Replication confirms the association of loci in FOXE1, PDE8B, CAPZB and PDE10A with thyroid traits

Soto-Pedre, Enrique; Siddiqui, Moneeza K; Doney, Alex S.F.; Palmer, Colin N.A.; Pearson, Ewan R.; Leese, Graham

doi:10.1097/fpc.0000000000000299

Cited by 6 publications

(10 citation statements)

References 16 publications

(14 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This approach focuses on associations between genetic variation within pre-specified genes of interest and phenotypes. In this study, a GWAS-identified INSR locus (rs4804416) replicated in a Scottish population was the candidate gene (Soto-Pedre et al, 2017). This gene encodes a preproprotein that is processed to generate two alpha and two beta subunits that work together as a functioning insulin receptor.…”

Section: Discussionmentioning

confidence: 97%

“…A GWAS-identified INSR locus (rs4804416) associated with average serum TSH concentrations and replicated in the GoDARTS cohort ( Soto-Pedre et al, 2017 ) was the candidate gene. To strengthen the choice of this candidate, additional single-nucleotide polymorphisms (SNPs) associated with TSH were also considered regarding AF in patients on L -thyroxine (see Supplementary Table 1 ).…”

Section: Methodsmentioning

confidence: 95%

“…To strengthen the choice of this candidate, additional single-nucleotide polymorphisms (SNPs) associated with TSH were also considered regarding AF in patients on L -thyroxine (see Supplementary Table 1 ). Genotype data was available from several platforms as previously described ( Soto-Pedre et al, 2017 ; see Supplementary Material ).…”

Section: Methodsmentioning

confidence: 99%

“…We have previously replicated in a Scottish population a number of GWAS-identified loci associated with serum TSH concentrations including the insulin receptor- INSR locus ( Soto-Pedre et al, 2017 ). Insulin resistance and serum TSH concentration have both been highlighted as being possible underlying mechanisms for AF ( Flynn et al, 2010 ; Bell and Goncalves, 2019 ; Bohne et al, 2019 ; Ellervik et al, 2019 ; Salem et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Polymorphism in INSR Locus Modifies Risk of Atrial Fibrillation in Patients on Thyroid Hormone Replacement Therapy

et al. 2021

Self Cite

View full text Add to dashboard Cite

AimsAtrial fibrillation (AF) is a risk for patients receiving thyroid hormone replacement therapy. No published work has focused on pharmacogenetics relevant to thyroid dysfunction and AF risk. We aimed to assess the effect of L-thyroxine on AF risk stratified by a variation in a candidate gene.Methods and ResultsA retrospective follow-up study was done among European Caucasian patients from the Genetics of Diabetes Audit and Research in Tayside Scotland cohort (Scotland, United Kingdom). Linked data on biochemistry, prescribing, hospital admissions, demographics, and genetic biobank were used to ascertain patients on L-thyroxine and diagnosis of AF. A GWAS-identified insulin receptor-INSR locus (rs4804416) was the candidate gene. Cox survival models and sensitivity analyses by taking competing risk of death into account were used. Replication was performed in additional sample (The Genetics of Scottish Health Research register, GoSHARE), and meta-analyses across the results of the study and replication cohorts were done. We analyzed 962 exposed to L-thyroxine and 5,840 unexposed patients who were rs4804416 genotyped. The rarer G/G genotype was present in 18% of the study population. The total follow-up was up to 20 years, and there was a significant increased AF risk for patients homozygous carriers of the G allele exposed to L-thyroxine (RHR = 2.35, P = 1.6e–02). The adjusted increased risk was highest within the first 3 years of exposure (RHR = 9.10, P = 8.5e–04). Sensitivity analysis yielded similar results. Effects were replicated in GoSHARE (n = 3,190).ConclusionHomozygous G/G genotype at the INSR locus (rs4804416) is associated with an increased risk of AF in patients on L-thyroxine, independent of serum of free thyroxine and thyroid-stimulating hormone serum concentrations.

show abstract

Section: Discussionmentioning

confidence: 97%

Section: Methodsmentioning

confidence: 95%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Polymorphism in INSR Locus Modifies Risk of Atrial Fibrillation in Patients on Thyroid Hormone Replacement Therapy

