du.sePublications
Change search
Link to record
Permanent link

Direct link
BETA
Publications (10 of 249) Show all publications
Wuttke, M., Li, Y., Sieber, K. B., Feitosa, M. F., Gorski, M., Tin, A., . . . Pattaro, C. (2019). A catalog of genetic loci associated with kidney function from analyses of a million individuals. Nature Genetics, 51(6), 957-972
Open this publication in new window or tab >>A catalog of genetic loci associated with kidney function from analyses of a million individuals
Show others...
2019 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 51, no 6, p. 957-972Article in journal (Refereed) Published
Abstract [en]

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry 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.

National Category
Clinical Medicine
Research subject
Health and Welfare
Identifiers
urn:nbn:se:du-30209 (URN)10.1038/s41588-019-0407-x (DOI)000469996900008 ()31152163 (PubMedID)2-s2.0-85066607502 (Scopus ID)
Available from: 2019-06-13 Created: 2019-06-13 Last updated: 2019-06-20Bibliographically approved
Mok, Y., Ballew, S. H., Sang, Y., Grams, M. E., Coresh, J., Evans, M., . . . Matsushita, K. (2019). Albuminuria as a predictor of cardiovascular outcomes in patients with acute myocardial infarction. Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, 8(8), Article ID e010546.
Open this publication in new window or tab >>Albuminuria as a predictor of cardiovascular outcomes in patients with acute myocardial infarction
Show others...
2019 (English)In: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, ISSN 2047-9980, E-ISSN 2047-9980, Vol. 8, no 8, article id e010546Article in journal (Refereed) Published
Abstract [en]

Background. In patients with myocardial infarction ( MI ), reduced kidney function is recognized as an important predictor of poor prognosis, but the impact of albuminuria, a representative measure of kidney damage, has not been extensively evaluated.

Methods and Results. In the SCREAM (Stockholm Creatinine Measurements) project (2006-2012), we identified 2469 patients with incident MI with dipstick proteinuria measured within a year before MI (427 patients also had urine albumin to creatinine ratio [ ACR ] measured concurrently) and obtained estimates for ACR with multiple imputation in participants with data solely on dipstick proteinuria. We quantified the association of ACR with the post- MI composite and individual outcomes of all-cause mortality, cardiovascular mortality, recurrent MI , ischemic stroke, or heart failure using Cox models and then evaluated the improvement in C statistic. During a median follow-up of 1.0 year after MI , 1607 participants (65.1%) developed the post- MI composite outcome. Higher ACR levels were independently associated with all outcomes except for ischemic stroke. Per 8-fold higher ACR (eg, 40 versus 5 mg/g), the hazard ratio of composite outcome was 1.21 (95% CI , 1.08-1.35). The addition of the ACR improved the C statistic of the post- MI composite by 0.040 (95% CI, 0.030-0.051). Largely similar results were obtained regardless of diabetic status and when ACR or dipstick was separately analyzed without imputation.

Conclusions. In patients with MI , albuminuria was a potent predictor of subsequent outcomes, suggesting the importance of paying attention to the information on albuminuria, in addition to kidney function, in this high-risk population.

Keywords
albuminuria, chronic kidney disease, myocardial infarction, prognosis
National Category
Clinical Medicine
Research subject
Health and Welfare
Identifiers
urn:nbn:se:du-29863 (URN)10.1161/JAHA.118.010546 (DOI)000484574500003 ()30947615 (PubMedID)2-s2.0-85064323096 (Scopus ID)
Available from: 2019-04-08 Created: 2019-04-08 Last updated: 2019-09-20Bibliographically approved
Fellström, B., Helmersson-Karlqvist, J., Lind, L., Soveri, I., Wu, P.-H., Thulin, M., . . . Larsson, A. (2019). Associations Between Apolipoprotein A1, High-Density Lipoprotein Cholesterol, and Urinary Cytokine Levels in Elderly Males and Females. Journal of Interferon and Cytokine Research
Open this publication in new window or tab >>Associations Between Apolipoprotein A1, High-Density Lipoprotein Cholesterol, and Urinary Cytokine Levels in Elderly Males and Females
Show others...
2019 (English)In: Journal of Interferon and Cytokine Research, ISSN 1079-9907, E-ISSN 1557-7465Article in journal (Refereed) Epub ahead of print
Abstract [en]

