| 1. |
- Ahluwalia, Tarunveer S., et al.
(författare)
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A novel rare CUBN variant and three additional genes identified in Europeans with and without diabetes : results from an exome-wide association study of albuminuria
- 2019
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 62:2, s. 292-305
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis: Identifying rare coding variants associated with albuminuria may open new avenues for preventing chronic kidney disease and end-stage renal disease, which are highly prevalent in individuals with diabetes. Efforts to identify genetic susceptibility variants for albuminuria have so far been limited, with the majority of studies focusing on common variants. Methods: We performed an exome-wide association study to identify coding variants in a two-stage (discovery and replication) approach. Data from 33,985 individuals of European ancestry (15,872 with and 18,113 without diabetes) and 2605 Greenlanders were included. Results: We identified a rare (minor allele frequency [MAF]: 0.8%) missense (A1690V) variant in CUBN (rs141640975, β = 0.27, p = 1.3 × 10−11) associated with albuminuria as a continuous measure in the combined European meta-analysis. The presence of each rare allele of the variant was associated with a 6.4% increase in albuminuria. The rare CUBN variant had an effect that was three times stronger in individuals with type 2 diabetes compared with those without (pinteraction = 7.0 × 10−4, β with diabetes = 0.69, β without diabetes = 0.20) in the discovery meta-analysis. Gene-aggregate tests based on rare and common variants identified three additional genes associated with albuminuria (HES1, CDC73 and GRM5) after multiple testing correction (pBonferroni < 2.7 × 10−6). Conclusions/interpretation: The current study identifies a rare coding variant in the CUBN locus and other potential genes associated with albuminuria in individuals with and without diabetes. These genes have been implicated in renal and cardiovascular dysfunction. The findings provide new insights into the genetic architecture of albuminuria and highlight target genes and pathways for the prevention of diabetes-related kidney disease.
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| 2. |
- Ericson, Ulrika, et al.
(författare)
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Dietary and genetic risk scores and incidence of type 2 diabetes
- 2018
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Ingår i: Genes and Nutrition. - : Springer Science and Business Media LLC. - 1555-8932 .- 1865-3499. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Both lifestyle and genetic predisposition determine the development of type 2 diabetes (T2D), and studies have indicated interactions between specific dietary components and individual genetic variants. However, it is unclear whether the importance of overall dietary habits, including T2D-related food intakes, differs depending on genetic predisposition to T2D. We examined interaction between a genetic risk score for T2D, constructed from 48 single nucleotide polymorphisms identified in genome-wide association studies, and a diet risk score of four foods consistently associated with T2D in epidemiological studies (processed meat, sugar-sweetened beverages, whole grain and coffee). In total, 25,069 individuals aged 45-74 years with genotype information and without prevalent diabetes from the Malmö Diet and Cancer cohort (1991-1996) were included. Diet data were collected with a modified diet history method. Results: During 17-year follow-up, 3588 incident T2D cases were identified. Both the diet risk score (HR in the highest risk category 1.40; 95% CI 1.26, 1.58; P trend=6×10-10) and the genetic risk score (HR in the highest tertile of the genetic risk score 1.67; 95% CI 1.54, 1.81; P trend=7×10-35) were associated with increased incidence of T2D. No significant interaction between the genetic risk score and the diet risk score (P=0.83) or its food components was observed. The highest risk was seen among the 6% of the individuals with both high genetic and dietary risk scores (HR 2.49; 95% CI 2.06, 3.01). Conclusions: The findings thus show that both genetic heredity and dietary habits previously associated with T2D add to the risk of T2D, but they seem to act in an independent fashion, with the consequence that all individuals, whether at high or low genetic risk, would benefit from favourable food choices.
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| 3. |
- Gorski, Mathias, et al.
(författare)
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Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline
- 2021
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Ingår i: Kidney International. - : Elsevier. - 0085-2538 .- 1523-1755. ; 99:4, s. 926-939
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Tidskriftsartikel (refereegranskat)abstract
- Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m2/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m2 at follow-up among those with eGFRcrea 60 mL/min/1.73m2 or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
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| 4. |
- Schulz, Christina-Alexandra, et al.
(författare)
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High Level of Fasting Plasma Proenkephalin-A Predicts Deterioration of Kidney Function and Incidence of CKD
- 2017
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Ingår i: Journal of the American Society of Nephrology: JASN. - 1046-6673. ; 28:1, s. 291-303
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Tidskriftsartikel (refereegranskat)abstract
- High levels of proenkephalin-A (pro-ENK) have been associated with decreased eGFR in an acute setting. Here, we examined whether pro-ENK levels predict CKD and decline of renal function in a prospective cohort of 2568 participants without CKD (eGFR>60 ml/min per 1.73 m2) at baseline. During a mean follow-up of 16.6 years, 31.7% of participants developed CKD. Participants with baseline pro-ENK levels in the highest tertile had significantly greater yearly mean decline of eGFR (Ptrend<0.001) and rise of cystatin C (Ptrend=0.01) and creatinine (Ptrend<0.001) levels. Furthermore, compared with participants in the lowest tertile, participants in the highest tertile of baseline pro-ENK concentration had increased CKD incidence (odds ratio, 1.51; 95% confidence interval, 1.18 to 1.94) when adjusted for multiple factors. Adding pro-ENK to a model of conventional risk factors in net reclassification improvement analysis resulted in reclassification of 14.14% of participants. Genome-wide association analysis in 4150 participants of the same cohort revealed the strongest association of pro-ENK levels with rs1012178 near the PENK gene, where the minor T-allele associated with a 0.057 pmol/L higher pro-ENK level per allele (P=4.67x10-21). Furthermore, the T-allele associated with a 19% increased risk of CKD per allele (P=0.03) and a significant decrease in the instrumental variable estimator for eGFR (P<0.01) in a Mendelian randomization analysis. In conclusion, circulating plasma pro-ENK level predicts incident CKD and may aid in identifying subjects in need of primary preventive regimens. Additionally, the Mendelian randomization analysis suggests a causal relationship between pro-ENK level and deterioration of kidney function over time.
