Mendelian randomization supports a causative effect of TSH on thyroid carcinoma

in Endocrine-Related Cancer
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  • 1 Head and Neck Surgery, Royal Devon and Exeter Hospital, Exeter, UK
  • 2 Genetics of Complex Traits, Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK
  • 3 Endocrinology, Royal Devon and Exeter Hospital, Exeter, UK

Correspondence should be addressed to J M Fussey: jfussey@doctors.org.uk

Evidence from observational studies suggest a positive association between serum thyroid-stimulating hormone (TSH) levels and differentiated thyroid carcinoma. However, the cause–effect relationship is poorly understood and these studies are susceptible to bias and confounding. This study aimed to investigate the causal role of TSH in both benign thyroid nodules and thyroid cancer in up to 451,025 UK Biobank participants, using a genetic technique, known as Mendelian randomization (MR). Hospital Episode Statistics and Cancer Registry databases were used to identify 462 patients with differentiated thyroid carcinoma and 2031 patients with benign nodular thyroid disease. MR methods using genetic variants associated with serum TSH were used to test causal relationships between TSH and the two disease outcomes. Mendelian randomization provided evidence of a causal link between TSH and both thyroid cancer and benign nodular thyroid disease. Two-sample MR suggested that a 1 s.d. higher genetically instrumented TSH (approximately 0.8 mIU/L) resulted in 4.96-fold higher odds of benign nodular disease (95% CI 2.46–9.99) and 2.00-fold higher odds of thyroid cancer (95% CI 1.09–3.70). Our results thus support a causal role for TSH in both benign nodular thyroid disease and thyroid cancer.

Abstract

Evidence from observational studies suggest a positive association between serum thyroid-stimulating hormone (TSH) levels and differentiated thyroid carcinoma. However, the cause–effect relationship is poorly understood and these studies are susceptible to bias and confounding. This study aimed to investigate the causal role of TSH in both benign thyroid nodules and thyroid cancer in up to 451,025 UK Biobank participants, using a genetic technique, known as Mendelian randomization (MR). Hospital Episode Statistics and Cancer Registry databases were used to identify 462 patients with differentiated thyroid carcinoma and 2031 patients with benign nodular thyroid disease. MR methods using genetic variants associated with serum TSH were used to test causal relationships between TSH and the two disease outcomes. Mendelian randomization provided evidence of a causal link between TSH and both thyroid cancer and benign nodular thyroid disease. Two-sample MR suggested that a 1 s.d. higher genetically instrumented TSH (approximately 0.8 mIU/L) resulted in 4.96-fold higher odds of benign nodular disease (95% CI 2.46–9.99) and 2.00-fold higher odds of thyroid cancer (95% CI 1.09–3.70). Our results thus support a causal role for TSH in both benign nodular thyroid disease and thyroid cancer.

Introduction

Thyroid cancer is the most common endocrine malignancy, with recent years seeing a significant increase in incidence (Kitahara & Sosa 2016). The majority of patients present with a thyroid nodule; however, nodules are common with a prevalence of up to 34% on ultrasound (Moon et al. 2018) and only 5–10% of nodules are malignant (Hegedüs 2004, Perros et al. 2014). Following clinical assessment, ultrasonography and cytological analysis of fine-needle aspiration biopsy the true nature of the nodule remains indeterminate in up to 25% of cases and up to one-third of surgically excised nodules are in fact benign (Bongiovanni et al. 2012). There is, therefore, a need for better stratification of thyroid nodules according to risk of malignancy, and while recent years have seen the development of genomic tests to aid diagnosis (Nikiforov & Baloch 2019), these are yet to be widely used in clinical practice.

In addition to ultrasonography and fine-needle aspiration biopsy, thyroid function tests including serum thyroid-stimulating hormone (TSH) level are recommended in the investigation of a thyroid nodule (Perros et al. 2014, Haugen et al. 2016). The role of serum TSH testing is primarily to identify hyperthyroidism caused by a toxic nodule; however, several authors have reported an association between raised serum TSH and thyroid cancer (Boelaert et al. 2006, Fighera et al. 2015, Zafón et al. 2015, Golbert et al. 2017) as well as a correlation between serum TSH and aggressiveness of thyroid cancer (Haymart et al. 2008, 2009, McLeod et al. 2014).

Despite the strong observational basis for an association between serum TSH and thyroid cancer in patients with thyroid nodules, there is significant difficulty in establishing a causal link due to the difficulty in adequately adjusting for confounding factors, such as iodine deficiency, autoimmune thyroid disease and cigarette smoking (Singh et al. 1999, Zimmermann & Galetti 2015, Cho et al. 2018) and the possibility of reverse causality. This difficulty can be overcome by using genetic epidemiological techniques such as Mendelian randomization (MR), which relies upon the fact that genetic variants predisposing to a certain trait are inherited randomly at conception and are not affected by many confounders acting upon observational associations. The aim of this study was to test the hypothesis that elevated serum TSH has a causal role in the development of benign thyroid nodules and differentiated thyroid cancer, using genetic data from 451,025 participants in the UK Biobank.