There exists a close relationship between cardiovascular diseases and chronic kidney disease. Apolipoprotein A1 and high-density lipoprotein (HDL) cholesterol are widely used as cardiovascular risk markers but they also have anti-inflammatory properties. The aim of this study was to investigate any associations between HDL levels and cytokine levels in urine. We randomly selected 90 urine samples from the Prospective Investigation of the Vasculature in Uppsala Seniors Study (41 males and 49 females). The samples were analyzed with 2 multiplex assays, Multiplex Inflammation I and Cardiovascular II kits (Olink Bioscience, Uppsala, Sweden). We analyzed the correlations between 158 cytokines in urine with apolipoprotein A1, HDL cholesterol, apolipoprotein B, and low-density lipoprotein cholesterol. There were strong correlations for apolipoprotein A1 and HDL cholesterol with individual cytokines. After adjustment for multiplicity testing, there were 33 significant correlations between apolipoprotein A1 and cytokine levels and 14 of these were also significantly correlated with HDL cholesterol. The strongest associations were observed for IL-1α, SPON2, RAGE, PAR-1, TRAIL-R2, IL-4RA, TNFRSF11A, and SCF. A total of 28 out of 33 correlations were negative, indicating a negative relationship between apolipoprotein A1 and urinary cytokines. The study shows a negative correlation between apolipoprotein A1 and HDL cholesterol and urinary cytokine levels. The finding is in agreement with the anti-inflammatory properties of HDL.

Keywords
HDL cholesterol, apolipoprotein A1, cytokines, multiplex assays, urine
National Category
Clinical Medicine
Research subject
Health and Welfare
Identifiers
urn:nbn:se:du-30960 (URN)10.1089/jir.2019.0074 (DOI)31599692 (PubMedID)
Available from: 2019-10-16 Created: 2019-10-16 Last updated: 2019-10-16Bibliographically approved
Wändell, P., Carlsson, A. C., Li, X., Gasevic, D., Ärnlöv, J., Holzmann, M. J., . . . Sundquist, K. (2019). Atrial fibrillation in immigrants under the age of 45 y in Sweden. International Health, 11(3), 193-202
Open this publication in new window or tab >>Atrial fibrillation in immigrants under the age of 45 y in Sweden
Show others...
2019 (English)In: International Health, ISSN 1876-3413, E-ISSN 1876-3405, Vol. 11, no 3, p. 193-202Article in journal (Refereed) Published
Abstract [en]

Aim: To study association between country of birth and risk of first-onset atrial fibrillation (AF) in first- and second-generation immigrants to Sweden under 45 y of age.

Methods: The study population included all individuals (n = 3 248 457) under the age of 45 y in Sweden, including immigrants (n = 722 249). AF was defined as first registered diagnosis in the National Patient Register. Association between country of birth and risk of AF was assessed by Cox regression, calculating HRs and 95% CIs, using Swedish-born individuals as referents. All models were stratified by sex, and in different models were adjusted for age, area of residence in Sweden, educational level, marital status, neighbourhood socioeconomic status and co-morbidity(ies).

Results: A higher fully adjusted HR of incident AF was found in the total sample of first-generation immigrants, 1.44 (95% CI 1.35 to 1.54), in males born in Denmark, Lebanon and Iraq, and in females born in Turkey and Iraq. Lower HRs were found in male and female immigrants from Latin America and Iran, and female immigrants from Finland. Among second-generation immigrants, the fully adjusted HR was significantly lower, 0.70 (95% CI 0.58 to 0.83).

Conclusions: Clinicians may show a greater awareness of AF in some groups of younger immigrants to enable early diagnosis.

