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Transcriptomic identification of ADH1B as a novel candidate gene for obesity and insulin resistance in human adipose tissue in Mexican Americans from the Veterans Administration Genetic Epidemiology Study (VAGES).

Winnier DA, Fourcaudot M, Norton L, Abdul-Ghani MA, Hu SL, Farook VS, Coletta DK, Kumar S, Puppala S, Chittoor G, Dyer TD, Arya R, Carless M, Lehman DM, Curran JE, Cromack DT, Tripathy D, Blangero J, Duggirala R, Göring HH, DeFronzo RA, Jenkinson CP - PLoS ONE (2015)

Bottom Line: Adipose tissue had 3,012 genes significantly associated with the traits of interest (false discovery rate, FDR ≤ 0.05).Gene sets/Pathways analysis identified one gene, alcohol dehydrogenase 1B (ADH1B) that was significantly enriched (P < 10(-60)) as a prime candidate for involvement in multiple relevant metabolic pathways.We observed significant inverse correlations with waist circumference (2.8 x 10(-9)), BMI (5.4 x 10(-6)), and fasting plasma insulin (P < 0.001).

View Article: PubMed Central - PubMed

Affiliation: Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States of America.

ABSTRACT
Type 2 diabetes (T2D) is a complex metabolic disease that is more prevalent in ethnic groups such as Mexican Americans, and is strongly associated with the risk factors obesity and insulin resistance. The goal of this study was to perform whole genome gene expression profiling in adipose tissue to detect common patterns of gene regulation associated with obesity and insulin resistance. We used phenotypic and genotypic data from 308 Mexican American participants from the Veterans Administration Genetic Epidemiology Study (VAGES). Basal fasting RNA was extracted from adipose tissue biopsies from a subset of 75 unrelated individuals, and gene expression data generated on the Illumina BeadArray platform. The number of gene probes with significant expression above baseline was approximately 31,000. We performed multiple regression analysis of all probes with 15 metabolic traits. Adipose tissue had 3,012 genes significantly associated with the traits of interest (false discovery rate, FDR ≤ 0.05). The significance of gene expression changes was used to select 52 genes with significant (FDR ≤ 10(-4)) gene expression changes across multiple traits. Gene sets/Pathways analysis identified one gene, alcohol dehydrogenase 1B (ADH1B) that was significantly enriched (P < 10(-60)) as a prime candidate for involvement in multiple relevant metabolic pathways. Illumina BeadChip derived ADH1B expression data was consistent with quantitative real time PCR data. We observed significant inverse correlations with waist circumference (2.8 x 10(-9)), BMI (5.4 x 10(-6)), and fasting plasma insulin (P < 0.001). These findings are consistent with a central role for ADH1B in obesity and insulin resistance and provide evidence for a novel genetic regulatory mechanism for human metabolic diseases related to these traits.

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Correlation of ADH1B Expression with Key Traits (I).Log2 transformed gene expression measurements of ADH1B mRNA obtained by Illumina BeadArray were analyzed for correlation with A lnWC, B lnBMI, C lnFPI and D lnMatsuda Insulin Sensitivity Index. Variables were log transformed to minimize the issue of non-normality.
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pone.0119941.g003: Correlation of ADH1B Expression with Key Traits (I).Log2 transformed gene expression measurements of ADH1B mRNA obtained by Illumina BeadArray were analyzed for correlation with A lnWC, B lnBMI, C lnFPI and D lnMatsuda Insulin Sensitivity Index. Variables were log transformed to minimize the issue of non-normality.

Mentions: For illustrative purposes, we have provided a series of graphs showing the correlations between isolated ADH1B expression and key metabolic traits (Figs. 3–4). These results visually demonstrate the correlations which were used to initially identify ADH1B as a candidate gene strongly associated with obesity/IR traits. Variables were log transformed to minimize the issue of non-normality, and only batch 1 data, accounting for 80% of the fat samples, is shown (Figs. 3 and 4). Results using both Beadarray and qRT-PCR data, are summarized in Table 6. Correlations obtained using qRT-PCR were comparable and in agreement with those obtained with the Illumina BeadArray data. ADH1B gene expression in adipose tissue was strongly inversely correlated with lnWC (R = -0.70, P = 2.8 x 10–9), lnBMI (R = -0.63, P < 0.0001), lnFPI (R = -0.48, P < 0.001) and positively correlated with a measure of insulin sensitivity, the lnMatsuda Insulin Sensitivity Index (R = 0.41, P < 0.01) (Fig. 3 A-D). Consistent with these findings, ADH1B gene expression was inversely correlated with lnHOMA-IR (Fig. 4 A, R = -0.41, P < 0.01). No significant correlations were obtained for lnFFA and lnFPG (Fig. 4 B-C).


