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Article ; Online: The Promise of Metabolomics in Decelerating CKD Progression in Children.

Schultheiss, Ulla T / Sekula, Peggy

Clinical journal of the American Society of Nephrology : CJASN

2021 Volume 16, Issue 8, Page(s) 1152–1154

MeSH term(s)	Child ; Humans ; Metabolome ; Metabolomics ; Renal Insufficiency, Chronic/diagnosis
Language	English
Publishing date	2021-07-23
Publishing country	United States
Document type	Editorial ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	2226665-3
ISSN	1555-905X ; 1555-9041
ISSN (online)	1555-905X
ISSN	1555-9041
DOI	10.2215/CJN.07400521
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Conference proceedings: Design of observational studies and the need for guidance – prognostic studies as an example

Sekula, Peggy

2017 , Page(s) Abstr. 236

Event/congress	62. Jahrestagung der Deutschen Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie e.V. (GMDS); Oldenburg; Deutsche Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie; 2017
Keywords	Medizin, Gesundheit ; Biometrie ; Epidemiologie
Publishing date	2017-08-29
Publisher	German Medical Science GMS Publishing House; Düsseldorf
Document type	Conference proceedings
DOI	10.3205/17gmds050
Database	German Medical Science

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Article ; Online: pgainsim: an R-package to assess the mode of inheritance for quantitative trait loci in GWAS.

Scherer, Nora / Sekula, Peggy / Pfaffelhuber, Peter / Schlosser, Pascal

Bioinformatics (Oxford, England)

2021 Volume 37, Issue 18, Page(s) 3061–3063

Abstract: Motivation: When performing genome-wide association studies conventionally the additive genetic model is used to explore whether a single nucleotide polymorphism (SNP) is associated with a quantitative trait. But for variants, which do not follow an ... ...

Abstract	Motivation: When performing genome-wide association studies conventionally the additive genetic model is used to explore whether a single nucleotide polymorphism (SNP) is associated with a quantitative trait. But for variants, which do not follow an intermediate mode of inheritance (MOI), the recessive or the dominant genetic model can have more power to detect associations and furthermore the MOI is important for downstream analyses and clinical interpretation. When multiple MOIs are modelled the question arises, which describes the true underlying MOI best. Results: We developed an R-package allowing for the first time to determine study specific critical values when one of the three models is more informative than the other ones for a quantitative trait locus. The package allows for user-friendly simulations to determine these critical values with predefined minor allele frequencies and study sizes. For application scenarios with extensive multiple testing we integrated an interpolation functionality to determine critical values already based on a moderate number of random draws. Availability and implementation: The R-package pgainsim is freely available for download on Github at https://github.com/genepi-freiburg/pgainsim. Supplementary information: Supplementary data are available at Bioinformatics online.
MeSH term(s)	Quantitative Trait Loci ; Genome-Wide Association Study ; Phenotype ; Inheritance Patterns ; Polymorphism, Single Nucleotide ; Software
Language	English
Publishing date	2021-03-16
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1422668-6
ISSN	1367-4811 ; 1367-4803
ISSN (online)	1367-4811
ISSN	1367-4803
DOI	10.1093/bioinformatics/btab150
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Article ; Online: Incidence of Epidermal Necrolysis: Results of the German Registry.

Naegele, David / Sekula, Peggy / Paulmann, Maren / Mockenhaupt, Maja

The Journal of investigative dermatology

2020 Volume 140, Issue 12, Page(s) 2525–2527

MeSH term(s)	Adolescent ; Adult ; Age Factors ; Aged ; Aged, 80 and over ; Child ; Child, Preschool ; Female ; Germany/epidemiology ; Hospital Mortality ; Humans ; Incidence ; Infant ; Infant, Newborn ; Male ; Middle Aged ; Registries/statistics & numerical data ; Risk Factors ; Stevens-Johnson Syndrome/epidemiology ; Young Adult
Language	English
Publishing date	2020-04-28
Publishing country	United States
Document type	Letter
ZDB-ID	80136-7
ISSN	1523-1747 ; 0022-202X
ISSN (online)	1523-1747
ISSN	0022-202X
DOI	10.1016/j.jid.2020.03.968
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Book ; Online ; Thesis: <dc:title>Using transgenic Drosophila model to study the mechanism of APOL1-associated cytotoxicity</dc:title>

