Genotype-based recall to study metabolic effects of genetic variation: a pilot study of<i>PPARG</i>Pro12Ala carriers

Kamble, Prasad G.; Gustafsson, Stefan; Pereira, Maria J.; Lundkvist, Per; Cook, Naomi L.; Lind, Lars; Franks, Paul W.; Fall, Tove; Eriksson, Jan W.; Ingelsson, Erik

doi:10.1080/03009734.2017.1405127

Cited by 5 publications

(9 citation statements)

References 43 publications

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“…After rare variant genotype calling with zCall version 3.3 (https://github.com/jigold/zCall), markers with a call rate <99% or a Fisher’s exact test p value for Hardy–Weinberg equilibrium <10 −4 were also excluded. Further details can be found in the study by Kamble et al [17]. In total, 2432 samples passed quality control, and 2378 samples remained after further exclusion of related individuals.…”

Section: Methodsmentioning

confidence: 99%

In search of causal pathways in diabetes: a study using proteomics and genotyping data from a cross-sectional study

et al. 2019

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Aims/hypothesisThe pathogenesis of type 2 diabetes is not fully understood. We investigated whether circulating levels of preselected proteins were associated with the outcome ‘diabetes’ and whether these associations were causal.MethodsIn 2467 individuals of the population-based, cross-sectional EpiHealth study (45–75 years, 50% women), 249 plasma proteins were analysed by the proximity extension assay technique. DNA was genotyped using the Illumina HumanCoreExome-12 v1.0 BeadChip. Diabetes was defined as taking glucose-lowering treatment or having a fasting plasma glucose of ≥7.0 mmol/l. The associations between proteins and diabetes were assessed using logistic regression. To investigate causal relationships between proteins and diabetes, a bidirectional two-sample Mendelian randomisation was performed based on large, genome-wide association studies belonging to the DIAGRAM and MAGIC consortia, and a genome-wide association study in the EpiHealth study.ResultsTwenty-six proteins were positively associated with diabetes, including cathepsin D, retinal dehydrogenase 1, α-l-iduronidase, hydroxyacid oxidase 1 and galectin-4 (top five findings). Three proteins, lipoprotein lipase, IGF-binding protein 2 and paraoxonase 3 (PON-3), were inversely associated with diabetes. Fourteen of the proteins are novel discoveries. The Mendelian randomisation study did not disclose any significant causal effects between the proteins and diabetes in either direction that were consistent with the relationships found between the protein levels and diabetes.Conclusions/interpretationThe 29 proteins associated with diabetes are involved in several physiological pathways, but given the power of the study no causal link was identified for those proteins tested in Mendelian randomisation. Therefore, the identified proteins are likely to be biomarkers for type 2 diabetes, rather than representing causal pathways.Electronic supplementary materialThe online version of this article (10.1007/s00125-019-4960-8) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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Section: Methodsmentioning

confidence: 99%

In search of causal pathways in diabetes: a study using proteomics and genotyping data from a cross-sectional study

et al. 2019

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“…The gene expression analysis using PCR is often influenced by the choice of housekeeping genes and therefore we acknowledge that if genes other than 18S rRNA or GUSB were used, this might possibly modify the results slightly. In addition, the number of subjects included was small due to a limited number of subjects to invite, in particular within the Ala/Ala group, and the participation rate was reduced by the extensive investigation.- 35 This decreased the probability of finding statistically significant differences, especially when studying a common variant like Pro12Ala with an effect size of a modest magnitude. However, based on power calculations, a comparison of two groups with the current sample sizes allowed 80% power to detect a 20% difference in insulin action on adipocyte lipolysis as well as on glucose uptake.…”

