A genome-wide association study of thyroid stimulating hormone and free thyroxine in Danish children and adolescents

<div><p>Background</p><p>Hypothyroidism is associated with obesity, and thyroid hormones are involved in the regulation of body composition, including fat mass. Genome-wide association studies (GWAS) in adults have identified 19 and 6 loci associated with plasma concentrations of thyroid stimulating hormone (TSH) and free thyroxine (fT4), respectively.</p><p>Objective</p><p>This study aimed to identify and characterize genetic variants associated with circulating TSH and fT4 in Danish children and adolescents and to examine whether these variants associate with obesity.</p><p>Methods</p><p>Genome-wide association analyses of imputed genotype data with fasting plasma concentrations of TSH and fT4 from a population-based sample of Danish children, adolescents, and young adults, and a group of children, adolescents, and young adults with overweight and obesity were performed (N = 1,764, mean age = 12.0 years [range 2.5−24.7]). Replication was performed in additional comparable samples (N = 2,097, mean age = 11.8 years [1.2−22.8]). Meta-analyses, using linear additive fixed-effect models, were performed on the results of the discovery and replication analyses.</p><p>Results</p><p>No novel loci associated with TSH or fT4 were identified. Four loci previously associated with TSH in adults were confirmed in this study population (<i>PDE10A</i> (rs2983511: <i>β</i> = 0.112<i>SD</i>, <i>p</i> = 4.8 ∙ 10⁻¹⁶), <i>FOXE1</i> (rs7847663: <i>β</i> = 0.223<i>SD</i>, <i>p</i> = 1.5 ∙ 10⁻²⁰), <i>NR3C2</i> (rs9968300: <i>β</i> = 0.194<i>SD</i>), <i>p</i> = 2.4 ∙ 10⁻¹¹), <i>VEGFA (</i>rs2396083: <i>β</i> = 0.088<i>SD</i>, <i>p</i> = 2.2 ∙ 10⁻¹⁰)). Effect sizes of variants known to associate with TSH or fT4 in adults showed a similar direction of effect in our cohort of children and adolescents, 11 of which were associated with TSH or fT4 in our study (<i>p</i><0.0002). None of the TSH or fT4 associated SNPs were associated with obesity in our cohort, indicating no pleiotropic effects of these variants on obesity.</p><p>Conclusion</p><p>In a group of Danish children and adolescents, four loci previously associated with plasma TSH concentrations in adults, were associated with plasma TSH concentrations in children, suggesting comparable genetic determinants of thyroid function in adults and children.</p></div

Subclinical Hypothyroidism in Danish Lean and Obese Children and Adolescents

OBJECTIVE: Thyroid abnormalities are common in obese children. The aim of the present study was to examine the prevalence of subclinical hypothyroidism (SH) and to determine how circulating thyroid hormone concentrations correlate with anthropometrics in Danish lean and obese children and adolescents. METHODS: In this cross-sectional study, we included 3006 children and adolescents, aged 6-18 years, from the Registry of the Danish Childhood Obesity Biobank. The overweight/obese group (n=1796) consisted of study participants with a body mass index (BMI) standard deviation score (SDS) ≥1.28. The control group (n=1210) comprised lean children with a BMI SDS <1.28. All participants were characterized by anthropometrics (weight, height, and waist circumference) and fasting serum concentrations of thyroid-stimulating hormone (TSH), free triiodothyronine, and free thyroxine (fT(4)) at baseline. RESULTS: The prevalence of SH was higher among overweight/obese compared to lean study participants (10.4% vs. 6.4%, p=0.0001). In the overweight/obese group, fasting serum TSH concentrations were associated positively with BMI SDS (p<0.0001) and waist-height ratio (WHtR) (p<0.0001) independent of age, sex, and pubertal developmental stage, whereas fasting serum fT(4) concentrations were associated positively only with WHtR. The odds ratio of exhibiting SH was 1.8 when being overweight/obese compared with lean (p=0.0007) and 1.8 when presenting with a WHtR >0.5 (p=0.0003). CONCLUSION: The prevalence of SH was higher among overweight/obese study participants. The positive correlations of circulating TSH and fT(4) with WHtR suggest that central obesity, independent of the overall degree of obesity, augments the risk of concurrent thyroid abnormalities in children and adolescents with obesity

