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A meta-analysis of the associations between common variation in the PDE8B gene and thyroid hormone parameters, including assessment of longitudinal stability of associations over time and effect of thyroid hormone replacement.

ABSTRACT: Common variants in PDE8B are associated with TSH but apparently without any effect on thyroid hormone levels that is difficult to explain. Furthermore, the stability of the association has not been examined in longitudinal studies or in patients on levothyroxine (l-T(4)).Totally, four cohorts were used (n=2557): the Busselton Health Study (thyroid function measured on two occasions), DEPTH, EFSOCH (selective cohorts), and WATTS (individuals on l-T(4)).Meta-analysis to clarify associations between the rs4704397 single nucleotide polymorphism in PDE8B on TSH, tri-iodothyronine (T(3)), and T(4) levels.Meta-analysis confirmed that genetic variation in PDE8B was associated with TSH (P=1.64 × 10(-10) 0.20 s.d./allele, 95% confidence interval (CI) 0.142, 0.267) and identified a possible new association with free T(4) (P=0.023, -0.07 s.d./allele, 95% CI -0.137, -0.01), no association was seen with free T(3) (P=0.218). The association between PDE8B and TSH was similar in 1981 (0.14 s.d./allele, 95% CI 0.04, 0.238) and 1994 (0.20 s.d./allele, 95% CI 0.102, 0.300) and even more consistent between PDE8B and free T(4) in 1981 (-0.068 s.d./allele, 95% CI -0.167, 0.031) and 1994 (-0.07 s.d./allele, 95% CI -0.170, 0.030). No associations were seen between PDE8B and thyroid hormone parameters in individuals on l-T(4).Common genetic variation in PDE8B is associated with reciprocal changes in TSH and free T(4) levels that are consistent over time and lost in individuals on l-T(4). These findings identify a possible genetic marker reflecting variation in thyroid hormone output that will be of value in epidemiological studies and provides additional evidence that PDE8B is involved in TSH signaling in the thyroid.

SUBMITTER: Taylor PN

PROVIDER: S-EPMC3080745 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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A meta-analysis of the associations between common variation in the PDE8B gene and thyroid hormone parameters, including assessment of longitudinal stability of associations over time and effect of thyroid hormone replacement.

Taylor Peter N PN Panicker Vijay V Sayers Adrian A Shields Beverley B Iqbal Ahmed A Bremner Alexandra P AP Beilby John P JP Leedman Peter J PJ Hattersley Andrew T AT Vaidya Bijay B Frayling Timothy T Evans Jonathan J Tobias Jonathan H JH Timpson Nicholas J NJ Walsh John P JP Dayan Colin M CM

European journal of endocrinology 20110211 5

<h4>Objective</h4>Common variants in PDE8B are associated with TSH but apparently without any effect on thyroid hormone levels that is difficult to explain. Furthermore, the stability of the association has not been examined in longitudinal studies or in patients on levothyroxine (l-T(4)).<h4>Design</h4>Totally, four cohorts were used (n=2557): the Busselton Health Study (thyroid function measured on two occasions), DEPTH, EFSOCH (selective cohorts), and WATTS (individuals on l-T(4)).<h4>Methods ...[more]

PMID: 21317282

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Project description:IntroductionOvert thyroid disease in pregnancy is associated with numerous maternal and neonatal complications including preterm birth. Less is known about the contribution of trimester-specific subclinical alterations in individual thyroid hormones, especially in late gestation, on the risk of preterm birth. Herein, we examined the associations between subclinical changes in maternal thyroid hormone concentrations (TSH, total T3, free and total T4), measured at multiple time points in pregnancy, and the odds of preterm birth in pregnant women without clinical thyroid disease.Participants and methodsData were obtained from pregnant women participating in a nested case-control study of preterm birth within on ongoing birth cohort study at Brigham and Women's Hospital in Boston, MA (N = 439; 116 cases and 323 controls). We measured thyroid hormones in plasma collected at up to four time points in pregnancy (median = 10, 18, 26, and 35 weeks). We used multivariate logistic regression models stratified by study visit of sample collection to examine associations. To reveal potential biological pathways, we also explored these relationships by obstetric presentation of preterm birth (e.g., spontaneous preterm delivery) that have been previously hypothesized to share common underlying mechanisms.ResultsIn samples collected at median 10 and 26 weeks of gestation, we found inverse associations between FT4 and the odds of overall preterm birth (odds ratio [OR] = 0.57, 95% confidence interval (CI) = 0.33, 1.00; and OR = 0.53, 95% CI = 0.34, 0.84, respectively). Positive associations were detected for total T3 at these same time points (OR = 2.52, 95% CI = 1.20, 5.31; and OR = 3.40, 95% CI = 1.56, 7.40, respectively). These effect estimates were stronger for spontaneous preterm birth.ConclusionsOur results suggest that subclinical alterations in individual maternal thyroid hormones may influence the risk of preterm birth, and the strength of these associations vary by gestational age.