Chen, Mengmeng [Verfasser] / Walz, Gerd [Akademischer Betreuer] / Hermle, Tobias Franz [Akademischer Betreuer] / Walz, Gerd [Sonstige] / Sekula, Peggy [Sonstige]

2022

Keywords	Medizin, Gesundheit ; Medicine, Health
Subject code	sg610
Language	English
Publisher	Universität
Publishing place	Freiburg
Document type	Book ; Online ; Thesis
Database	Digital theses on the web

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Article ; Online: Genome-Wide Association Studies of Metabolite Concentrations (mGWAS): Relevance for Nephrology.

Köttgen, Anna / Raffler, Johannes / Sekula, Peggy / Kastenmüller, Gabi

Seminars in nephrology

2018 Volume 38, Issue 2, Page(s) 151–174

Abstract: Metabolites are small molecules that are intermediates or products of metabolism, many of which are freely filtered by the kidneys. In addition, the kidneys have a central role in metabolite anabolism and catabolism, as well as in active metabolite ... ...

Abstract	Metabolites are small molecules that are intermediates or products of metabolism, many of which are freely filtered by the kidneys. In addition, the kidneys have a central role in metabolite anabolism and catabolism, as well as in active metabolite reabsorption and/or secretion during tubular passage. This review article illustrates how the coupling of genomics and metabolomics in genome-wide association analyses of metabolites can be used to illuminate mechanisms underlying human metabolism, with a special focus on insights relevant to nephrology. First, genetic susceptibility loci for reduced kidney function and chronic kidney disease (CKD) were reviewed systematically for their associations with metabolite concentrations in metabolomics studies of blood and urine. Second, kidney function and CKD-associated metabolites reported from observational studies were interrogated for metabolite-associated genetic variants to generate and discuss complementary insights. Finally, insights originating from the simultaneous study of both blood and urine or by modeling intermetabolite relationships are summarized. We also discuss methodologic questions related to the study of metabolite concentrations in urine as well as among CKD patients. In summary, genome-wide association analyses of metabolites using metabolite concentrations quantified from blood and/or urine are a promising avenue of research to illuminate physiological and pathophysiological functions of the kidney.
MeSH term(s)	Genetic Loci ; Genome-Wide Association Study ; Glomerular Filtration Rate/genetics ; Humans ; Kidney/metabolism ; Kidney/physiology ; Metabolomics ; Renal Insufficiency, Chronic/genetics ; Renal Insufficiency, Chronic/metabolism ; Renal Insufficiency, Chronic/physiopathology
Language	English
Publishing date	2018-03-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	604652-6
ISSN	1558-4488 ; 0270-9295
ISSN (online)	1558-4488
ISSN	0270-9295
DOI	10.1016/j.semnephrol.2018.01.009
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Article ; Online: Meta-GWAS on PCSK9 concentrations reveals associations of novel loci outside the PCSK9 locus in White populations.

Kheirkhah, Azin / Schachtl-Riess, Johanna Franziska / Lamina, Claudia / Di Maio, Silvia / Koller, Adriana / Schönherr, Sebastian / Coassin, Stefan / Forer, Lukas / Sekula, Peggy / Gieger, Christian / Peters, Annette / Köttgen, Anna / Eckardt, Kai-Uwe / Kronenberg, Florian

Atherosclerosis

2023 Volume 386, Page(s) 117384

Abstract: Background and aims: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of lipid homeostasis. A few earlier genome-wide association studies (GWAS) investigated genetic variants associated with circulating PCSK9 concentrations. ... ...

