele of rs77878271 increased the risk of CVD, independent of confounders. Findings were tested for replication in 852 Danish and 3,678 Finnish individuals with type 1 diabetes. In the meta-analysis, each G allele increased the risk of stroke by 26% ( = 0.04), CAD by 26% ( = 0.006), and CVD by 17% ( = 0.003). In Mendelian randomization, a 1-SD unit decrease in FABP4 increased risk of CAD 2.4-fold. Hence, in contrast with the general population, among patients with type 1 diabetes the low-expression G allele of rs77878271 increased CVD risk, suggesting that genetically low FABP4 levels may be detrimental in the context of type 1 diabetes.
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http://dx.doi.org/10.2337/db21-0056DOI Listing
October 2021

The Relationship Between Body Fat Distribution and Nonalcoholic Fatty Liver in Adults With Type 1 Diabetes.

Diabetes Care 2021 07 24;44(7):1706-1713. Epub 2021 May 24.

Folkhälsan Research Center, Helsinki, Finland.

Objective: 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.

Research Design And Methods: 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 rs738409 and 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.

Results: 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 rs738409, the volume ( = 0.03) and percentage ( = 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 ( = 0.04). The WHtR cutoff of 0.5 showed the highest sensitivity (86%) and specificity (55%), whereas the BMI of 26.6 kg/m showed 79% sensitivity and 57% specificity.

Conclusions: 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.
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http://dx.doi.org/10.2337/dc20-3175DOI Listing
July 2021

The pattern-recognition molecule H-ficolin in relation to diabetic kidney disease, mortality, and cardiovascular events in type 1 diabetes.

Sci Rep 2021 04 26;11(1):8919. Epub 2021 Apr 26.

Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.

H-ficolin recognizes patterns on microorganisms and stressed cells and can activate the lectin pathway of the complement system. We aimed to assess H-ficolin in relation to the progression of diabetic kidney disease (DKD), all-cause mortality, diabetes-related mortality, and cardiovascular events. Event rates per 10-unit H-ficolin-increase were compared in an observational follow-up of 2,410 individuals with type 1 diabetes from the FinnDiane Study. DKD progression occurred in 400 individuals. The unadjusted hazard ratio (HR) for progression was 1.29 (1.18-1.40) and 1.16 (1.05-1.29) after adjustment for diabetes duration, sex, HbA, systolic blood pressure, and smoking status. After adding triglycerides to the model, the HR decreased to 1.07 (0.97-1.18). In all, 486 individuals died, including 268 deaths of cardiovascular causes and 192 deaths of complications to diabetes. HRs for all-cause mortality and cardiovascular mortality were 1.13 (1.04-1.22) and 1.05 (0.93-1.17), respectively, in unadjusted analyses. These estimates lost statistical significance in adjusted models. However, the unadjusted HR for diabetes-related mortality was 1.19 (1.05-1.35) and 1.18 (1.02-1.37) with the most stringent adjustment level. Our results, therefore, indicate that H-ficolin predicts diabetes-related mortality, but neither all-cause mortality nor fatal/non-fatal cardiovascular events. Furthermore, H-ficolin is associated with DKD progression, however, not independently of the fully adjusted model.
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http://dx.doi.org/10.1038/s41598-021-88352-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076270PMC
April 2021

Decreased plasma kallikrein activity is associated with reduced kidney function in individuals with type 1 diabetes.

Diabetologia 2020 07 8;63(7):1349-1354. Epub 2020 Apr 8.

Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Haartmaninkatu 8, 00290, Helsinki, Finland.

Aims/hypothesis: Plasma kallikrein is the central mediator of the plasma kallikrein-kinin system, which is involved both in vascular control and thrombin formation cascades. The plasma kallikrein-kinin system has also been considered protective in pathological conditions, but the impact of plasma kallikreins on diabetic nephropathy remains unknown. The objective of this cross-sectional study was to explore the association of plasma kallikrein with diabetic nephropathy.

Methods: We measured plasma kallikrein activity in 295 individuals with type 1 diabetes at various stages of diabetic nephropathy, and we tested the genetic association between the plasma kallikrein-kinin system and kidney function in 4400 individuals with type 1 diabetes.

Results: Plasma kallikrein activity was associated with diabetes duration (p < 0.001) and eGFR (p < 0.001), and plasma kallikrein activity was lower with more advanced diabetic nephropathy, being lowest in individuals on dialysis. The minor alleles of the KNG1 rs5030062 and rs710446 variants, which have previously been associated with increased plasma pre-kallikrein and/or factor XI (FXI) protein levels, were associated with higher eGFR (rs5030062 β = 0.03, p = 0.01; rs710446 β = 0.03, p = 0.005) in the FinnDiane cohort of 4400 individuals with type 1 diabetes.