Section: Discussionmentioning

confidence: 99%

Role of peroxisome proliferator-activated receptor gamma Pro12Ala polymorphism in human adipose tissue: assessment of adipogenesis and adipocyte glucose and lipid turnover

et al. 2018

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The protective mechanisms of peroxisome proliferator-activated receptor gamma (PPARγ) Pro12Ala polymorphism in type 2 diabetes (T2D) are unclear. We obtained subcutaneous adipose tissue (AT) before and 3 h after oral glucose (OGTT) in carriers and non-carriers of the Ala allele (12 Pro/Pro, 15 Pro/Ala, and 13 Ala/Ala). Adipogenesis, adipocyte glucose uptake and lipolysis as well as PPARγ target gene expression were investigated and compared between the genotype groups. During fasting and post-OGTT, neither basal nor insulin-stimulated adipocyte glucose uptake differed between genotypes. Compared to fasting, a decreased hormone-sensitive lipase gene expression in Pro/Pro (p < 0.05) was accompanied with a higher antilipolytic effect of insulin post-OGTT (p < 0.01). The adipocyte size was similar across groups. Preadipocyte differentiation rates between Pro/Pro and Ala/Ala were unchanged. In conclusion, no major differences in AT differentiation, glucose uptake, lipolysis or expression of PPARγ target genes were observed between different PPARγ Pro12Ala genotypes. Albeit small, our study may suggest that other pathways in AT or effects exerted in other tissues might contribute to the Pro12Ala-mediated protection against T2D.

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“…As our narrative review shows, the literature on GBR studies as applied to cardiometabolic health outcomes is expanding but remains small. Most existing GBR studies are descriptive in nature 4, 8–11, 13–15, 20 , having used recall to minimize the sample size required to deploy bespoke phenotyping methods; a handful of additional GBR studies have examined gene-drug or gene-diet interactions 12, 17–19, 24, 25 ; and only one GBR study has incorporated MR to enhance causal inference 26 , whilst one further study combined GBR and gene-editing technologies to study mechanism of action 7 .…”

Section: Discussionmentioning

confidence: 99%

“…Other forms of GBR have looked to assess the causal impact of specific risk factors and also to enhance trial design through informed participant selection 2, 3 . More than a dozen GBR studies focusing on cardiometabolic traits have been reported in the past two decades 4–20 with contrasting genetic characteristics, with the PPARG Pro12Ala variant (rs1801282) being the single most extensively studied locus.…”

Section: Overview Of Published Gbr Studiesmentioning

confidence: 99%

Genotype-Based Recall Studies in Complex Cardiometabolic Traits

Franks

Timpson

2018

Circ Genom Precis Med.

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In genotype-based recall (GBR) studies, people (or their biological samples) who carry genotypes of special interest for a given hypothesis test are recalled from a larger cohort (or biobank) for more detailed investigations. There are several GBR study designs that offer a range of powerful options to elucidate i) genotype-phenotype associations (by increasing the efficiency of genetic association studies, thereby allowing bespoke phenotyping in relatively small cohorts), ii) the effects of environmental exposures (within the Mendelian randomization framework), and iii) gene-treatment interactions (within the setting of GBR interventional trials). In this review we overview the literature on GBR studies, as applied to cardiometabolic health outcomes. We also review the GBR approaches used to date and outline new methods and study designs that might enhance the utility of GBR-focused studies. Specifically, we highlight how GBR methods have the potential to augment randomized controlled trials, providing an alternative application for the now increasingly accepted MR methods usually applied to large-scale population-based datasets. Further to this, we consider how functional and basic science approaches alongside GBR designs offer intellectually intriguing and potentially powerful ways to explore the implications of alterations to specific (and potentially druggable) biological pathways.

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Genotype-based recall to study metabolic effects of genetic variation: a pilot study ofPPARGPro12Ala carriers

Cited by 5 publications

References 43 publications

In search of causal pathways in diabetes: a study using proteomics and genotyping data from a cross-sectional study

In search of causal pathways in diabetes: a study using proteomics and genotyping data from a cross-sectional study

Role of peroxisome proliferator-activated receptor gamma Pro12Ala polymorphism in human adipose tissue: assessment of adipogenesis and adipocyte glucose and lipid turnover

Genotype-Based Recall Studies in Complex Cardiometabolic Traits

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