Abstract	Background and aims: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of lipid homeostasis. A few earlier genome-wide association studies (GWAS) investigated genetic variants associated with circulating PCSK9 concentrations. However, uncertainty remains about some of the genetic loci discovered beyond the PCSK9 locus. By conducting the largest PCSK9 meta-analysis of GWAS (meta-GWAS) so far, we aimed to identify novel loci and validate the previously reported loci that regulate PCSK9 concentrations. Methods: We performed GWAS for PCSK9 concentrations in two large cohorts (GCKD (n = 4,963) and KORA F3 (n = 2,895)). These were meta-analyzed with previously published data encompassing together 20,579 individuals. We further conducted a second meta-analysis in statin-naïve individuals (n = 15,390). A genetic risk score (GRS) was constructed on PCSK9-increasing SNPs and assessed its impact on the risk for coronary artery disease (CAD) in 394,943 statin-naïve participants (17,077 with events) of the UK Biobank by performing CAD-free survival analysis. Results: Nine loci were genome-wide significantly associated with PCSK9 concentrations. These included the previously described PCSK9, APOB, KCNA1/KCNA5, and TM6SF2/SUGP1 loci. All imputed SNPs in the PCSK9 locus account for ∼15% of variance of PCSK9 concentrations. We further identified FADS2 as a novel locus that was also found in statin-naïve participants. All imputed SNPs within the FADS2 locus explain ∼1.2% of variance of PCSK9 concentrations. Additionally, four further loci (a region on chromosome 5, SDK1, SPATA16 and HPR) were genome-wide significant in either the main model or the statin-naïve subset. The linear increase in a PCSK9 genetic risk score was associated with 1.41-fold (95%CI 1.16-1.72, p < 0.001) higher risk for incident CAD. Conclusions: We identified five novel loci (FADS2, SPATA16, SDK1, HPR and a region on chromosome 5) for PCSK9 concentrations that would require further research. Additionally, we confirm the genome-wide significant loci that were previously detected.
MeSH term(s)	Humans ; Proprotein Convertase 9/genetics ; Genome-Wide Association Study ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; Coronary Artery Disease/genetics ; White People
Chemical Substances	PCSK9 protein, human (EC 3.4.21.-) ; Proprotein Convertase 9 (EC 3.4.21.-) ; Hydroxymethylglutaryl-CoA Reductase Inhibitors
Language	English
Publishing date	2023-11-10
Publishing country	Ireland
Document type	Meta-Analysis ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80061-2
ISSN	1879-1484 ; 0021-9150
ISSN (online)	1879-1484
ISSN	0021-9150
DOI	10.1016/j.atherosclerosis.2023.117384
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Article ; Online: The relationship between blood metabolites of the tryptophan pathway and kidney function: a bidirectional Mendelian randomization analysis.

Cheng, Yurong / Li, Yong / Benkowitz, Paula / Lamina, Claudia / Köttgen, Anna / Sekula, Peggy

Scientific reports

2020 Volume 10, Issue 1, Page(s) 12675

Abstract: Blood metabolites of the tryptophan pathway were found to be associated with kidney function and disease in observational studies. In order to evaluate causal relationship and direction, we designed a study using a bidirectional Mendelian randomization ... ...

Abstract	Blood metabolites of the tryptophan pathway were found to be associated with kidney function and disease in observational studies. In order to evaluate causal relationship and direction, we designed a study using a bidirectional Mendelian randomization approach. The analyses were based on published summary statistics with study sizes ranging from 1,960 to 133,413. After correction for multiple testing, results provided no evidence of an effect of metabolites of the tryptophan pathway on estimated glomerular filtration rate (eGFR). Conversely, lower eGFR was related to higher levels of four metabolites: C-glycosyltryptophan (effect estimate = - 0.16, 95% confidence interval [CI] (- 0.22; - 0.1); p = 9.2e-08), kynurenine (effect estimate = - 0.18, 95% CI (- 0.25; - 0.11); p = 1.1e-06), 3-indoxyl sulfate (effect estimate = - 0.25, 95% CI (- 0.4; - 0.11); p = 6.3e-04) and indole-3-lactate (effect estimate = - 0.26, 95% CI (- 0.38; - 0.13); p = 5.4e-05). Our study supports that lower eGFR causes higher blood metabolite levels of the tryptophan pathway including kynurenine, C-glycosyltryptophan, 3-indoxyl sulfate, and indole-3-lactate. These findings aid the notion that metabolites of the tryptophan pathway are a consequence rather than a cause of reduced eGFR. Further research is needed to specifically examine relationships with respect to chronic kidney disease (CKD) progression among patients with existing CKD.
MeSH term(s)	Biomarkers/blood ; Disease Progression ; Glomerular Filtration Rate ; Humans ; Indican/blood ; Indoles/blood ; Kynurenine/blood ; Mendelian Randomization Analysis ; Renal Insufficiency, Chronic/blood ; Renal Insufficiency, Chronic/physiopathology ; Tryptophan/blood ; Tryptophan/chemistry
Chemical Substances	Biomarkers ; Indoles ; Kynurenine (343-65-7) ; indole-3-lactic acid (5SW11R7M7M) ; Tryptophan (8DUH1N11BX) ; Indican (N187WK1Y1J)
Language	English
Publishing date	2020-07-29
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-020-69559-x
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Article ; Online: A polygenic score for reduced kidney function and adverse outcomes in a cohort with chronic kidney disease.