Conclusions/interpretation: Plasma kallikrein activity and genetic variants known to increase the plasma kallikrein level are associated with higher eGFR in individuals with type 1 diabetes, suggesting that plasma kallikrein might have a protective effect in diabetic nephropathy.
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http://dx.doi.org/10.1007/s00125-020-05144-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286847PMC
July 2020

The role of blood pressure in risk of ischemic and hemorrhagic stroke in type 1 diabetes.

Cardiovasc Diabetol 2019 07 9;18(1):88. Epub 2019 Jul 9.

Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Haartmaninkatu 8, 00290, Helsinki, Finland.

Background: Hypertension is one of the strongest risk factors for stroke in the general population, while systolic blood pressure has been shown to independently increase the risk of stroke in type 1 diabetes. The aim of this study was to elucidate the association between different blood pressure variables and risk of stroke in type 1 diabetes, and to explore potential nonlinearity of this relationship.

Methods: We included 4105 individuals with type 1 diabetes without stroke at baseline, participating in the nationwide Finnish Diabetic Nephropathy Study. Mean age at baseline was 37.4 ± 11.9 years, median duration of diabetes 20.9 (interquartile range 11.5-30.4) years, and 52% were men. Office systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured. Based on these pulse pressure (PP) and mean arterial pressure (MAP) were calculated. Strokes were classified based on medical and autopsy records, as well as neuroimaging. Cox proportional hazard models were performed to study how the different blood pressure variables affected the risk of stroke and its subtypes.

Results: During median follow-up time of 11.9 (9.21-13.9) years, 202 (5%) individuals suffered an incident stroke; 145 (72%) were ischemic and 57 (28%) hemorrhagic. SBP, DBP, PP, and MAP all independently increased the risk of any stroke. SBP, PP, and MAP increased the risk of ischemic stroke, while SBP, DBP, and MAP increased the risk of hemorrhagic stroke. SBP was strongly associated with stroke with a hazard ratio of 1.20 (1.11-1.29)/10 mmHg. When variables were modeled using restricted cubic splines, the risk of stroke increased linearly for SBP, MAP, and PP, and non-linearly for DBP.

Conclusions: The different blood pressure variables are all independently associated with increased risk of stroke in individuals with type 1 diabetes. The risk of stroke, ischemic stroke, and hemorrhagic stroke increases linearly at blood pressure levels less than the current recommended treatment guidelines.
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http://dx.doi.org/10.1186/s12933-019-0891-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6617855PMC
July 2019

Soluble receptor for AGE in diabetic nephropathy and its progression in Finnish individuals with type 1 diabetes.

Diabetologia 2019 07 24;62(7):1268-1274. Epub 2019 May 24.

Folkhälsan Research Center, Biomedicum Helsinki, University of Helsinki, Haartmaninkatu 8, 00014, Helsinki, Finland.

Aims/hypothesis: Activation of the receptor for AGE (RAGE) has been shown to be associated with diabetic nephropathy. The soluble isoform of RAGE (sRAGE) is considered to function as a decoy receptor for RAGE ligands and thereby protects against diabetic complications. A possible association between sRAGE and diabetic nephropathy is still, however, controversial and a more comprehensive analysis of sRAGE with respect to diabetic nephropathy in type 1 diabetes is therefore warranted.

Methods: sRAGE was measured in baseline serum samples from 3647 participants with type 1 diabetes from the nationwide multicentre Finnish Diabetic Nephropathy (FinnDiane) Study. Associations between sRAGE and diabetic nephropathy, as well as sRAGE and diabetic nephropathy progression, were evaluated by regression, competing risks and receiver operating characteristic curve analyses. The non-synonymous SNP rs2070600 (G82S) was used to test causality in the Mendelian randomisation analysis.

Results: Baseline sRAGE concentrations were highest in participants with diabetic nephropathy, compared with participants with a normal AER or those with microalbuminuria. Baseline sRAGE was associated with progression from macroalbuminuria to end-stage renal disease (ESRD) in the competing risks analyses, but this association disappeared when eGFR was entered into the model. The SNP rs2070600 was strongly associated with sRAGE concentrations and with progression from macroalbuminuria to ESRD. However, Mendelian randomisation analysis did not support a causal role for sRAGE in progression to ESRD.

