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Genotype-based recall to study metabolic effects of genetic variation: a pilot study of PPARG Pro12Ala carriers
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.ORCID iD: 0000-0001-5498-3899
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
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2017 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 122, no 4, p. 234-242Article in journal (Refereed) Published
Abstract [en]

AIM: To assess practical implications of genotype-based recall (GBR) studies, an increasingly popular approach for in-depth characterization of genotype-phenotype relationships.

METHODS: We genotyped 2500 participants from the Swedish EpiHealth cohort and considered loss-of-function and missense variants in genes with relation to cardiometabolic traits as the basis for our GBR study. Therefore, we focused on carriers and non-carriers of the PPARG Pro12Ala (rs1801282) variant, as it is a relatively common variant with a minor allele frequency (MAF) of 0.14. It has also been shown to affect ligand binding and transcription, and carriage of the minor allele (Ala12) is associated with a reduced risk of type 2 diabetes. We re-invited 39 Pro12Pro, 34 Pro12Ala, and 30 Ala12Ala carriers and performed detailed anthropometric and serological assessments.

RESULTS: The participation rates in the GBR study were 31%, 44%, and 40%, and accordingly we included 12, 15, and 13 individuals with Pro12Pro, Pro12Ala, and Ala12Ala variants, respectively. There were no differences in anthropometric or metabolic variables among the different genotype groups.

CONCLUSIONS: Our report highlights that from a practical perspective, GBR can be used to study genotype-phenotype relationships. This approach can prove to be a valuable tool for follow-up findings from large-scale genetic discovery studies by undertaking detailed phenotyping procedures that might not be feasible in large studies. However, our study also illustrates the need for a larger pool of genotyped or sequenced individuals to allow for selection of rare variants with larger effects that can be examined in a GBR study of the present size.

Place, publisher, year, edition, pages
Taylor & Francis, 2017. Vol. 122, no 4, p. 234-242
Keywords [en]
Genotype-based recall, PPARG Pro12Ala, metabolism
National Category
Endocrinology and Diabetes Medical Genetics
Identifiers
URN: urn:nbn:se:uu:diva-342240DOI: 10.1080/03009734.2017.1405127ISI: 000423294800005PubMedID: 29303622OAI: oai:DiVA.org:uu-342240DiVA, id: diva2:1183898
Funder
Swedish Research Council, 2015-02907Göran Gustafsson Foundation for Research in Natural Sciences and MedicineSwedish Heart Lung Foundation, 20140422Knut and Alice Wallenberg Foundation, 2013.0126Swedish Diabetes AssociationAvailable from: 2018-02-19 Created: 2018-02-19 Last updated: 2018-08-12Bibliographically approved
In thesis
1. Role of nuclear receptors in the regulation of human adipose tissue metabolism
Open this publication in new window or tab >>Role of nuclear receptors in the regulation of human adipose tissue metabolism
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Nuclear receptors modulate expression of genes involved in adipose tissue (AT) metabolism. Their improved understanding may provide new treatment options for metabolic disorders such as obesity, insulin resistance (IR) and type 2 diabetes (T2D).

This thesis explored the role of nuclear receptors, mainly, glucocorticoid and estrogen receptors (GR and ER, respectively) and peroxisome proliferator-activated receptor gamma (PPARγ), and their interplay in the regulation of metabolic function and dysfunction in human AT.

In Paper I, the regulation of adipokine lipocalin 2 (LCN2) expression by synthetic glucocorticoid, dexamethasone and effect of LCN2 on glucose and lipid metabolism in AT were studied. In pre-menopausal but not post-menopausal women or men, dexamethasone upregulated LCN2 gene expression, which also correlated with markers of obesity and IR. LCN2 inhibited adipocyte glucose uptake.

In Paper II, the effect of estrogen (E2) and its interaction with GR in LCN2 regulation in AT from post-menopausal women were examined. E2 increased LCN2 expression, what seems to be mediated by ERβ. E2 and dexamethasone co-treatment increased LCN2 gene expression in presence of ERα but not ERβ antagonist. Dexamethasone decreased ERα, while increased ERβ gene expression.

In Paper III and IV, the feasibility of genotype-based recall (GBR), a participant recruitment approach, was tested by undertaking clinical and AT phenotyping of different PPARγ Pro12Ala carriers. The baseline characteristics were comparable between genotypes. Compared to fasting, a decreased hormone-sensitive lipase gene expression in Pro/Pro group also accompanied with a higher antilipolytic effect of insulin after oral glucose. Adipocyte glucose uptake and adipogenesis remained unchanged between genotypes.

Overall, LCN2 can induce IR in human AT and may mediate metabolic defects by excess glucocorticoids in pre-menopausal women. GR selectively interacts with ERα and ERβ, the latter two acts oppositely to control LCN2 expression in AT. PPARγ Pro12Ala had no major effect on clinical and adipose phenotype, likely due to a small sample size in relation to the modest effect the Ala variant or tissues other than adipose could be critical in conferring protection by Pro12Ala against T2D risk. Further, the GBR approach deemed feasible, however, would be more suitable in the characterization of rare genetic variants.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 77
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1489
Keywords
human adipose tissue, nuclear receptors, glucocorticoids, estrogen, PPARγ, lipocalin 2, glucose uptake, lipolysis, adipogenesis, genotype-based recall
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-357119 (URN)978-91-513-0401-4 (ISBN)
Public defence
2018-09-28, Rudbeckssalen, Rudbeck entréplan, C11, Rudbeck laboratory, Uppsala, 09:30 (English)
Opponent
Supervisors
Available from: 2018-09-07 Created: 2018-08-12 Last updated: 2018-09-07

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Kamble, Prasad G.Gustafsson, StefanPereira, Maria JLundkvist, PerLind, LarsFall, ToveEriksson, Jan W.Ingelsson, Erik

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