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| 5. |
- Schulz, Christina-Alexandra, et al.
(författare)
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Plasma kidney injury molecule-1 (p-KIM-1) levels and deterioration of kidney function over 16 years
- 2020
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Ingår i: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. - : Oxford University Press (OUP). - 1460-2385. ; 35:2, s. 265-273
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Tidskriftsartikel (refereegranskat)abstract
- Background: The kidney injury molecule-1 (KIM-1) has previously been associated with kidney function in rodents and humans. Yet its role as a predictive marker for future decline in kidney function has remained less clear.Methods: At baseline (1991-1994), fasting plasma KIM-1 (p-KIM-1) was measured in 4739 participants of the population-based Malmö Diet and Cancer Study. Creatinine and cystatin C were used to calculate estimated glomerular filtration rate (eGFR) according to Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Collaboration 2012 creatinine-cystatin C equation at baseline and follow-up examination (2007-2012). Incident CKD was defined as an eGFR <60 mL/min/1.73 m2 at follow-up.Results: During a mean follow-up time of 16.6 years, high p-KIM-1 levels were associated with a greater decline in eGFR (quartile 1 -1.36 versus quartile 4 -1.54 mL/min/1.73 m2; P < 0.001). In multivariate analyses, the risk for incident CKD at the follow-up examination was higher among participants with baseline p-KIM-1 levels in the highest quartile {odds ratio [OR] 1.45 [95% confidence interval (CI) 1.10-1.92]} compared with those within the lowest quartile. The relative impact of baseline p-KIM-1 on incidence of CKD [OR 1.20 (95% CI 1.08-1.33) per 1 standard deviation (SD) increase in p-KIM-1] was comparable to those of age and systolic blood pressure (SBP) [OR 1.55 (95% CI 1.38-1.74) and OR 1.21 (95% CI 1.09-1.35) per 1 SD increase, respectively]. Adding p-KIM-1 to a conventional risk model resulted in significantly improved C-statistics (P = 0.04) and reclassified 9% of the individuals into the correct risk direction (continuous net reclassification improvement P = 0.02). Furthermore, the risk for hospitalization due to impaired renal function increased with increasing baseline p-KIM-1 [hazard ratio per 1 SD 1.43; (95% CI 1.18-1.74)] during a mean follow-up time of 19.2 years.Conclusion: Our results show that p-KIM-1 predicts the future decline of eGFR and risk of CKD in healthy middle-aged participants. Whether p-KIM-1 can be used to prioritize preventive action that needs to be further investigated.
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| 6. |
- Schulz, Christina-Alexandra, et al.
(författare)
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Soluble Urokinase-type Plasminogen Activator Receptor (suPAR) and Impaired Kidney Function in the Population-based Malmö Diet and Cancer Study
- 2017
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Ingår i: Kidney International Reports. - : Elsevier BV. - 2468-0249. ; 2:2, s. 239-247
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: The soluble urokinase-type plasminogen activator receptor (suPAR) has recently been associated with a decline in kidney function and incidence of chronic kidney disease in patients with cardiovascular disease undergoing cardiac catheterization, yet little is known whether suPAR is associated with deterioration of kidney function in the general population.METHODS: In the population-based Malmö Diet and Cancer Study cohort, plasma levels of suPAR were quantified in 5381 participants at baseline (1991-1994), and creatinine was measured and used to calculate estimated glomerulus filtration rate (eGFR) at baseline and follow-up (2007-2012). Incident chronic kidney disease was defined as eGFR < 60 ml/min per 1.73 m2 at follow-up.RESULTS: Participants within the highest quartile of suPAR had a significantly lower mean eGFR at follow-up than those within the lowest quartile (mean 68 vs. 74 ml/min per 1.73 m2; P-trend = 4.3 × 10-7). In multivariate regression analysis, suPAR (per 1 SD increment of log-transformed suPAR) was associated with a decline in eGFR (P = 3.3 × 10-9) and incident chronic kidney disease (561 events, odds ratio = 1.25; 95% confidence interval, 1.10-1.41). Furthermore, we identified 110 cases of hospitalization due to impaired kidney function via linkage to national registers of inpatient and outpatient hospital diagnoses. During a mean follow-up time of 19 years, suPAR was associated with risk for hospitalization due to impaired kidney function (hazard ratio = 1.49; 95% confidence interval, 1.27-1.74) in multivariate Cox proportional hazard analysis.DISCUSSION: The increased suPAR level at baseline was associated with a significantly higher longitudinal decline in eGFR, higher incidence of chronic kidney disease, and hospitalization due to impaired kidney function in a cohort of healthy middle-aged participants.
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| 7. |
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| 8. |
- van Zuydam, NR, et al.
(författare)
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A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes
- 2018
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 67:7, s. 1414-1427
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Tidskriftsartikel (refereegranskat)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 samples, 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 sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.
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| 9. |
- Wuttke, Matthias, et al.
(författare)
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A catalog of genetic loci associated with kidney function from analyses of a million individuals
- 2019
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Ingår i: Nature Genetics. - : NATURE PUBLISHING GROUP. - 1061-4036 .- 1546-1718. ; 51:6, s. 957-972
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Tidskriftsartikel (refereegranskat)abstract
- Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
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