The Effect of a Mutation in the Thyroid Stimulating Hormone Receptor (TSHR) on Development, Behaviour and TH Levels in Domesticated Chickens.
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ABSTRACT:
SUBMITTER: Karlsson AC
PROVIDER: S-EPMC4460094 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Our laboratory identified six distinct inactivating TSHR gene mutations in Arab tribes living in Israel. We recently reported three nucleotide substitutions in exon 3 producing p.[L89L;Q90P] and one in exon 9 of the same allele producing p.P264S in Family A. Family B, reported herein, harbors the identical mutation in exon 3 only. We set to determine whether the mutations have common ancestral origin.Coding regions of the TSHR were sequenced and flanking microsatellite markers spanning 5.3 cM were used for haplotyping.Two siblings of Family B were compound heterozygous for TSHR gene mutations. The paternal allele contained the exon 3 mutation and the maternal allele harbored a mutation in exon 10 (p.L653V). We investigated the possibility of a founder effect with subsequent mutational events for the presence of the same exon 3 mutation in different families. The haplotype of the allele harboring the exon 3 mutation in Family B was identical to that of Family A, also harboring the exon 9 mutation on the same allele, indicating that the latter occurred subsequently. The ancestral wild-type TSHR was present in Family B, suggesting that the mutation in exon 3 was also new in the history of that population.It is more likely that two consecutive mutational events occurred on the ancestral wild-type allele instead of a recombination bringing exon 3 and exon 9 mutations together on the same allele. New mutational events contribute to the high prevalence of TSHR mutations in this population in addition to a founder effect and limited gene pool due to inbreeding.
| S-EPMC3286805 | biostudies-literature
Project description:BackgroundElevations or deficits in thyroid hormone levels are responsible for a wide range of neonatal and adult phenotypes. Several genome-wide, candidate gene, and meta-analysis studies have examined thyroid hormones in adults; however, to our knowledge, no genetic association studies have been performed with neonatal thyroid levels.MethodsA population of Iowa neonates, term (n = 827) and preterm (n = 815), were genotyped for 45 single-nucleotide polymorphisms (SNPs). Thyroid-stimulating hormone (TSH) values were obtained from the Iowa Neonatal Metabolic Screening Program. ANOVA was performed to identify genetic associations with TSH concentrations.ResultsThe strongest association was rs4704397 in the PDE8B gene (P = 1.3 × 10(-4)), followed by rs965513 (P = 6.4 × 10(-4)) on chromosome 9 upstream of the FOXE1 gene. Both of these SNPs met statistical significance after correction for multiple testing. Six other SNPs were marginally significant (P < 0.05).ConclusionWe demonstrated for the first time two genetic associations with neonatal TSH levels that replicate findings with adult TSH levels. These SNPs should be considered early predictors of risk for adult diseases and conditions associated with thyroid hormone levels. Furthermore, this study provides a better understanding of the thyroid profile and potential risk for thyroid disorders in newborns.
| S-EPMC3775497 | biostudies-literature
Project description:Domestic chickens are less fearful, have a faster sexual development, grow bigger, and lay more eggs than their primary ancestor, the red junglefowl. Several candidate genetic variants selected during domestication have been identified, but only a few studies have directly linked them with distinct phenotypic traits. Notably, a variant of the thyroid stimulating hormone receptor (TSHR) gene has been under strong positive selection over the past millennium, but it's function and mechanisms of action are still largely unresolved. We therefore assessed the abundance of the domestic TSHR variant and possible genomic selection signatures in an extensive data set comprising multiple commercial and village chicken populations as well as wild-living extant members of the genus Gallus. Furthermore, by mean of extensive backcrossing we introgressed the wild-type TSHR variant from red junglefowl into domestic White Leghorn chickens and investigated gene expression, hormone levels, cold adaptation, and behavior in chickens possessing either the wild-type or domestic TSHR variant. While the domestic TSHR was the most common variant in all studied domestic populations and in one of two red junglefowl population, it was not detected in the other Gallus species. Functionally, the individuals with the domestic TSHR variant had a lower expression of the TSHR in the hypothalamus and marginally higher in the thyroid gland than wild-type TSHR individuals. Expression of TSHB and DIO2, two regulators of sexual maturity and reproduction in birds, was higher in the pituitary gland of the domestic-variant chickens. Furthermore, the domestic variant was associated with higher activity in the open field test. Our findings confirm that the spread of the domestic TSHR variant is limited to domesticated chickens, and to a lesser extent, their wild counterpart, the red junglefowl. Furthermore, we showed that effects of genetic variability in TSHR mirror key differences in gene expression and behavior previously described between the red junglefowl and domestic chicken.