Keywords
Atrial fibrillation, co-morbidity, gender, younger immigrants
National Category
Clinical Medicine
Research subject
Health and Welfare
Identifiers
urn:nbn:se:du-28849 (URN)10.1093/inthealth/ihy075 (DOI)000480697100006 ()30364949 (PubMedID)2-s2.0-85064837373 (Scopus ID)
Available from: 2018-10-29 Created: 2018-10-29 Last updated: 2019-08-29Bibliographically approved
Velders, M. A., Calais, F., Dahle, N., Fall, T., Hagström, E., Leppert, J., . . . Hedberg, P. (2019). Cathepsin D improves the prediction of undetected diabetes in patients with myocardial infarction. Upsala Journal of Medical Sciences, 1-6
Open this publication in new window or tab >>Cathepsin D improves the prediction of undetected diabetes in patients with myocardial infarction
Show others...
2019 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, p. 1-6Article in journal (Refereed) Epub ahead of print
Abstract [en]

Background: Newer therapeutic agents for type 2 diabetes mellitus can improve cardiovascular outcomes, but diabetes remains underdiagnosed in patients with myocardial infarction (MI). We sought to identify proteomic markers of undetected dysglycaemia (impaired fasting glucose, impaired glucose tolerance, or diabetes mellitus) to improve the identification of patients at highest risk for diabetes. Materials and methods: In this prospective cohort, 626 patients without known diabetes underwent oral glucose tolerance testing (OGTT) during admission for MI. Proximity extension assay was used to measure 81 biomarkers. Multivariable logistic regression, adjusting for risk factors, was used to evaluate the association of biomarkers with dysglycaemia. Subsequently, lasso regression was performed in a 2/3 training set to identify proteomic biomarkers with prognostic value for dysglycaemia, when added to risk factors, fasting plasma glucose, and glycated haemoglobin A1c. Determination of discriminatory ability was performed in a 1/3 test set. Results: In total, 401/626 patients (64.1%) met the criteria for dysglycaemia. Using multivariable logistic regression, cathepsin D had the strongest association with dysglycaemia. Lasso regression selected seven markers, including cathepsin D, that improved prediction of dysglycaemia (area under the receiver operator curve [AUC] 0.848 increased to 0.863). In patients with normal fasting plasma glucose, only cathepsin D was selected (AUC 0.699 increased to 0.704). Conclusions: Newly detected dysglycaemia, including manifest diabetes, is common in patients with acute MI. Cathepsin D improved the prediction of dysglycaemia, which may be helpful in the a priori risk determination of diabetes as a motivation for confirmatory OGTT.

Keywords
Acute myocardial infarction, biomarkers, diabetes mellitus, proteomics
National Category
Clinical Medicine
Research subject
Health and Welfare
Identifiers
urn:nbn:se:du-30629 (URN)10.1080/03009734.2019.1650141 (DOI)000482489400001 ()31429631 (PubMedID)2-s2.0-85071043913 (Scopus ID)
Available from: 2019-08-22 Created: 2019-08-22 Last updated: 2019-09-17Bibliographically approved
Coresh, J., Heerspink, H. J., Sang, Y., Matsushita, K., Ärnlöv, J., Astor, B. C., . . . Gansevoort, R. T. (2019). Change in albuminuria and subsequent risk of end-stage kidney disease: an individual participant-level consortium meta-analysis of observational studies.. The Lancet Diabetes and Endocrinology, 7(2), 115-127
Open this publication in new window or tab >>Change in albuminuria and subsequent risk of end-stage kidney disease: an individual participant-level consortium meta-analysis of observational studies.
Show others...
2019 (English)In: The Lancet Diabetes and Endocrinology, ISSN 2213-8587, E-ISSN 2213-8595, Vol. 7, no 2, p. 115-127Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Change in albuminuria as a surrogate endpoint for progression of chronic kidney disease is strongly supported by biological plausibility, but empirical evidence to support its validity in epidemiological studies is lacking. We aimed to assess the consistency of the association between change in albuminuria and risk of end-stage kidney disease in a large individual participant-level meta-analysis of observational studies.

