Family history and obesity in youth, their effect on acylcarnitine/aminoacids metabolomics and non-alcoholic fatty liver disease (NAFLD). Structural equation modeling approach

Background: Structural equation modeling (SEM) can help understanding complex functional relationships among obesity, non-alcoholic fatty liver disease (NAFLD), family history of obesity, targeted metabolomics and pro-inflammatory markers. We tested two hypotheses: 1) If obesity precedes an excess of free fatty acids that increase oxidative stress and mitochondrial dysfunction, there would be an increase of serum acylcarnitines, amino acids and cytokines in obese subjects. Acylcarnitines would be related to non-alcoholic fatty disease that will induce insulin resistance. 2) If a positive family history of obesity and type 2 diabetes are the major determinants of the metabolomic profile, there would be higher concentration of amino acids and acylcarnitines in patients with this background that will induce obesity and NAFLD which in turn will induce insulin resistance. Methods/Results 137 normoglycemic subjects, mean age (SD) of 30.61 (8.6) years divided in three groups: BMI30 with absence of NAFLD (G2), n = 24; and BMI>30 with NAFLD (G3), n = 31. Family history of obesity (any) was present in 53%. Both models were adjusted in SEM. Family history of obesity predicted obesity but could not predict acylcarnitines and amino acid concentrations (effect size <0.2), but did predict obesity phenotype. Conclusion: Family history of obesity is the major predictor of obesity, and the metabolic abnormalities on amino acids, acylcarnitines, inflammation, insulin resistance, and NAFLD

Heritability and genetic correlation between GERD symptoms severity, metabolic syndrome, and inflammation markers in families living in Mexico City

<div><p>Objective</p><p>The aim of this study was to estimate the heritability (h²) and genetic correlation (ρG) between GERD symptoms severity, metabolic syndrome components, and inflammation markers in Mexican families.</p><p>Methods</p><p>Cross-sectional study which included 32 extended families resident in Mexico City. GERD symptoms severity was assessed by the ReQuest in Practice questionnaire. Heritability and genetic correlation were determined using the Sequential Oligogenic Linkage Analysis Routines software.</p><p>Results</p><p>585 subjects were included, the mean age was 42 (±16.7) years, 57% were women. The heritability of the severity of some GERD symptoms was h² = 0.27, 0.27, 0.37, and 0.34 (p-value <1.0x10^-5) for acidity complaints, lower abdominal complaints, sleep disturbances, and total ReQuest score, respectively. Heritability of metabolic syndrome components ranged from 0.40 for fasting plasma glucose to 0.61 for body mass index and diabetes mellitus. The heritability for fibrinogen and C-reactive protein was 0.64 and 0.38, respectively. Statistically significant genetic correlations were found between acidity complaints and fasting plasma glucose (ρG = 0.40); sleep disturbances and fasting plasma glucose (ρG = 0.36); acidity complaints and diabetes mellitus (ρG = 0.49) and between total ReQuest score and fasting plasma glucose (ρG = 0.43). The rest of metabolic syndrome components did not correlate with GERD symptoms.</p><p>Conclusion</p><p>Genetic factors substantially explain the phenotypic variance of the severity of some GERD symptoms, metabolic syndrome components and inflammation markers. Observed genetic correlations suggest that these phenotypes share common genes. These findings suggest conducting further investigation, as the determination of a linkage analysis in order to identify regions of susceptibility for developing of GERD and metabolic syndrome.</p></div

Heritability estimates (h2) for the severity of GERD symptoms, metabolic syndrome components and inflammation components.

<p>Heritability estimates (h2) for the severity of GERD symptoms, metabolic syndrome components and inflammation components.</p

Genetic correlation^a between severity of GERD symptoms, inflammation components and metabolic syndrome components.

<p>Genetic correlation<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0178815#t004fn002" target="_blank">^a</a> between severity of GERD symptoms, inflammation components and metabolic syndrome components.</p

Description of general data, severity of GERD symptoms, metabolic syndrome components and inflammation components by sex.

<p>Description of general data, severity of GERD symptoms, metabolic syndrome components and inflammation components by sex.</p

Heritability estimates (h2) for the severity of GERD symptoms, metabolic syndrome components and inflammation components.

<p>Heritability estimates (h2) for the severity of GERD symptoms, metabolic syndrome components and inflammation components.</p

Results of factor analysis, variance components and heritability estimation.

<p>Results of factor analysis, variance components and heritability estimation.</p

Family history of obesity and diabetes in 3 groups.

<p>Family history of obesity and diabetes in 3 groups.</p

SEM hypothesis 2.

<p>Positive family history of obesity was the mayor determinant of acylcarnitines and amino acids, This were associated with NAFLD, obesity, insulin resistance and pro-inflammatory process. In this model we proposed obesity as a secondary, or a consequence of a previous alteration of fatty acid and amino acids metabolism. Circles = latent variables, rectangles = observed variables, e = error term. Family History of obesity is formed by: IndFOB = Second degree family history of obesity. DadFHOB = Parental history of obesity. MomFHOB = Maternal family history of Obesity. Latent variable obesity is formed by: BMI = Body mass Index, Abd_circumf = abdominal circumference, FAT = % of Fat. AA1 and AA2 = latent variables that represent factor for amino acids AC1, AC2, AC3 and AC4 = latent variables that represent factors grouped for acylcarnitines. C:0,C2-C18:2. ALA = alanine, CIT = citrulline, Met = methionine, TYR = tyrosine, ORN = ornithine, PRO = proline, ARG = arginine, GLY = glycine, LEU = leucine, PHE = phenylalanine, VAL = valine. CRP = C reactive protein. TNF<b>α</b> = Tumor necrosis factor alpha, IL-6 = Interleukine-6, both form latent variable INFL = inflammatory markers. Latent variable NAFLD integrates USG = liver ultrasound. ALT = Alanine aminotransferase, AST = Aspartate aminotransferase,. Lines in bold correspond to standardized β estimates > 0.2. Numbers in each line corresponds to standardized β estimate Lines in bold correspond to standarized B estimates > 0.2. Numbers in line correspond to standardized β estimates. To simplify, error terms were not included in the figure.</p

PLS-DA of metabolytes in 3 groups.

<p>1 = BMI<25, 2 = BMI<30 and NAFLD negative, and 3 = BMI>30 and NAFLD positive.</p