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Genetic variants near the MGAT1 gene are associated with body weight, BMI and fatty acid metabolism among adults and children
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
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2012 (English)In: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 36, no 1, 119-129 p.Article in journal (Refereed) Published
Abstract [en]

Objective: Recently a genome-wide association analysis from five European populations identified a polymorphism located downstream of the mannosyl-(α-1,3)-glycoprotein-β-1,2-N-acetylglucosaminyltransferase (MGAT1) gene that was associated with body-weight. In the present study, associations between MGAT1 variants combined with obesity and insulin measurements were investigated in three cohorts. Levels of fatty acids and estimated measures of Δ desaturases were also investigated among adult men.

Design: Six polymorphisms downstream of MGAT1 were genotyped in a cross-sectional cohort of 1152 Swedish men. Three polymorphisms were further analyzed in a case-control study of 1076 Swedish children and in a cross-sectional study of 2249 Greek children.

Results: Three polymorphisms, rs12186500 (odds ratio (OR): 1.892, 95% confidence interval (CI): 1.237-2.895, P=0.003), rs1021001 (OR: 2.102, 95% CI: 1.280-3.455, P=0.003) and rs4285184 (OR: 1.587, 95% CI: 1.024-2.459, P=0.038) were associated with a higher prevalence of obesity among the adult men and a trend for obesity was observed for rs4285184 among the Swedish (OR: 1.205, 95% CI: 0.987-1.471, P=0.067) and Greek children (OR: 1.192, 95%CI: 0.978-1.454, P=0.081). Association with body weight was observed for rs12186500 (P=0.017) and rs4285184 (P=0.024) among the men. The rs1021001 and rs4285184 were also associated with body mass index (BMI) in the two Swedish cohorts and similar trends were observed among the Greek children. The combined effect size for rs1021001 and rs4285184 on BMI z-score from a meta-analysis was 0.233 (95% CI:0.093-0.373, P=0.001) and 0.147 (95% CI:0.057-0.236, P=0.001), respectively. We further observed associations between the genetic variants and fatty acids (P<0.039) and estimated measures of Δ desaturases (P<0.040), as well as interactions for rs12186500 (P<0.019) with an effect on BMI. No association was found with homeostatic model assessment-insulin resistance in any cohort but increased insulin levels, insulin response and decreased insulin sensitivity were observed among the children (P<0.038).

Conclusion: Genetic variants downstream MGAT1 seem to influence susceptibility to obesity. Moreover, these genetic variants affect the levels of serum unsaturated fatty acids and Δ desaturase indices, variables previously shown to correlate with obesity.

Place, publisher, year, edition, pages
2012. Vol. 36, no 1, 119-129 p.
Keyword [en]
MGAT1, body weight, BMI, insulin, fatty acids
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-146214DOI: 10.1038/ijo.2011.11ISI: 000299306700018PubMedID: 21304485OAI: oai:DiVA.org:uu-146214DiVA: diva2:397748
Available from: 2011-02-15 Created: 2011-02-15 Last updated: 2017-12-11Bibliographically approved
In thesis
1. Obesity and Increased Susceptibility : Role of FTO and MGAT1 Genetic Variants
Open this publication in new window or tab >>Obesity and Increased Susceptibility : Role of FTO and MGAT1 Genetic Variants
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Obesity is a complex and a highly individualized disease and the molecular mechanisms behind this disorder need to be better elucidated. Identification of genes and genetic variants that are involved provide opportunities to establish a genetic understanding of the disease. These findings may also provide more rational approaches to therapy, either by identifying underlying causes or point out the need for different treatments. In addition, the timing and severity of obesity may provide insights into the aetiology of obesity and also identify age-specific determinants of weight gain. Recently, genome-wide association studies have led to a rapid progress in our understanding of the genetic basis of various diseases and candidate genes for obesity have been identified. The overall aim of this thesis was to investigate the genetic impact on severity of childhood obesity and the associations between obesity and genetic variants in the fat mass and obesity associated gene, FTO, and MGAT1, the gene encoding mannosyl (α-1,3-)-glycoprotein β-1,2-N-acetyl-glucosaminyltransferase.

We show that the impact of parental body mass index (BMI) on the severity of obesity in children is strengthened as the child grows older, whereas the age at obesity onset is of limited importance.

By association studies, we show that single nucleotide polymorphisms downstream MGAT1 influence susceptibility to obesity. Moreover, these variants affect the levels of unsaturated fatty acids and desaturase indices, variables previously shown to correlate with obesity. Furthermore, one variant in the first intronic region of FTO is associated with obesity among children but not with BMI or other measures of adiposity at older ages. However, this variant shows a weight-dependent association with cognitive function among elderly men. By direct sequencing, we identified novel variants in FTO, affecting glucose homeostasis in a BMI-independent manner. Furthermore, we found gender specific effects for FTO, both regarding obesity susceptibility and related phenotypes.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2011. 68 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 658
Keyword
Obesity, BMI, SNP, haplotype, association study, FTO, MGAT1
National Category
Pharmacology and Toxicology
Research subject
Pharmacology
Identifiers
urn:nbn:se:uu:diva-149332 (URN)978-91-554-8039-4 (ISBN)
Public defence
2011-05-07, B22, BMC, Husargatan 3, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2011-04-14 Created: 2011-03-17 Last updated: 2011-06-13Bibliographically approved

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Jacobsson, JosefinRask-Andersen, MathiasRisérus, UlfLannfelt, LarsGyllensten, UlfSchiöth, Helgi BFredriksson, Robert

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