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…Future studies should also investigate potential immunotoxic effects of contaminants and their relationships with diseases in Arctic marine mammals. (Panicker et al, 2010;Soto-Pedre et al, 2017); 2 (Yen, 2001); 3 (Arnaud-Lopez et al, 2008); 4 (Mangelsdorf and Evans, 1995); 5 (Jansen et al, 2005); 6 (van der Spek et al, 2017); 7 (Nicolaides et al, 2010);8 (Cristancho and Lazar, 2011;Desvergne et al, 2006;Makowski et al, 2005;Ohashi et al, 2010); 9 (Capone et al, 2016;Maltais et al, 2006;Matesanz-Isabel et al, 2011;Polson et al, 2006); 10 (Teft et al, 2006;Waterhouse et al, 1996); 11 (Malek and Castro, 2010); 12 (Jofra et al, 2017); 13 (Elgueta et al, 2009); 14 (Ciofani and Zuniga-Pflucker, 2005;Radtke et al, 1999); 15 (Malathi et al, 2007) PeCB,oxychlordane,transnonachlor,Mirex,p,BDE47 and BDE153 b PFHxS, PFOS, PFOA, PFNA and PFDA Table 3. Transcript levels of genes of interest determined in a) blubber and b) blood cells explained by blubber concentrations of persistent organic pollutants (POP) and plasma concentrations of perfluoroalkyl substances (PFAS) in adult male walruses.…”

Section: Discussionmentioning

confidence: 99%

Contaminants in Atlantic walruses in Svalbard Part 2: Relationships with endocrine and immune systems

Routti

Diot

Panti

et al. 2019

Environmental Pollution

View full text Add to dashboard Cite

Marine mammals in the Barents Sea region have among the highest levels of contaminants recorded in the Arctic and the Atlantic walrus (Odobenus rosmarus rosmarus) is one of the most contaminated species within this region. We therefore investigated the relationships bewteen blubber concentrations of lipophilic persistent organic pollutants (POPs) and plasma concentrations of perfluoroalkyl substances (PFASs) and markers of endocrine and immune functions in adult male Atlantic walruses (n=38) from Svalbard, Norway. To do so, we assessed plasma concentrations of five forms of thyroid hormones and transcript levels of genes related to the endocrine and immune systems as endpoints; transcript levels of seven genes in blubber and 23 genes in blood cells were studied. Results indicated that plasma total thyroxine (TT4) concentrations decreased with increasing blubber concentrations of lipophilic POPs. Blood cell transcript levels of genes involved in the function of T and B cells (FC like receptors 2 and 5, cytotoxic T-lymphocyte associated protein 4 and protein tyrosine phosphatase non-receptor type 22) were increased with plasma PFAS concentrations. These results suggest that changes in thyroid and immune systems in adult male walruses are linked to current levels of contaminant exposure. Capsule: The first investigation on the effects of contaminants in walruses suggest that changes in thyroid and immune systems in adult male walruses are linked to current levels of contaminant exposure.

show abstract

Evidence of a Causal Relationship between Serum Thyroid-Stimulating Hormone and Osteoporotic Bone Fractures

Soto-Pedre¹,

Siddiqui²,

Mordi³

et al. 2021

Eur Thyroid J

Self Cite

View full text Add to dashboard Cite

Objective: We aimed to validate the association of genome-wide association study (GWAS)-identified loci and polygenic risk score with serum thyroid-stimulating hormone (TSH) concentrations and the diagnosis of hypothyroidism. Then, the causal relationship between serum TSH and osteoporotic bone fracture risk was tested. Methods: A cross-sectional study was done among patients of European Caucasian ethnicity recruited in Tayside (Scotland, UK). Electronic medical records (EMRs) were used to identify patients and average serum TSH concentration and linked to genetic biobank data. Genetic associations were performed by linear and logistic regression models. One-sample Mendelian randomization (MR) was used to test causality of serum TSH on bone fracture risk. Results: Replication in 9,452 euthyroid individuals confirmed known loci previously reported. The 58 polymorphisms accounted for 11.08% of the TSH variation (p < 1e−04). TSH-GRS was directly associated with the risk of hypothyroidism with an odds ratio (OR) of 1.98 for the highest quartile compared to the first quartile (p = 2.2e−12). MR analysis of 5,599 individuals showed that compared with those in the lowest tertile of the TSH-GRS, men in the highest tertile had a decreased risk of osteoporotic bone fracture (OR = 0.59, p = 2.4e−03), while no difference in a similar comparison was observed in women (OR = 0.93, p = 0.61). Sensitivity analysis yielded similar results. Conclusions: EMRs linked to genomic data in large populations allow replication of GWAS discoveries without additional genotyping costs. This study suggests that genetically raised serum TSH concentrations are causally associated with decreased bone fracture risk in men.

show abstract

Replication confirms the association of loci in FOXE1, PDE8B, CAPZB and PDE10A with thyroid traits

Cited by 6 publications

References 16 publications

Polymorphism in INSR Locus Modifies Risk of Atrial Fibrillation in Patients on Thyroid Hormone Replacement Therapy

Polymorphism in INSR Locus Modifies Risk of Atrial Fibrillation in Patients on Thyroid Hormone Replacement Therapy

Contaminants in Atlantic walruses in Svalbard Part 2: Relationships with endocrine and immune systems

Evidence of a Causal Relationship between Serum Thyroid-Stimulating Hormone and Osteoporotic Bone Fractures

Contact Info

Product

Resources

About