Association of BMI and Obesity Related Traits in Relation to the Metabolomic Profile of Blood Plasma 公开

Eagar, Robert Yardley (2016)

Permanent URL: https://etd.library.emory.edu/concern/etds/6m311p88b?locale=zh
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Abstract

Background: Approximately 35% of American adults currently suffer from obesity, which is known to cause numerous negative health outcomes, including type 2 diabetes and cardiovascular diseases. Prior studies have reported changes in metabolite profile associated with obesity and overweight. Modern high throughput metabolomic studies have recently increased the ability to detect changes in the metabolite profile, allowing for the garnering of novel associations and verifying changes in amino acid concentrations with overweight and obesity. Methods: Data utilized in this project was obtained through the Emory Twin Study. Participant data including a medical history and complete physical exam were paired with blood plasma metabolomic data, including over 20,000 metabolomic markers obtained through high-performance liquid chromatography - mass spectrometry. A twin specific linear mixed effects regression model was fit to identify biomarkers associated with BMI and waist-to-hip ratio (WHR). Metabolomic features were annotated via the Metlin database and Mummichog pathway analysis. Results: Among 92 twin pairs and 3 singletons, WHR was directly associated (Bonferroni corrected p-value <0.05) with three metabolomic features: glutamate, acoric acid, and quinoclamine. The glutathione metabolism pathway was also significantly associated with WHR. BMI had a significant direct association with mevalonic acid (MVA) and an undefined porphyrin and a significant inverse association with 2,3-dinor Prostaglandin E1. Further significant associations with BMI were not conclusively annotated. Discussion: Metabolites associated with WHR were significant between twin pairs only, suggesting greater significance of genetic factors than environmental factors. The glutathione metabolism pathway, which contains glutamate, contributes to oxidative stress. Acoric acid and quinoclamine are not associated with normal human metabolism and demonstrate the need for a targeted approach to verification of annotation. Of the metabolites significantly associated with BMI, MVA was the only metabolite with a clear metabolic pathway association. MVA, which is known to be directly associated with in vivo cholesterol synthesis, was directly associated with BMI within twin pairs, suggesting environmental effects alter the relationship between MVA and BMI. Future studies should aim to ascertain the identities of significantly associated metabolites and the evaluation of the causal relationship between metabolomic markers and obesity.

Table of Contents

Table of Contents

Background ......................................................................................................................... 1 Methods ............................................................................................................................. 8 Data Collection .................................................................................................................... 8 Specific Aims ...................................................................................................................... 9 Statistical Methods ............................................................................................................... 9 Results............................................................................................................................... 12 Discussion.......................................................................................................................... 14 References ........................................................................................................................ 18 Tables ............................................................................................................................... 23 Figures ............................................................................................................................. 26 List of Tables Table 1. Phenotypic Characteristics of Twins, ETS...................................................................... 23 Table 2. Significant Metabolomic Features Associated Between Pairs with WHR, Bonferroni p<0.05 ... 23 Table 3. Annotation of Significant Metabolomic Features Associated with WHR ............................... 23 Table 4. Significant Metabolomic Features Associated Within Pairs with BMI, Bonferroni p<0.05 ....... 24 Table 5. Annotation of Significant Metabolomic Features Associated with BMI ................................ 24 Table 6. Cross Reference of Significant Metabolomic Features Associated with WHR and BMI ........... 25 List of Figures Figure 1. Q-Q Plot of LME Regression of WHR Between Pair Effects for Negative Charge Ions .......... 26 Figure 2. Q-Q Plot of LME Regression of WHR Within Pair Effects for Negative Charge Ions ............. 26 Figure 3. Manhattan Plots of Association Strength by M/Z, WHR ................................................. 27 Figure 4. Manhattan Plots of Association Strength by M/Z, BMI .................................................. 28 Figure 5. Mummichog Output Pathway, WHR Between Twin Pairs, Positive Ion .............................. 28

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