Project description:OBJECTIVE:To explore whether thyroid stimulating hormone (TSH) concentration in patients with a diagnosis of hypothyroidism is associated with increased all cause mortality and a higher risk of cardiovascular disease and fractures. DESIGN:Retrospective cohort study. SETTING:The Health Improvement Network (THIN), a database of electronic patient records from UK primary care. PARTICIPANTS:Adult patients with incident hypothyroidism from 1 January 1995 to 31 December 2017. EXPOSURE:TSH concentration in patients with hypothyroidism. MAIN OUTCOME MEASURES:Ischaemic heart disease, heart failure, stroke/transient ischaemic attack, atrial fibrillation, any fractures, fragility fractures, and mortality. Longitudinal TSH measurements from diagnosis to outcomes, study end, or loss to follow-up were collected. An extended Cox proportional hazards model with TSH considered as a time varying covariate was fitted for each outcome. RESULTS:162 369 patients with hypothyroidism and 863 072 TSH measurements were included in the analysis. Compared with the reference TSH category (2-2.5 mIU/L), risk of ischaemic heart disease and heart failure increased at high TSH concentrations (>10 mIU/L) (hazard ratio 1.18 (95% confidence interval 1.02 to 1.38; P=0.03) and 1.42 (1.21 to 1.67; P<0.001), respectively). A protective effect for heart failure was seen at low TSH concentrations (hazard ratio 0.79 (0.64 to 0.99; P=0.04) for TSH <0.1 mIU/L and 0.76 (0.62 to 0.92; P=0.006) for 0.1-0.4 mIU/L). Increased mortality was observed in both the lowest and highest TSH categories (hazard ratio 1.18 (1.08 to 1.28; P<0.001), 1.29 (1.22 to 1.36; P<0.001), and 2.21 (2.07 to 2.36; P<0.001) for TSH <0.1 mIU/L, 4-10 mIU/L, and >10 mIU/L. An increase in the risk of fragility fractures was observed in patients in the highest TSH category (>10 mIU/L) (hazard ratio 1.15 (1.01 to 1.31; P=0.03)). CONCLUSIONS:In patients with a diagnosis of hypothyroidism, no evidence was found to suggest a clinically meaningful difference in the pattern of long term health outcomes (all cause mortality, atrial fibrillation, ischaemic heart disease, heart failure, stroke/transient ischaemic attack, fractures) when TSH concentrations were within recommended normal limits. Evidence was found for adverse health outcomes when TSH concentration is outside this range, particularly above the upper reference value.

Project description:BACKGROUND:Maintaining thyroid homeostasis during pregnancy is essential for normal fetal growth and development. Growing evidence suggests that phthalates interfere with normal thyroid function. Few human studies have investigated the degree to which phthalates may affect thyroid hormone levels in particularly susceptible populations such as pregnant women. OBJECTIVES:We examined the associations between repeated measures of urinary phthalate metabolites and plasma thyroid hormone levels in samples collected at up to four time points per subject in pregnancy. Additionally, we investigated the potential windows of susceptibility to thyroid hormone disturbances related to study visit of sample collection. METHODS:Data were obtained from pregnant women (n = 439) participating in a nested case-control study of preterm birth with 116 cases and 323 controls. We measured 9 phthalate metabolite concentrations in urine samples collected at up to four study visits per subject during pregnancy (median = 10, 18, 26, and 35 weeks of gestation, respectively). We also measured a panel of thyroid function markers in plasma collected at the same four time points per subject during pregnancy. RESULTS:Although our results were generally null, in repeated measures analyses we observed that phthalate metabolites were largely inversely associated with thyrotropin and positively associated with free and total thyroid hormones. Cross-sectional analyses by study visit revealed that the magnitude and/or direction of these relationships varied by timing of exposure during gestation. CONCLUSIONS:These results support previous reports showing the potential for environmental phthalate exposure to alter circulating levels of thyroid hormones in pregnant women. Citation: Johns LE, Ferguson KK, McElrath TF, Mukherjee B, Meeker JD. 2016. Associations between repeated measures of maternal urinary phthalate metabolites and thyroid hormone parameters during pregnancy. Environ Health Perspect 124:1808-1815;?http://dx.doi.org/10.1289/EHP170.