| S-EPMC8045693 | biostudies-literature
Project description:High serum thyroid-stimulating hormone (TSH) levels are linked to many metabolic disorders, but the effects of TSH levels on the oral microbiota are still largely unknown. This study aimed to explore the association between the salivary microbiome in adults and serum TSH levels. Saliva and fasting blood samples were obtained from a health census conducted in Southeast China. All participants were divided according to serum TSH levels. The microbial genetic profiles and changes were acquired by 16S rDNA sequencing and bioinformatics analysis. Relevant anthropometric and biochemical measurements such as insulin resistance, blood lipids, and body composition were evaluated with laboratory tests and physical examinations. The salivary microbiome in individuals with higher TSH level showed significantly higher taxa diversity. Principal coordinates analysis and partial least squares discriminant analysis showed distinct clustering in the Abnormal and Normal Groups (Adonis, P=0.0320). Granulicatella was identified as a discriminative genus for comparison of the two groups. Fasting serum insulin, Homeostatic Model Assessment for Insulin Resistance, and hemoglobin A1 were elevated in the Abnormal Group (P<0.05), showing the presence of insulin resistance in individuals with abnormal higher serum TSH levels. Distance-based redundancy analysis revealed the association of this distinctive difference with salivary microbiome. In conclusion, shifts in microbial profile were observed in the saliva of individuals with different serum TSH levels, and insulin resistance may play an important role in the biochemical and microbial alteration.
| S-EPMC7952758 | biostudies-literature
Project description:The thyroid stimulating hormone receptor (TSHR) gene is an established susceptibility locus for Graves' disease (GD), with recent studies refining association to two single nucleotide polymorphisms (SNPs), rs179247 and rs12101255, within TSHR intron 1.We aimed to validate association of rs179247 and rs12101255 in Polish and UK Caucasian GD case-control subjects, determine the mode of inheritance and to see if association correlates with specific GD clinical manifestations. We investigated three case-control populations; 558 GD patients and 520 controls from Warsaw, Poland, 196 GD patients and 198 controls from Gliwice, Poland and 2504 GD patients from the UK National collection and 2784 controls from the 1958 British Birth cohort. Both rs179247 (P?=?1.2×10(-2)-6.2×10(-15), OR?=?1.38-1.45) and rs12101255 (P?=?1.0×10(-4)-3.68×10(-21), OR?=?1.47-1.87) exhibited strong association with GD in all three cohorts. Logistic regression suggested association of rs179247 is secondary to rs12101255 in all cohorts. Inheritance modeling suggested a co-dominant mode of inheritance in all cohorts. Genotype-phenotype correlations provided no clear evidence of association with any specific clinical characteristics.We have validated association of TSHR intron 1 SNPs with GD in three independent European cohorts and have demonstrated that the aetiological variant within the TSHR is likely to be in strong linkage disequilibrium with rs12101255. Fine mapping is now required to determine the exact location of the aetiological DNA variants within the TSHR.
