ZBTB16 Gene Variability Influences Obesity-Related Parameters and Serum Lipid Levels in Czech Adults

Bendlová, Běla; Vaňková, Markéta; Hill, Martin; Vacínová, Gabriela; Lukasova, Petra; Vejražková, Daniela; Šedová, Lucie; Seda, O.; Včelák, Josef

doi:10.33549/physiolres.933731

Cited by 21 publications

(18 citation statements)

References 22 publications

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“…While alternatives exist, the preferred imaging modality for diagnosing FMD is computed tomographic angiography (CTA), 1,9,48 with current data supporting one-time 'head-to-pelvis' CTA in all FMD patients. 2,6,48,49 Screening for FMD is challenging, and asymptomatic FMD patients or those with non-specific symptoms (e.g. pulsatile tinnitus) may remain undiagnosed for many years or until they suffer a major event.…”

Section: Discussionmentioning

confidence: 99%

A plasma proteogenomic signature for fibromuscular dysplasia

Olin

Narzo

d’Escamard

et al. 2019

Cardiovascular Research

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Aims Fibromuscular dysplasia (FMD) is a poorly understood disease that predominantly affects women during middle-life, with features that include stenosis, aneurysm, and dissection of medium-large arteries. Recently, plasma proteomics has emerged as an important means to understand cardiovascular diseases. Our objectives were: (i) to characterize plasma proteins and determine if any exhibit differential abundance in FMD subjects vs. matched healthy controls and (ii) to leverage these protein data to conduct systems analyses to provide biologic insights on FMD, and explore if this could be developed into a blood-based FMD test. Methods and results Females with ‘multifocal’ FMD and matched healthy controls underwent clinical phenotyping, dermal biopsy, and blood draw. Using dual-capture proximity extension assay and nuclear magnetic resonance-spectroscopy, we evaluated plasma levels of 981 proteins and 31 lipid sub-classes, respectively. In a discovery cohort (Ncases = 90, Ncontrols = 100), we identified 105 proteins and 16 lipid sub-classes (predominantly triglycerides and fatty acids) with differential plasma abundance in FMD cases vs. controls. In an independent cohort (Ncases = 23, Ncontrols = 28), we successfully validated 37 plasma proteins and 10 lipid sub-classes with differential abundance. Among these, 5/37 proteins exhibited genetic control and Bayesian analyses identified 3 of these as potential upstream drivers of FMD. In a 3rd cohort (Ncases = 506, Ncontrols = 876) the genetic locus of one of these upstream disease drivers, CD2-associated protein (CD2AP), was independently validated as being associated with risk of having FMD (odds ratios = 1.36; P = 0.0003). Immune-fluorescence staining identified that CD2AP is expressed by the endothelium of medium-large arteries. Finally, machine learning trained on the discovery cohort was used to develop a test for FMD. When independently applied to the validation cohort, the test showed a c-statistic of 0.73 and sensitivity of 78.3%. Conclusion FMD exhibits a plasma proteogenomic and lipid signature that includes potential causative disease drivers, and which holds promise for developing a blood-based test for this disease.

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Section: Discussionmentioning

confidence: 99%

A plasma proteogenomic signature for fibromuscular dysplasia

Olin

Narzo

d’Escamard

et al. 2019

Cardiovascular Research

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“…Polymorphisms in Zbtb16 are associated with obesity-related traits in humans, whereas in mice this gene influences fat cell-regulated thermogenesis and body weight ( Plaisier et al. 2012 ; Bendlová et al. 2017 ).…”

Section: Resultsmentioning

confidence: 99%

“…2012 ; Claussnitzer et al. 2015 ; Bendlová et al. 2017 ) ( supplementary table 3 available at https://doi.org/10.5061/dryad.cjsxksn34).…”

Section: Resultsmentioning

confidence: 99%

Giant Island Mice Exhibit Widespread Gene Expression Changes in Key Metabolic Organs

