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The STK33-linked SNP rs4929949 is associated with obesity and BMI in two independent cohorts of Swedish and Greek children
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
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2013 (English)In: PLoS ONE, ISSN 1932-6203, Vol. 8, no 8, e71353- p.Article in journal (Refereed) Published
Abstract [en]

Recent genome wide association studies (GWAS) have identified a locus on chromosome 11p15.5, closely associated with serine/threonine kinase 33 (STK33), to be associated with body mass. STK33, a relatively understudied protein, has been linked to KRAS mutation-driven cancers and explored as a potential antineoplastic drug target. The strongest association with body mass observed at this loci in GWAS was rs4929949, a single nucleotide polymorphism located within intron 1 of the gene encoding STK33. The functional implications of rs4929949 or related variants have not been explored as of yet. We have genotyped rs4929949 in two cohorts, an obesity case-control cohort of 991 Swedish children, and a cross-sectional cohort of 2308 Greek school children. We found that the minor allele of rs4929949 was associated with obesity in the cohort of Swedish children and adolescents (OR=1.199 (95%CI: 1.002 – 1.434), p= 0.047), and with body mass in the cross-sectional cohort of Greek children (β = 0.08147 (95% CI: 0.1345-0.1618), p = 0.021). We observe the effects of rs4929949 on body mass to be detectable already at adolescence. Subsequent analysis did not detect any association of rs4929949 to phenotypic measurements describing body adiposity or to metabolic factors such as insulin levels, triglycerides and insulin resistance (HOMA).

Place, publisher, year, edition, pages
2013. Vol. 8, no 8, e71353- p.
National Category
URN: urn:nbn:se:uu:diva-204438DOI: 10.1371/journal.pone.0071353ISI: 000323378000046OAI: diva2:639022
Available from: 2013-08-05 Created: 2013-08-05 Last updated: 2014-01-07Bibliographically approved
In thesis
1. Obesity Genetics: Functional Aspects of Four Genetic Loci Associated with Obesity and Body Mass
Open this publication in new window or tab >>Obesity Genetics: Functional Aspects of Four Genetic Loci Associated with Obesity and Body Mass
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Obesity is a complex disorder which has reached epidemic proportions in many parts of the world. Twin studies have demonstrated a high heritability for obesity. The subsequent appli-cation of genome wide association studies (GWAS) in the last decade have identified at least 32 genetic loci associated with body mass and obesity. Despite these great advances, these loci are almost exclusively completely naïve in a functional context. Genetic variations within the gene encoding the fat mass and obesity associated gene (FTO) are the strongest and most consistently observed genetic variants associated with obesity and body mass throughout various studied populations from all parts of the world. The identification of association of FTO with obesity has spurred immense interest in the function of the FTO protein and the functional consequences of its variants. However, the implications of genetic variants at other genetic loci on protein molecular function and body mass development remain undetermined. This thesis aims to examine more closely four of the genetic loci associated with obesity; in proximity of, or associated with: FTO, TMEM18, MAP2K5 and STK33, in two cohorts of children of European descent: a case-control of clinically obese children and normal weight controls from the Stockholm area; and a cross sectional cohort of Greek children. These smaller cohorts allow for studies of more specific effects of genetic variants as individuals in these cohorts can be more carefully studied. TMEM18 gene expression was also studied in the rat-brain where a positive correlation was observed between the body weight of the animal and TMEM18 expression. We also employed next generation sequencing to more carefully study obesity-associated genetic loci related to FTO and TMEM18. We utilized a novel strategy in this project to study genetic variation in the entire FTO- and TMEM18 genes, as well as in the GWAS-identified BMI-associated loci located downstream from TMEM18. This analysis was performed on a case-control cohort of Swedish children (n = ~1000). Through this analysis, we were able to observe genetic variants within intron 1 of the FTO gene to be the main genetic variants asso-ciated with obesity at this locus. We also observed, for the first time, obesity-associated genetic variants within the gene encoding TMEM18. To analyze the potential functional context of FTO we used an in silico approach, utilizing public information databases on mRNA co-expression and protein-protein interaction. Based on our findings, we speculate on a wider functional role of FTO in extracellular ligand-induced neuronal plasticity, possibly via interaction or modulation of the BDNF/NTRK2 signaling pathway.

Place, publisher, year, edition, pages
Upssala: Acta Universitatis Upsaliensis, 2013. 48 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 921
National Category
urn:nbn:se:uu:diva-204449 (URN)978-91-554-8713-3 (ISBN)
Public defence
2013-09-19, A1:111, BMC, Husargatan 3, Uppsala, 09:15 (English)
Available from: 2013-08-29 Created: 2013-08-05 Last updated: 2014-01-07

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Rask-Andersen, MathiasFredriksson, RobertSchiöth, Helgi B.
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