Multidisciplinary care of obese children and adolescents for one year reduces ectopic fat content in liver and skeletal muscle

BACKGROUND: Ectopic fat deposition in liver and skeletal muscle tissue is related to cardiovascular disease risk and is a common metabolic complication in obese children. We evaluated the hypotheses of ectopic fat in these organs could be diminished following 1 year of multidisciplinary care specialized in childhood obesity, and whether this reduction would associate with changes in other markers of metabolic function. METHODS: This observational longitudinal study evaluated 40 overweight children and adolescents enrolled in a multidisciplinary treatment protocol at the Children’s Obesity Clinic, Holbæk, Denmark. The participants were assessed by anthropometry, fasting blood samples (HbA1c, glucose, insulin, lipids, and biochemical variables of liver function), and liver and muscle fat content assessed by magnetic resonance spectroscopy at enrollment and following an average of 12.2 months of care. Univariate linear regression models adjusted for age, sex, treatment duration, baseline degree of obesity, and pubertal developmental stage were used for investigating possible associations. RESULTS: The standard deviation score (SDS) of baseline median body mass index (BMI) was 2.80 (range: 1.49–3.85) and the median age was 14 years (10–17). At the end of the observational period, the 40 children and adolescents (21 girls) significantly decreased their BMI SDS, liver fat, muscle fat, and visceral adipose tissue volume. The prevalence of hepatic steatosis changed from 28 to 20 % (p = 0.26) and the prevalence of muscular steatosis decreased from 75 to 45 % (p = 0.007). Changes in liver and muscle fat were independent of changes in BMI SDS, baseline degree of obesity, duration of treatment, age, sex, and pubertal developmental stage. CONCLUSIONS: A 1-year multidisciplinary intervention program in the setting of a childhood obesity outpatient clinic confers a biologically important reduction in liver and muscle fat; metabolic improvements that are independent of the magnitude of concurrent weight loss. TRIAL REGISTRATION: ClinicalTrials.gov registration number: NCT00928473, the Danish Childhood Obesity Biobank. Registered June 25, 2009. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12887-015-0513-6) contains supplementary material, which is available to authorized users

Baseline characteristics of 287 overweight/obese (cases) and 40 lean (controls) children and adolescents.

<p>Data are presented as medians (interquartile range) due to a non-normal distribution. BMI, body mass index; diaBP, diastolic blood pressure; EMCL, extramyocellular lipid content; HbA1c, glycosylated hemoglobin; HDL, high density lipoprotein; HOMA-IR, homeostatic model assessment of insulin resistance; IMCL, intramyocellular lipid content; LDL, low density lipoprotein; LFC, liver fat content; MFC, muscle fat content; SAT, subcutaneous adipose tissue volume; SDS, standard deviation score; sysBP, systolic blood pressure; VAT, visceral adipose tissue volume.</p><p>Baseline characteristics of 287 overweight/obese (cases) and 40 lean (controls) children and adolescents.</p

The correlation between MFC and HbA1c.

<p>The correlation between proton magnetic resonance spectroscopy measured muscle fat content (MFC) and glycosylated hemoglobin (HbA1c) in the 287 overweight/obese children and adolescents: R² = 0.07, <i>p</i> = 0.04.</p

The correlation between LFC and HbA1c.

<p>The correlation between proton magnetic resonance spectroscopy measured liver fat content (LFC) and glycosylated hemoglobin (HbA1c) in the 287 overweight/obese children and adolescents: R² = 0.09, <i>p</i> = 0.004.</p

Lead SNPs from the discovery-, replication- and meta-analyses.

<p>Lead SNPs from the discovery-, replication- and meta-analyses.</p

Association of genome-wide variants with plasma TSH concentrations.

<p>SNPs are plotted on the x-axis according to their chromosomal position against the–log10(<i>p</i>-value). The results were considered genome-wide significant with a <i>p</i><5·10⁻⁸. A threshold for replication was set at <i>p</i><1·10⁻⁶.</p

Association of genome-wide variants with plasma fT4 concentrations.

<p>SNPs that passed QC are plotted on the x-axis according to their chromosomal position against their–log10(<i>p</i>-value). The results were considered genome-wide significant with a <i>p</i><5·10⁻⁸ and a replication threshold was set at <i>p</i><1·10⁻⁶.</p