Transcriptomic identification of ADH1B as a novel candidate gene for obesity and insulin resistance in human adipose tissue in Mexican Americans from the Veterans Administration Genetic Epidemiology Study (VAGES).

Winnier DA, Fourcaudot M, Norton L, Abdul-Ghani MA, Hu SL, Farook VS, Coletta DK, Kumar S, Puppala S, Chittoor G, Dyer TD, Arya R, Carless M, Lehman DM, Curran JE, Cromack DT, Tripathy D, Blangero J, Duggirala R, Göring HH, DeFronzo RA, Jenkinson CP - PLoS ONE (2015)

Correlation of ADH1B Expression with Key Traits (I).Log2 transformed gene expression measurements of ADH1B mRNA obtained by Illumina BeadArray were analyzed for correlation with A lnWC, B lnBMI, C lnFPI and D lnMatsuda Insulin Sensitivity Index. Variables were log transformed to minimize the issue of non-normality.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4382323&req=5

pone.0119941.g003: Correlation of ADH1B Expression with Key Traits (I).Log2 transformed gene expression measurements of ADH1B mRNA obtained by Illumina BeadArray were analyzed for correlation with A lnWC, B lnBMI, C lnFPI and D lnMatsuda Insulin Sensitivity Index. Variables were log transformed to minimize the issue of non-normality.
Mentions: For illustrative purposes, we have provided a series of graphs showing the correlations between isolated ADH1B expression and key metabolic traits (Figs. 3–4). These results visually demonstrate the correlations which were used to initially identify ADH1B as a candidate gene strongly associated with obesity/IR traits. Variables were log transformed to minimize the issue of non-normality, and only batch 1 data, accounting for 80% of the fat samples, is shown (Figs. 3 and 4). Results using both Beadarray and qRT-PCR data, are summarized in Table 6. Correlations obtained using qRT-PCR were comparable and in agreement with those obtained with the Illumina BeadArray data. ADH1B gene expression in adipose tissue was strongly inversely correlated with lnWC (R = -0.70, P = 2.8 x 10–9), lnBMI (R = -0.63, P < 0.0001), lnFPI (R = -0.48, P < 0.001) and positively correlated with a measure of insulin sensitivity, the lnMatsuda Insulin Sensitivity Index (R = 0.41, P < 0.01) (Fig. 3 A-D). Consistent with these findings, ADH1B gene expression was inversely correlated with lnHOMA-IR (Fig. 4 A, R = -0.41, P < 0.01). No significant correlations were obtained for lnFFA and lnFPG (Fig. 4 B-C).

Bottom Line: Adipose tissue had 3,012 genes significantly associated with the traits of interest (false discovery rate, FDR ≤ 0.05).Gene sets/Pathways analysis identified one gene, alcohol dehydrogenase 1B (ADH1B) that was significantly enriched (P < 10(-60)) as a prime candidate for involvement in multiple relevant metabolic pathways.We observed significant inverse correlations with waist circumference (2.8 x 10(-9)), BMI (5.4 x 10(-6)), and fasting plasma insulin (P < 0.001).

View Article: PubMed Central - PubMed

Affiliation: Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States of America.

ABSTRACT
Type 2 diabetes (T2D) is a complex metabolic disease that is more prevalent in ethnic groups such as Mexican Americans, and is strongly associated with the risk factors obesity and insulin resistance. The goal of this study was to perform whole genome gene expression profiling in adipose tissue to detect common patterns of gene regulation associated with obesity and insulin resistance. We used phenotypic and genotypic data from 308 Mexican American participants from the Veterans Administration Genetic Epidemiology Study (VAGES). Basal fasting RNA was extracted from adipose tissue biopsies from a subset of 75 unrelated individuals, and gene expression data generated on the Illumina BeadArray platform. The number of gene probes with significant expression above baseline was approximately 31,000. We performed multiple regression analysis of all probes with 15 metabolic traits. Adipose tissue had 3,012 genes significantly associated with the traits of interest (false discovery rate, FDR ≤ 0.05). The significance of gene expression changes was used to select 52 genes with significant (FDR ≤ 10(-4)) gene expression changes across multiple traits. Gene sets/Pathways analysis identified one gene, alcohol dehydrogenase 1B (ADH1B) that was significantly enriched (P < 10(-60)) as a prime candidate for involvement in multiple relevant metabolic pathways. Illumina BeadChip derived ADH1B expression data was consistent with quantitative real time PCR data. We observed significant inverse correlations with waist circumference (2.8 x 10(-9)), BMI (5.4 x 10(-6)), and fasting plasma insulin (P < 0.001). These findings are consistent with a central role for ADH1B in obesity and insulin resistance and provide evidence for a novel genetic regulatory mechanism for human metabolic diseases related to these traits.

Show MeSH
Related in: MedlinePlus