METHODS: In this meta-analysis, we collected individual-level data from eligible cohorts in the Chronic Kidney Disease Prognosis Consortium (CKD-PC) with data on serum creatinine and change in albuminuria and more than 50 events on outcomes of interest. Cohort data were eligible if participants were aged 18 years or older, they had a repeated measure of albuminuria during an elapsed period of 8 months to 4 years, subsequent end-stage kidney disease or mortality follow-up data, and the cohort was active during this consortium phase. We extracted participant-level data and quantified percentage change in albuminuria, measured as change in urine albumin-to-creatinine ratio (ACR) or urine protein-to-creatinine ratio (PCR), during baseline periods of 1, 2, and 3 years. Our primary outcome of interest was development of end-stage kidney disease after a baseline period of 2 years. We defined an end-stage kidney disease event as initiation of kidney replacement therapy. We quantified associations of percentage change in albuminuria with subsequent end-stage kidney disease using Cox regression in each cohort, followed by random-effects meta-analysis. We further adjusted for regression dilution to account for imprecision in the estimation of albuminuria at the participant level. We did multiple subgroup analyses, and also repeated our analyses using participant-level data from 14 clinical trials, including nine clinical trials not in CKD-PC.

FINDINGS: Between July, 2015, and June, 2018, we transferred and analysed data from 28 cohorts in the CKD-PC, which included 693 816 individuals (557 583 [80%] with diabetes). Data for 675 904 individuals and 7461 end-stage kidney disease events were available for our primary outcome analysis. Change in ACR was consistently associated with subsequent risk of end-stage kidney disease. The adjusted hazard ratio (HR) for end-stage kidney disease after a 30% decrease in ACR during a baseline period of 2 years was 0·83 (95% CI 0·74-0·94), decreasing to 0·78 (0·66-0·92) after further adjustment for regression dilution. Adjusted HRs were fairly consistent across cohorts and subgroups (ie, estimated glomerular filtration rate, diabetes, and sex), but the association was somewhat stronger among participants with higher baseline ACR than among those with lower baseline ACR (pinteraction<0·0001). In individuals with baseline ACR of 300 mg/g or higher, a 30% decrease in ACR over 2 years was estimated to confer a more than 1% absolute reduction in 10-year risk of end-stage kidney disease, even at early stages of chronic kidney disease. Results were generally similar when we used change in PCR and when study populations from clinical trials were assessed.

INTERPRETATION: Change in albuminuria was consistently associated with subsequent risk of end-stage kidney disease across a range of cohorts, lending support to the use of change in albuminuria as a surrogate endpoint for end-stage kidney disease in clinical trials of progression of chronic kidney disease in the setting of increased albuminuria.

FUNDING: US National Kidney Foundation and US National Institute of Diabetes and Digestive and Kidney Diseases.

National Category
Clinical Medicine
Research subject
Health and Welfare
Identifiers
urn:nbn:se:du-29275 (URN)10.1016/S2213-8587(18)30313-9 (DOI)000456442200017 ()30635225 (PubMedID)2-s2.0-85060314551 (Scopus ID)
Available from: 2019-01-14 Created: 2019-01-14 Last updated: 2019-06-27Bibliographically approved
Ruge, T., Carlsson, A. C., Kjøller, E., Hilden, J., Kolmos, H. J., Sajadieh, A., . . . Ärnlöv, J. (2019). Circulating endostatin as a risk factor for cardiovascular events in patients with stable coronary heart disease: A CLARICOR trial sub-study. Atherosclerosis, 284, 202-208
Open this publication in new window or tab >>Circulating endostatin as a risk factor for cardiovascular events in patients with stable coronary heart disease: A CLARICOR trial sub-study
Show others...
2019 (English)In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 284, p. 202-208Article in journal (Refereed) Published
Abstract [en]

BACKGROUND AND AIMS: Raised levels of serum endostatin, a biologically active fragment of collagen XVIII, have been observed in patients with ischemic heart disease but association with incident cardiovascular events in patients with stable coronary heart disease is uncertain.