Steinbrenner, Inga / Yu, Zhi / Jin, Jin / Schultheiss, Ulla T / Kotsis, Fruzsina / Grams, Morgan E / Coresh, Josef / Wuttke, Matthias / Kronenberg, Florian / Eckardt, Kai-Uwe / Chatterjee, Nilanjan / Sekula, Peggy / Köttgen, Anna

Kidney international

2022 Volume 103, Issue 2, Page(s) 421–424

MeSH term(s)	Humans ; Multifactorial Inheritance ; Risk Factors ; Renal Insufficiency, Chronic/diagnosis ; Renal Insufficiency, Chronic/genetics ; Kidney
Language	English
Publishing date	2022-12-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	120573-0
ISSN	1523-1755 ; 0085-2538
ISSN (online)	1523-1755
ISSN	0085-2538
DOI	10.1016/j.kint.2022.11.013
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Zs.A 797: Show issues

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Article ; Online: Imaging Markers Derived From MRI-Based Automated Kidney Segmentation—an Analysis of Data From the German National Cohort (NAKO Gesundheitsstudie)

Deutsches Arzteblatt international

2024 , Issue Forthcoming

Abstract: Background: Population-wide research on potential new imaging biomarkers of the kidney depends on accurate automated segmentation of the kidney and its compartments (cortex, medulla, and sinus).: Methods: We developed a robust deep-learning framework ...

Abstract	Background: Population-wide research on potential new imaging biomarkers of the kidney depends on accurate automated segmentation of the kidney and its compartments (cortex, medulla, and sinus). Methods: We developed a robust deep-learning framework for kidney (sub-)segmentation based on a hierarchical, three-dimensional convolutional neural network (CNN) that was optimized for multi-scale problems of combined localization and segmentation. We applied the CNN to abdominal magnetic resonance images from the population-based German National Cohort (NAKO) study. Results: There was good to excellent agreement between the model predictions and manual segmentations. The median values for the body-surface normalized total kidney, cortex, medulla, and sinus volumes of 9934 persons were 158, 115, 43, and 24 mL/m2. Distributions of these markers are provided both for the overall study population and for a subgroup of persons without kidney disease or any associated conditions. Multivariable adjusted regression analyses revealed that diabetes, male sex, and a higher estimated glomerular filtration rate (eGFR) are important predictors of higher total and cortical volumes. Each increase of eGFR by one unit (i.e., 1 mL/min per 1.73 m2 body surface area) was associated with a 0.98 mL/m2 increase in total kidney volume, and this association was significant. Volumes were lower in persons with eGFR-defined chronic kidney disease. Conclusion: The extraction of image-based biomarkers through CNN-based renal sub-segmentation using data from a population-based study yields reliable results, forming a solid foundation for future investigations.
Language	English
Publishing date	2024-05-03
Publishing country	Germany
Document type	Observational Study
ZDB-ID	2406159-1
ISSN	1866-0452 ; 1866-0452
ISSN (online)	1866-0452
ISSN	1866-0452
DOI	10.3238/arztebl.m2024.0040
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