RESUMO
CONTEXT: Circulating concentrations of free triiodothyronine (fT3), free thyroxine (fT4), and thyrotropin (TSH) are partly heritable traits. Recent studies have advanced knowledge of their genetic architecture. Epigenetic modifications, such as DNA methylation (DNAm), may be important in pituitary-thyroid axis regulation and action, but data are limited. OBJECTIVE: To identify novel associations between fT3, fT4, and TSH and differentially methylated positions (DMPs) in the genome in subjects from 2 Australian cohorts. METHOD: We performed an epigenome-wide association study (EWAS) of thyroid function parameters and DNAm using participants from: Brisbane Systems Genetics Study (median age 14.2 years, nâ =â 563) and the Raine Study (median age 17.0 years, nâ =â 863). Plasma fT3, fT4, and TSH were measured by immunoassay. DNAm levels in blood were assessed using Illumina HumanMethylation450 BeadChip arrays. Analyses employed generalized linear mixed models to test association between DNAm and thyroid function parameters. Data from the 2 cohorts were meta-analyzed. RESULTS: We identified 2 DMPs with epigenome-wide significant (Pâ <â 2.4E-7) associations with TSH and 6 with fT3, including cg00049440 in KLF9 (Pâ =â 2.88E-10) and cg04173586 in DOT1L (Pâ =â 2.09E-16), both genes known to be induced by fT3. All DMPs had a positive association between DNAm and TSH and a negative association between DNAm and fT3. There were no DMPs significantly associated with fT4. We identified 23 differentially methylated regions associated with fT3, fT4, or TSH. CONCLUSIONS: This study has demonstrated associations between blood-based DNAm and both fT3 and TSH. This may provide insight into mechanisms underlying thyroid hormone action and/or pituitary-thyroid axis function.
Assuntos
Epigenoma/fisiologia , Histona-Lisina N-Metiltransferase/genética , Fatores de Transcrição Kruppel-Like/genética , Glândula Tireoide/fisiologia , Tri-Iodotironina/sangue , Adolescente , Austrália/epidemiologia , Criança , Estudos de Coortes , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Estudos Observacionais como Assunto/estatística & dados numéricos , Doenças da Glândula Tireoide/sangue , Doenças da Glândula Tireoide/epidemiologia , Doenças da Glândula Tireoide/genética , Testes de Função Tireóidea , Estudos em Gêmeos como Assunto/estatística & dados numéricosRESUMO
OBJECTIVE: There are no large, longitudinal studies of thyroid function across adolescence. The aims of this study were to examine longitudinal trends in thyrotropin (TSH), free triiodothyronine (fT3) and free thyroxine (fT4) and determine age-specific reference ranges. METHODS: Thyroid function was assessed in 3415 participants in the Brisbane Longitudinal Twin Study at ages 12, 14, and 16, using the Abbott ARCHITECT immunoassay. Longitudinal analyses were adjusted for body mass index and puberty. RESULTS: In girls, mean fT4 (± SE) increased between age 12 and 14 (by 0.30â ±â 0.08 pmol/L; Pâ <â 0.001), while remaining unchanged in boys; from age 14 to 16, fT4 increased in both girls (by 0.42â ±â 0.07 pmol/L; Pâ <â 0.001) and boys (0.64â ±â 0.07 pmol/L, Pâ <â 0.001). There was a slight increase in fT3 from age 12 to 14 years in girls (by 0.07â ±â 0.03 pmol/L; Pâ =â 0.042), with a more marked increase in boys (0.29â ±â 0.03 pmol/L; Pâ <â 0.001), followed by a decrease from age 14 to 16 in both sexes (girls, by 0.53â ±â 0.02 pmol/L; Pâ <â 0.001; boys, by 0.62â ±â 0.03 pmol/L; Pâ <â 0.001). From age 12 to 14, TSH showed no significant change in girls or boys, then levels increased from age 14 to 16 in both sexes (in girls, by 4.9%, 95% CI: 2.4%-10.3%, Pâ =â 0.020; in boys, by 7.2%, 95% CI: 3.0%-11.6%, Pâ =â 0.001). Reference ranges differed substantially from adults, particularly for fT4 and fT3. CONCLUSIONS: Thyroid function tests in adolescents display complex, sexually dimorphic patterns. Implementation of adolescence-specific reference ranges may be appropriate.