| S-EPMC2991361 | biostudies-literature
Project description:BackgroundThyroid-stimulating hormone (TSH) suppression is recommended for patients who undergo thyroidectomy for differentiated thyroid cancer (DTC). However, the impact of TSH suppression on clinical outcomes in low-risk DTC remains uncertain. Therefore, we investigated the effects of postoperative TSH levels on recurrence in patients with low-risk DTC after thyroid lobectomy.MethodsPatients (n=1,528) who underwent thyroid lobectomy for papillary thyroid carcinoma between 2000 and 2012 were included in this study. According to the mean and dominant TSH values during the entire follow-up period or 5 years, patients were divided into four groups (<0.5, 0.5 to 1.9, 2.0 to 4.4, and ≥4.5 mIU/L). Recurrence-free survival was compared among the groups.ResultsDuring the 5.6 years of follow-up, 21 patients (1.4%) experienced recurrence. Mean TSH levels were within the recommended low-normal range (0.5 to 1.9 mIU/L) during the total follow-up period or 5 years in 38.1% or 36.0% of patients. The mean and dominant TSH values did not affect recurrence-free survival. Adjustment for other risk factors did not alter the results.ConclusionSerum TSH levels did not affect short-term recurrence in patients with low-risk DTC after thyroid lobectomy. TSH suppression should be conducted more selectively.
| S-EPMC6599911 | biostudies-literature
Project description:BACKGROUND:Overt thyroid dysfunction has been associated with adverse obstetric outcomes. However, less is known regarding subclinical hypothyroidism or thyroid autoimmunity and their relationship to pregnancy complications. OBJECTIVE:The purpose of this study was to examine the association between prepregnancy anti-thyroid antibodies and subclinical hypothyroidism and preterm delivery, gestational diabetes mellitus, and preeclampsia. STUDY DESIGN:We conducted a secondary analysis of a prospective cohort of 18- to 40-year-old women with 1-2 previous pregnancy losses (n=1193) who participated in a multicenter randomized, placebo-controlled trial of low-dose aspirin. Prepregnancy levels of thyroid-stimulating hormone, free thyroxine, thyroglobulin antibody, and thyroid peroxidase antibody were measured. Relative risks and 95% confidence intervals were estimated with the use of generalized linear models with adjustment for age and body mass index. RESULTS:Among women with an ongoing pregnancy of >20 weeks estimated gestational age, there was no association between prepregnancy thyroid-stimulating hormone level (>2.5 vs ?2.5 mIU/L) and preterm delivery (adjusted relative risk, 0.77; 95% confidence interval, 0.40-1.47), gestational diabetes mellitus (adjusted relative risk, 1.28; 95% confidence interval, 0.54-3.04), or preeclampsia (adjusted relative risk, 1.20; 95% confidence interval, 0.71-2.04). Similarly, among women with thyroid antibodies, there was no increase in the likelihood of preterm delivery (relative risk, 1.26; 95% confidence interval, 0.65-2.45), gestational diabetes mellitus (relative risk, 1.33; 95% confidence interval, 0.51-3.49), or preeclampsia (relative risk, 1.02; 95% confidence interval, 0.54-1.92), compared with women without these antibodies. CONCLUSION:Among women with 1-2 previous pregnancy losses, subclinical hypothyroidism and thyroid autoimmunity were not associated with an increased risk of preterm delivery, gestational diabetes mellitus, or preeclampsia. These data support current recommendations that low-risk asymptomatic women should not be screened routinely for thyroid dysfunction or autoimmunity.