Conclusions/interpretation: sRAGE is associated with progression from macroalbuminuria to ESRD, but does not add predictive value on top of conventional risk factors. Although sRAGE is a biomarker of diabetic nephropathy, in light of the Mendelian randomisation analysis it does not seem to be causally related to progression from macroalbuminuria to ESRD.
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http://dx.doi.org/10.1007/s00125-019-4883-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6559996PMC
July 2019

Body Mass Index and Mortality in Individuals With Type 1 Diabetes.

J Clin Endocrinol Metab 2019 11;104(11):5195-5204

Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.

Context: The relationship between body mass index (BMI) and mortality may differ between patients with type 1 diabetes and the general population; it is not known which clinical characteristics modify the relationship.

Objective: Our aim was to assess the relationship between BMI and mortality and the interaction with clinically meaningful factors.

Design, Setting, And Participants: This prospective study included 5836 individuals with type 1 diabetes from the FinnDiane study.

Main Outcome Measure And Methods: We retrieved death data for all participants on 31 December 2015. We estimated the effect of BMI on the risk of mortality using a Cox proportional hazards model with BMI as a restricted cubic spline as well as effect modification by adding interaction terms to the spline.

Results: During a median of 13.7 years, 876 individuals died. The relationship between baseline BMI and all-cause mortality was reverse J-shaped. When analyses were restricted to those with normal albumin excretion rate, the relationship was U-shaped. The nadir BMI (BMI with the lowest mortality) was in the normal weight region (24.3 to 24.8 kg/m2); however, among individuals with diabetic nephropathy, the nadir BMI was in the overweight region (25.9 to 26.1 kg/m2). Diabetic nephropathy, diabetes-onset age, and sex modified the relationship between BMI and mortality (Pinteraction < 0.05).

Conclusions: Normal weight is optimal for individuals with type 1 diabetes to delay mortality, whereas underweight might be an indication of underlying complications. Maintaining normal weight may translate into reduced risk of mortality in type 1 diabetes, particularly for individuals of male sex, later diabetes-onset age, and normal albumin excretion rate.
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http://dx.doi.org/10.1210/jc.2019-00042DOI Listing
November 2019

Genetic Evidence for a Causal Role of Obesity in Diabetic Kidney Disease.

Diabetes 2015 Dec 25;64(12):4238-46. Epub 2015 Aug 25.

Program in Medical and Population Genetics, Broad Institute, Cambridge, MA Department of Medicine, Harvard Medical School, Boston, MA Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA

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/m(2) 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/m(2) 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.
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http://dx.doi.org/10.2337/db15-0254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4657582PMC
December 2015

Kidney injury molecule-1 and the loss of kidney function in diabetic nephropathy: a likely causal link in patients with type 1 diabetes.

Diabetes Care 2015 Jun 17;38(6):1130-7. Epub 2015 Mar 17.

Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia

Objective: We evaluated the predictive value and clinical benefit of urinary kidney injury molecule (KIM)-1 for progression of diabetic nephropathy (DN) in type 1 diabetes. We also investigated its causal role for the decrease of estimated glomerular filtration rate (eGFR) by a Mendelian randomization (MR) approach.

Research Design And Methods: We followed 1,573 patients with type 1 diabetes for 6 years. KIM-1 was measured at baseline and normalized with urinary creatinine. KIM-1 predictive value was evaluated by Cox regression, while its added predictive benefit was evaluated using a panel of statistical indexes. The causality for the loss of renal function was evaluated with MR, utilizing the top signal from our genome-wide association study (GWAS) as the instrumental variable.

Results: KIM-1 was not an independent predictor of progression of DN when adjusted for albumin excretion rate (AER) and added no prognostic benefit to AER or eGFR. In multiple regressions, KIM-1 was associated with lower eGFR independently of diabetes duration (β = -4.066; P < 0.0001) but not of AER. In our GWAS, rs2036402 in the KIM1 gene was strongly associated with KIM-1 (β = -0.51; P = 6.5 × 10(-38)). In the MR, KIM-1 was associated with lower eGFR, independently of diabetes duration and AER (β = -5.044; P = 0.040), suggesting a causal relationship.

Conclusions: KIM-1 did not predict progression to end-stage renal disease independently of AER and added no prognostic benefit to current biomarkers. Nevertheless, the MR showed that the inverse association of increased KIM-1 levels with lower eGFR is likely to represent a causal link.
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http://dx.doi.org/10.2337/dc14-2330DOI Listing
June 2015
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