Project description:The longitudinal course of temporomandibular joint (TMJ) disc displacement (DD) and degenerative joint disease (DJD) has never been conclusively described with magnetic resonance imaging and computed tomography, respectively. This 8-y observational study's objective was to assess the longitudinal stability of DD and DJD among 401 subjects. The Validation Project provided baseline measures; follow-up was performed in the TMJ Impact Project. With magnetic resonance imaging, 2 radiologists rendered a consensus diagnosis of normal/indeterminate, DD with reduction, or DD without reduction. Computed tomography consensus diagnoses included normal/indeterminate, grade 1 DJD, or grade 2 DJD. Radiologist reliability was assessed by kappa; a Hui-Walter model was used to estimate, after accounting for diagnostic disagreement, the frequency of diagnostic progression and reversal. Permutation tests were used to test the statistical influence of concurrent baseline diagnoses on diagnostic changes at follow-up. Of 789 baseline joint-specific soft tissue diagnoses of DD, 598 (76%) joints showed no change; 109 (14%) demonstrated progression; and 82 (10%) had reversal. Of 794 joints with baseline joint-specific hard tissue diagnoses of DJD, progression was observed in 122 (15%) joints, no change in 564 (71%), and reversal in 108 (14%). Radiologist reliability (kappa) was 0.73 (95% CI, 0.64 to 0.83) for DD and 0.76 (95% CI, 0.68 to 0.83) for DJD. After accounting for the influence of diagnostic disagreement, progression of hard tissue diagnoses in the right TMJ occurred in 15.2% of subjects (95% CI, 10.5% to 20.8%) and reversal in 8.3% (95% CI, 4.9% to 12.3%); results were similar for soft tissue diagnoses and the left TMJ. Concurrent baseline soft tissue diagnoses were associated with hard tissue diagnostic changes at follow-up ( P < 0.0001). Baseline hard tissue diagnoses showed no statistical association with soft tissue changes at follow-up ( P = 0.11). Longitudinally, 76% of baseline TMJ soft tissue diagnoses and 71% of the baseline hard tissue diagnoses remained stable. Diagnostic reversal and progression were confirmed for both soft and hard tissues.

Project description:Serum perfluoroalkyl acids (PFAAs) have been linked to disruption of maternal thyroid hormone homeostasis, but results have varied between studies which we hypothesized was due to timing of the thyroid hormone measurements, variability in PFAA isomer patterns, or presence of other stressors. In a longitudinal study design, we investigated the time-dependency of associations between PFAA isomers and thyroid hormones during pregnancy and post-partum while considering thyroid peroxidase antibody (TPOAb) status and mercury (Hg) co-exposure. In participants of a prospective Canadian birth cohort (n = 494), free thyroxine (FT4), free triiodothyronine (FT3), thyroid stimulating hormone (TSH) and TPOAb were quantified in maternal plasma collected in each trimester and 3-months postpartum, and 25 PFAAs (15 linear and 10 branched) and Hg were quantified in samples collected during the second trimester. Perfluorohexane sulfonate (PFHxS) and total branched isomers of perfluorooctane sulfonate (PFOS) were positively associated with TSH in mixed-effect models, with strongest associations early in gestation. Throughout pregnancy and post-partum, PFHxS was inversely associated with FT4, consistent with elevated TSH, while Hg was inversely associated with FT3. In TPOAb-positive women, negative associations were found between PFUnA and FT4, and 1m-PFOS and TSH, supporting previous studies that thyroid disorder could increase susceptibility to PFAA-mediated hormone dysregulation. Hg did not confound associations but was a significant interaction term, revealing further positive associations between PFOS isomers (∑3m+4m-PFOS) and TSH. Higher perfluoroalkyl sulfonate exposures were associated with higher TSH and/or lower FT4, strongly suggestive that PFHxS and branched PFOS isomers are risk factors for subclinical maternal hypothyroidism. Isomer-specific analysis is important in future studies, as crude measures of 'total-PFOS' masked the associations of branched isomers. A concerning result was for PFHxS which had consistent negative associations with FT4 at all time points and a positive association with TSH in early pregnancy when fetal development is most sensitive to disruption.

Dataset Information

A meta-analysis of the associations between common variation in the PDE8B gene and thyroid hormone parameters, including assessment of longitudinal stability of associations over time and effect of thyroid hormone replacement.

Publications

A meta-analysis of the associations between common variation in the PDE8B gene and thyroid hormone parameters, including assessment of longitudinal stability of associations over time and effect of thyroid hormone replacement.

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