METHODS: The CLARICOR-trial is a randomized, placebo-controlled trial of stable coronary heart disease patients evaluating 14-day treatment with clarithromycin. The primary outcome was a composite of acute myocardial infarction, unstable angina pectoris, cerebrovascular disease or all-cause mortality. In the present sub-study using 10-year follow-up data, we investigated associations between serum endostatin at entry (randomization) and the composite outcome and its components during follow-up. The placebo group was used as discovery sample (1204 events, n = 1998) and the clarithromycin-treated group as replication sample (1220 events, n = 1979).

RESULTS: In Cox regression models adjusting for cardiovascular risk factors, glomerular filtration rate, and current pharmacological treatment, higher serum endostatin was associated with an increased risk of the composite outcome in the discovery sample (hazard ratio per standard deviation increase 1.11, 95% CI 1.03-1.19, p = 0.004), but slightly weaker and not statistically significant in the replication sample (hazard ratio 1.06, 95% CI 1.00-1.14, p = 0.06). In contrast, strong and consistent associations were found between endostatin and cardiovascular and all-cause mortality in all multivariable models and sub-samples. Addition of endostatin to a model with established cardiovascular risk factors provided no substantial improvement of risk prediction (<1%).

CONCLUSIONS: Raised levels of serum endostatin might be associated with cardiovascular events in patients with stable coronary heart disease. The clinical utility of endostatin measurements remains to be established.

Keywords
Cardiovascular, Endostatin, Epidemiology, Extracellular matrix, Mortality
National Category
Clinical Medicine
Research subject
Health and Welfare
Identifiers
urn:nbn:se:du-29873 (URN)10.1016/j.atherosclerosis.2019.02.031 (DOI)000466155400027 ()30959314 (PubMedID)2-s2.0-85063916828 (Scopus ID)
Available from: 2019-04-11 Created: 2019-04-11 Last updated: 2019-06-03Bibliographically approved
Wändell, P., Carlsson, A. C., Li, X., Gasevic, D., Ärnlöv, J., Sundquist, J. & Sundquist, K. (2019). End-stage kidney diseases in immigrant groups: a nationwide cohort study in Sweden. American Journal of Nephrology, 49(3), 186-192
Open this publication in new window or tab >>End-stage kidney diseases in immigrant groups: a nationwide cohort study in Sweden
Show others...
2019 (English)In: American Journal of Nephrology, ISSN 0250-8095, E-ISSN 1421-9670, Vol. 49, no 3, p. 186-192Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Our aim was to study the association between the country of birth and incident end-stage kidney disease (ESKD) in several immigrant groups in Sweden, using individuals born in Sweden or with Swedish-born parents as referents.

METHODS: A cohort study of first- and second-generation immigrants residing in Sweden between January 1, 1998 and December 31, 2012 was performed. Outcomes were defined as having at least one registered diagnosis of ESKD in the National Patient Register. The incidence of ESKD in different immigrant groups was used in the Cox regression models to estimate hazard ratios (HRs) and 95% CIs. All models were stratified by sex and adjusted for age, geographical residence, educational level, marital status, and neighbourhood socioeconomic status.

RESULTS: Compared to their referents, higher incidence rates and HRs of ESKD (HR; 95% CI) were observed in general among foreign-born men (1.10; 1.04-1.16) and women (1.12; 1.04-1.21) but not among second-generation immigrants (persons born in Sweden with foreign-born parents). A particularly high -incidence was noted among men and women from -East-European countries, as well as from non-European regions. A lower incidence of ESKD was noted among men from Finland.

CONCLUSIONS: We observed substantial differences in incidence of ESKD between immigrant groups and the Swedish-born population, which may be clinically relevant when monitoring preventive measures in patient subgroups with a higher risk of deteriorating kidney disease, and suggest higher attention to hypertension and diabetes control in immigrants. Mechanisms attributable to the migration process or ethnic differences may lead to an increased risk of ESKD.