| S-EPMC5712235 | biostudies-literature
Project description:AimTo evaluate the relationship between thyroid-stimulating hormone (TSH) levels within the normal range and the risk of type 2 diabetes mellitus (T2DM) in a cohort of patients at high cardiovascular risk, and to perform a systematic review and meta-analysis of previous studies.MethodsWe included 5542 patients without T2DM from the prospective Secondary Manifestations of ARTerial disease study with TSH levels between 0.35 and 5.0 mIU/L without anti-thyroid medication or thyroid-hormone replacement therapy. Cox regression was used to investigate the relationship between baseline plasma TSH levels and incident T2DM. MEDLINE, EMBASE, and Cochrane were searched for prospective cohorts assessing TSH and incident T2DM. Hazard ratios (HR) from included prospective cohort studies were pooled using a random-effects model.ResultsIn patients at high cardiovascular risk, higher plasma TSH levels in the normal range were not associated [HR 1.07 per mIU/L increase in TSH (95% confidence interval (95% CI) 0.95-1.22)] with an increased risk of T2DM, adjusted for age, sex, smoking, total and HDL cholesterol, and triglycerides. In the meta-analysis involving three prospective cohort studies, including the present study, including 29,791 participants with 1930 incident events, there was no relation between plasma TSH levels in the normal range and incident T2DM [pooled HR 1.06 (95% CI 0.99-1.14)].ConclusionThere is no apparent relation between plasma TSH levels in the normal range and incident T2DM in patients at high cardiovascular risk.
| S-EPMC6420678 | biostudies-literature
Project description:PurposeTo study the effects of mildly elevated thyroid-stimulating hormone (TSH) levels and thyroid antibodies on pregnancy rates among infertile women and their potential contribution to prolonged infertility treatment.MethodsThis case-control study included 1479 women who underwent infertility treatment between March 2015 and August 2017. Cumulative pregnancy and miscarriage rates after assisted reproductive technology (ART) or non-ART treatments were compared between women with TSH <2.5 mIU/L and those with TSH 2.5-3.5 mIU/L and between women with and without thyroid antibody positivity.ResultsThe cumulative pregnancy rate of women with TSH 2.5-3.5 mIU/L was similar to that of women with TSH <2.5 mIU/L in the non-ART (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.56-1.23) and ART (HR, 1.17; 95% CI, 0.93-1.47) groups. Thyroglobulin antibody (TgAb) and thyroid peroxidase antibody (TPOAb) had no correlation with cumulative pregnancy rates. In the non-ART and ART groups, HRs for TgAb were 0.87 (95% CI, 0.55-1.32) and 1.09 (95% CI, 0.84-1.39) and HRs for TPOAb were 0.88 (95% CI, 0.52-1.39) and 1.29 (95% CI, 0.97-1.68), respectively.ConclusionsCumulative pregnancy rates and miscarriage rates were similar between women with TSH <2.5 mIU/L and those with TSH 2.5-3.5 mIU/L and were independent of thyroid antibody positivity.
| S-EPMC6955587 | biostudies-literature
Project description:Human thyroid stimulating hormone (TSH) is a glycoprotein secreted by the anterior part of the pituitary gland. TSH plays an important physiological role in the regulation of hypothalamic-pituitary-thyroid axis by modulating the release of the thyroid hormones from the thyroid gland. It induces iodine uptake by the thyroid, promotes thyroid epithelial differentiation and growth, and protects thyroid cells from apoptosis. Impairment of TSH signal transduction pathway leads to thyroid disorders such as goitre, hypothyroidism and hyperthyroidism, which can have complex clinical manifestations. TSH signaling is largely effected through two separate pathways, the adenylate cyclase and the phospholipase C pathways. In spite of its biomedical importance, a concise signaling map of TSH pathway is not available in the public domain. Therefore, we have generated a detailed signaling map of TSH pathway by systematically cataloging the molecular reactions induced by TSH including protein-protein interactions, post-translational modifications, protein translocation events and activation/inhibition reactions. We have cataloged 40 molecular association events, 42 enzyme-substrate reactions and 16 protein translocation events in TSH signaling pathway resource. Additionally, we have documented 208 genes, which are differentially regulated by TSH. We have provided the details of TSH pathway through NetPath (http://www.netpath.org), which is a publicly available resource for human signaling pathways developed by our group. We have also depicted the map of TSH signaling using NetSlim criteria (http://www.netpath.org/netslim/) and provided pathway maps in Wikipathways (http://www.wikipathways.org/). We anticipate that the availability of TSH pathway as a community resource will enhance further biomedical investigations into the function and effects of this important hormone.
| S-EPMC3830942 | biostudies-literature