| 1. |
- 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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| 2. |
- Breitfeld, Jana, et al.
(författare)
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Genetic dissection of serum vaspin highlights its causal role in lipid metabolism
- 2023
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Ingår i: Obesity. - 1930-7381. ; 31:11, s. 2862-2874
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Vaspin (visceral adipose tissue derived serine protease inhibitor, SERPINA12) is associated with obesity-related metabolic traits, but its causative role is still elusive. The role of genetics in serum vaspin variability to establish its causal relationship with metabolically relevant traits was investigated. Methods: A meta-analysis of genome-wide association studies for serum vaspin from six independent cohorts (N = 7446) was conducted. Potential functional variants of vaspin were included in Mendelian randomization (MR) analyses to assess possible causal pathways between vaspin and homeostasis model assessment and lipid traits. To further validate the MR analyses, data from Genotype-Tissue Expression (GTEx) were analyzed, db/db mice were treated with vaspin, and serum lipids were measured. Results: A total of 468 genetic variants represented by five independent variants (rs7141073, rs1956709, rs4905216, rs61978267, rs73338689) within the vaspin locus were associated with serum vaspin (all p < 5×10−8, explained variance 16.8%). MR analyses revealed causal relationships between serum vaspin and triglycerides, low-density lipoprotein, and total cholesterol. Gene expression correlation analyses suggested that genes, highly correlated with vaspin expression in adipose tissue, are enriched in lipid metabolic processes. Finally, in vivo vaspin treatment reduced serum triglycerides in obese db/db mice. Conclusions: The data show that serum vaspin is strongly determined by genetic variants within vaspin, which further highlight vaspin's causal role in lipid metabolism.
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| 3. |
- Dai, Qile, et al.
(författare)
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OTTERS: a powerful TWAS framework leveraging summary-level reference data
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Most existing TWAS tools require individual-level eQTL reference data and thus are not applicable to summary-level reference eQTL datasets. The development of TWAS methods that can harness summary-level reference data is valuable to enable TWAS in broader settings and enhance power due to increased reference sample size. Thus, we develop a TWAS framework called OTTERS (Omnibus Transcriptome Test using Expression Reference Summary data) that adapts multiple polygenic risk score (PRS) methods to estimate eQTL weights from summary-level eQTL reference data and conducts an omnibus TWAS. We show that OTTERS is a practical and powerful TWAS tool by both simulations and application studies.
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| 4. |
- Elhag, Sara, et al.
(författare)
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Differences in Cell-Intrinsic Inflammatory Programs of Yolk Sac and Bone Marrow Macrophages
- 2021
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Ingår i: Cells. - : MDPI AG. - 2073-4409. ; 10:12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Tissue-resident macrophages have mixed developmental origins. They derive in variable extent from yolk sac (YS) hematopoiesis during embryonic development. Bone marrow (BM) hematopoietic progenitors give rise to tissue macrophages in postnatal life, and their contribution increases upon organ injury. Since the phenotype and functions of macrophages are modulated by the tissue of residence, the impact of their origin and developmental paths has remained incompletely understood. Methods: In order to decipher cell-intrinsic macrophage programs, we immortalized hematopoietic progenitors from YS and BM using conditional HoxB8, and carried out an in-depth functional and molecular analysis of differentiated macrophages. Results: While YS and BM macrophages demonstrate close similarities in terms of cellular growth, differentiation, cell death susceptibility and phagocytic properties, they display differences in cell metabolism, expression of inflammatory markers and inflammasome activation. Reduced abundance of PYCARD (ASC) and CASPASE-1 proteins in YS macrophages abrogated interleukin-1 beta production in response to canonical and non-canonical inflammasome activation. Conclusions: Macrophage ontogeny is associated with distinct cellular programs and immune response. Our findings contribute to the understanding of the regulation and programming of macrophage functions.
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