Parent-offspring transmission of adipocytokine levels and their associations with metabolic traits

Abstract

Adipose tissue secreted cytokines (adipocytokines) have significant effects on the physiology and pathology of human metabolism relevant to diabetes and cardiovascular disease. We determined the relationship of the pattern of these circulating hormones with obesity-related phenotypes and whether such pattern is transmitted from parent to offspring. A combined total of 403 individuals from 156 consenting Saudi families divided into initial (119 families with 123 adults and 131 children) and replication (37 families with 58 adults and 91 children) cohorts were randomly selected from the RIYADH Cohort study. Anthropometrics were evaluated and metabolic measures such as fasting serum glucose, lipid profiles, insulin, leptin, adiponectin, resistin, tumor necrosis factor alpha (TNFα), activated plasminogen activator inhibitor 1 (aPAI1), high sensitivity C-reactive protein (hsCRP) and angiotensin II were also assessed. Parent-offspring regressions revealed that with the exception of hsCRP, all hormones measured showed evidence for significant inheritance. Principal component (PC) analysis of standardized hormone levels demonstrated surprising heritability of the three most common axes of variation. PC1, which explained 21% of the variation, was most strongly loaded on levels of leptin, TNFα, insulin, and aPAI1, and inversely with adiponectin. It was significantly associated with body mass index (BMI) and phenotypically stronger in children, and showed a heritability of ∼50%, after adjustment for age, gender and generational effects. We conclude that adipocytokines are highly heritable and their pattern of co-variation significantly influences BMI as early as the pre-teen years. Investigation at the genomic scale is required to determine the variants affecting the regulation of the hormones studied.

Figure 1. Parent-Offspring Regressions.

Each plot shows the regression for the indicated adipocytokine measure of the child against the parent or mid-parent (where both parents were measured). Each measure is normalized and adjusted for generation, gender, cohort, and age within generation. Gray circles and dashed line indicate the initial cohort (generally single parent-child pairs) and the black circles and solid line indicate the replication cohort (generally larger families). (A) Leptin. (B) Adiponectin. (C) Insulin. (D) Principal Component 1. (E) PC2. Note that removal of a dozen outliers with high levels of resistin results in a much stronger regression. (F) PC3. Regression coefficients and significance are indicated in Supplementary Tables, and in Table 2 for the combined dataset. R-squared and p-values correspond to the combined dataset as documented in Table 2.

Figure 2. Adipocytokine – Phenotype Correlations.

Each plot shows the regression of the indicated phenotype (A–C: Body Mass Index; D: serum HDL-Cholesterol) against the standardized measure of adipocytokine (B: Leptin; C: Adiponectin; D: Angiotensin II) or PC1 (A). Red points are the parents, blue points the children. Note that in each case the correlation is stronger in the children, and that although the regressions for PC1 and leptin explain similar proportions of the variance, as indicated in Table 3, the PC1 values cover a more even spread of values and are more consistent across the generations. R-squared and p-values correspond to the full model as documented in Table 4.

Figure 3. Clustering of Phenotypes in Families.

Several families in the replication cohort were observed where each of the parents and their children were in the upper or lower quartile for age-adjusted BMI, as well as for two or more adipocytokine measures. Shading of each circle corresponds to age-adjusted BMI (low BMI, light; high BMI dark), and the filled circles represent members of two families in each plot. (A) All members of families 124 and 128 were obese and had high leptin coupled with low resistin concentrations. (B) All members of families 157 and 160 had low TNFα but high resistin concentrations and were in the lowest third of age-adjusted BMI.