Keywords
End-stage kidney disease, First generation immigrants, Gender, Neighbourhood, Socioeconomic status
National Category
Clinical Medicine
Research subject
Health and Welfare
Identifiers
urn:nbn:se:du-29422 (URN)10.1159/000497063 (DOI)000462034300002 ()30712037 (PubMedID)2-s2.0-85061304574 (Scopus ID)
Available from: 2019-02-05 Created: 2019-02-05 Last updated: 2019-04-04Bibliographically approved
Xu, H., Matsushita, K., Su, G., Trevisan, M., Ärnlöv, J., Barany, P., . . . Carrero, J.-J. (2019). Estimated glomerular filtration rate and the risk of cancer. American Society of Nephrology. Clinical Journal, 14(4), 530-539
Open this publication in new window or tab >>Estimated glomerular filtration rate and the risk of cancer
Show others...
2019 (English)In: American Society of Nephrology. Clinical Journal, ISSN 1555-9041, E-ISSN 1555-905X, Vol. 14, no 4, p. 530-539Article in journal (Refereed) Published
Abstract [en]

BACKGROUND AND OBJECTIVES: Community-based reports regarding eGFR and the risk of cancer are conflicting. We here explore plausible links between kidney function and cancer incidence in a large Scandinavian population-based cohort.

DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In the Stockholm Creatinine Measurements project, we quantified the associations of baseline eGFR with the incidence of cancer among 719,033 Swedes ages ≥40 years old with no prior history of cancer. Study outcomes were any type and site-specific cancer incidence rates on the basis of International Classification of Diseases-10 codes over a median follow-up of 5 years. To explore the possibility of detection bias and reverse causation, we divided the follow-up time into different time periods (≤12 and >12 months) and estimated risks for each of these intervals.

RESULTS: In total, 64,319 cases of cancer (affecting 9% of participants) were detected throughout 3,338,226 person-years. The relationship between eGFR and cancer incidence was U shaped. Compared with eGFR of 90-104 ml/min, lower eGFR strata associated with higher cancer risk (adjusted hazard ratio, 1.08; 95% confidence interval, 1.05 to 1.11 for eGFR=30-59 ml/min and adjusted hazard ratio, 1.24; 95% confidence interval, 1.15 to 1.35 for eGFR<30 ml/min). Lower eGFR strata were significantly associated with higher risk of skin, urogenital, prostate, and hematologic cancers. Any cancer risk as well as skin (nonmelanoma) and urogenital cancer risks were significantly elevated throughout follow-up time, but they were higher in the first 12 months postregistration. Associations with hematologic and prostate cancers abrogated after the first 12 months of observation, suggesting the presence of detection bias and/or reverse causation.

CONCLUSIONS: There is a modestly higher cancer risk in individuals with mild to severe CKD driven primarily by skin and urogenital cancers, and this is only partially explained by bias.

Keywords
Bias, Cancer, Confidence Intervals, Follow-Up Studies, Hematologic Neoplasms, Incidence, International Classification of Diseases, Proportional Hazards Models, Prostatic Neoplasms, Renal Insufficiency, Chronic, Risk, Urogenital Neoplasms, chronic kidney disease, detection bias, estimated glomerular filtration rate, glomerular filtration rate, reverse causation
National Category
Clinical Medicine
Research subject
Health and Welfare
Identifiers
urn:nbn:se:du-29666 (URN)10.2215/CJN.10820918 (DOI)000463891100010 ()30872279 (PubMedID)2-s2.0-85064491897 (Scopus ID)
Available from: 2019-03-18 Created: 2019-03-18 Last updated: 2019-05-06Bibliographically approved
Teumer, A., Li, Y., Ghasemi, S., Prins, B. P., Wuttke, M., Hermle, T., . . . Köttgen, A. (2019). Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria. Nature Communications, 10, Article ID 4130.
Open this publication in new window or tab >>Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria
Show others...
2019 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, article id 4130Article in journal (Refereed) Published
Abstract [en]

Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n =192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.

National Category
Medical Genetics
Research subject
Health and Welfare
Identifiers
urn:nbn:se:du-30699 (URN)10.1038/s41467-019-11576-0 (DOI)000485216900016 ()31511532 (PubMedID)2-s2.0-85072119437 (Scopus ID)
Available from: 2019-09-17 Created: 2019-09-17 Last updated: 2019-09-27Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-6933-4637

Search in DiVA

Show all publications