Nolte

Jing

Dewey

et al. 2020

Genome Biology and Evolution

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Island populations repeatedly evolve extreme body sizes, but the genomic basis of this pattern remains largely unknown. To understand how organisms on islands evolve gigantism, we compared genome-wide patterns of gene expression in Gough Island mice, the largest wild house mice in the world, and mainland mice from the WSB/EiJ wild-derived inbred strain. We used RNASeq to quantify differential gene expression in three key metabolic organs: gonadal adipose depot, hypothalamus and liver. Between 4,000 and 8,800 genes were significantly differentially expressed across the evaluated organs, representing between 20 and 50% of detected transcripts, with 20% or more of differentially expressed transcripts in each organ exhibiting expression fold changes of at least 2X. A minimum of 73 candidate genes for extreme size evolution, including Irs1 and Lrp1, were identified by considering differential expression jointly with other data sets: (i) genomic positions of published quantitative trait loci for body weight and growth rate; (ii) whole genome sequencing of 16 wild-caught Gough Island mice that revealed fixed single nucleotide differences between the strains; (iii) publicly available tissue-specific regulatory elements. Additionally, patterns of differential expression across three time points in the liver revealed that Arid5b potentially regulates hundreds of genes. Functional enrichment analyses pointed to cell cycling, mitochondrial function, signaling pathways, inflammatory response, and nutrient metabolism as potential causes of weight accumulation in Gough Island mice. Collectively, our results indicate that extensive gene regulatory evolution in metabolic organs accompanied the rapid evolution of gigantism during the short time house mice have inhabited Gough Island.

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“…So far, there is not any pharmacogenetic study involving variation in human ZBTB16 gene available. In a study of 1517 non-diabetic subjects without hypolipidemic treatment, several single nucleotide polymorphisms in ZBTB16 gene were associated with adiposity measures, LDL, and total cholesterol ( 45 ), suggesting the importance of ZBTB16 for metabolic syndrome in humans. The metabolic disturbances including impaired glucose tolerance, dyslipidemia, and IR of skeletal muscle observed after DEX treatment in the congenic SHR- Lx .PD5 PD- Zbtb16 reveal the Zbtb1 6 locus as a possible sensitizing factor for side effects of GC therapy.…”

Section: Discussionmentioning

confidence: 99%

Single-Gene Congenic Strain Reveals the Effect of Zbtb16 on Dexamethasone-Induced Insulin Resistance

et al. 2018

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BackgroundGlucocorticoids (GCs) are potent therapeutic agents frequently used for treatment of number of conditions, including hematologic, inflammatory, and allergic diseases. Both their therapeutic and adverse effects display significant interindividual variation, partially attributable to genetic factors. We have previously isolated a seven-gene region of rat chromosome 8 sensitizing to dexamethasone (DEX)-induced dyslipidemia and insulin resistance (IR) of skeletal muscle. Using two newly derived congenic strains, we aimed to investigate the effect of one of the prime candidates for this pharmacogenetic interaction, the Zbtb16 gene.MethodsAdult male rats of SHR-Lx.PD5PD-Zbtb16 (n = 9) and SHR-Lx.PD5SHR-Zbtb16 (n = 8) were fed standard diet (STD) and subsequently treated with DEX in drinking water (2.6 µg/ml) for 3 days. The morphometric and metabolic profiles of both strains including oral glucose tolerance test, triacylglycerols (TGs), free fatty acids, insulin, and C-reactive protein levels were assessed before and after the DEX treatment. Insulin sensitivity of skeletal muscle and visceral adipose tissue was determined by incorporation of radioactively labeled glucose.ResultsThe differential segment of SHR-Lx.PD5SHR-Zbtb16 rat strain spans 563 kb and contains six genes: Htr3a, Htr3b, Usp28, Zw10, Tmprss5, and part of Drd2. The SHR-Lx.PD5PD-Zbtb16 minimal congenic strain contains only Zbtb16 gene on SHR genomic background and its differential segment spans 254 kb. Total body weight was significantly increased in SHR-Lx.PD5PD-Zbtb16 strain compared with SHR-Lx.PD5SHR-Zbtb16, however, no differences in the weights of adipose tissue depots were observed. While STD-fed rats of both strains did not show major differences in their metabolic profiles, after DEX treatment the SHR-Lx.PD5PD-Zbtb16 congenic strain showed increased levels of TGs, glucose, and blunted inhibition of lipolysis by insulin. Both basal and insulin-stimulated incorporation of radioactively labeled glucose into skeletal muscle glycogen were significantly reduced in SHR-Lx.PD5PD-Zbtb16 strain, but the insulin sensitivity of adipose tissue was comparable between the two strains.ConclusionThe metabolic disturbances including impaired glucose tolerance, dyslipidemia, and IR of skeletal muscle observed after DEX treatment in the congenic SHR-Lx.PD5PD-Zbtb16 reveal the Zbtb16 locus as a possible sensitizing factor for side effects of GC therapy.

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ZBTB16 Gene Variability Influences Obesity-Related Parameters and Serum Lipid Levels in Czech Adults

Cited by 21 publications

References 22 publications

A plasma proteogenomic signature for fibromuscular dysplasia

A plasma proteogenomic signature for fibromuscular dysplasia

Giant Island Mice Exhibit Widespread Gene Expression Changes in Key Metabolic Organs

Single-Gene Congenic Strain Reveals the Effect of Zbtb16 on Dexamethasone-Induced Insulin Resistance

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