Methods

Participants

We used data from the UK Biobank, a longitudinal study of 500,000 participants aged between 40 and 69 years who were recruited between 2006 and 2010 (Collins 2012, Sudlow et al. 2015). After giving informed written consent, participants gave blood, urine and saliva samples for biomarker measurement and genotyping, as well as having anthropometric measurements at the time of enrolment. In addition, patients filled out demographic and health questionnaires and consented to record linkage with national cancer and death registries as well as the Hospital Episode Statistics (HES) database. UK Biobank has received ethics approval from the National Health Service National Research Ethics Service (ref 11/NW/0382).

Genotyping was performed on DNA extracted from whole blood samples by Affymetrix, using two specially designed SNP arrays with over 95% content overlap. The UKBiobank Axiom array® was used for ~450,000 participants and the UK BiLEVE Axiom array® for 50,000 participants (Welsh et al. 2017). Extensive central quality control was carried out by the UK Biobank (Bycroft et al. 2018). Genotyping data were subjected to multilevel quality control, with exclusion of sex mismatches (genetic sex different from reported sex), duplicated individuals and outliers of heterozygosity. After these exclusions, as well as those individuals who have subsequently withdrawn from the UK Biobank Study, 451,025 individuals of White European descent were identified using principal components computed from the 1000 Genomes Project. The KING kinship matrix was then used to remove related individuals up to three degrees of separation and identify a subset of 379,708 unrelated individuals for sensitivity analysis. Ancestral principal components were generated among this group of individuals.

Exposure and outcome measures

We identified two outcome groups of interest within the UK Biobank: those with a diagnosis of differentiated thyroid cancer and those with a diagnosis of benign nodular thyroid disease. In order avoid reporting bias, we discounted self-reported diagnoses in the health questionnaire and used Cancer Registry and HES data only. Thyroid cancer cases were identified by the ICD-10 code ‘C73’. Histology codes were then used to exclude patients with medullary thyroid carcinoma, anaplastic carcinoma, thyroid lymphoma and unclassified subtypes, leaving only patients with differentiated thyroid carcinoma. This resulted in 462 cases. Patients with a diagnosis of benign nodular thyroid disease were identified by the ICD-10 code ‘D34‘. Patients diagnosed with both nodular thyroid disease and thyroid cancer were excluded to avoid bias caused by misdiagnosis (n = 147). This left 2031 cases in total. Control groups with no previous diagnosis of cancer and no previous diagnosis of benign thyroid disease were also created, numbering 391,458 and 448,532, respectively.

The exposure of interest in this study was a genetic predisposition to higher TSH levels. In order to quantify this, we utilized 20 SNPs associated with TSH levels at genome wide significance (P-value threshold of 5 × 10−8) in a meta-analysis of 26,420 individuals of European ancestry across 18 cohorts (Porcu et al. 2013) (Table 1). Linkage disequilibrium (LD) was calculated using the LDlink SNPClip application, with an R2 threshold of 0.1 and a minor allele frequency (MAF) threshold of 0.01 (Machiela & Chanock 2015). No SNPs were removed due to LD. The 20 SNPs have been reported to account for 5.64% of variance in serum TSH levels (Porcu et al. 2013). The effect of the included SNPs on thyroid-specific gene expression was investigated using the Genotype-Tissue Expression Consortium tool (www.gtexportal.org) and is shown in Table 1.

Table 1

TSH SNPs, their effect sizes on TSH (modified from Porcu et al. 2013) and their effect on thyroid-specific gene expression.

ChromosomePositionEffect/other alleleSNPEffect sizes.e.Thyroid-specific gene expression
576566105A/Grs6885099−0.1410.009No
6165966473C/Grs7537600.1000.010Yes
119713761A/Grs10799824−0.1130.012Yes
1678306854T/Crs38135820.0820.010Yes
643919740T/Crs9472138−0.0790.010Yes
644012758T/Crs11755845−0.0650.010Yes
4149888956T/Crs100322160.0870.011Yes
2217333768A/Grs130159930.0780.010Yes
1767639131T/Crs9915657−0.0640.009Yes
161393084A/Grs334699−0.1410.021No
1547533656A/Trs10519227−0.0720.011Yes
1145184143T/Crs17723470−0.0650.010Yes
1586920108A/Grs17776563−0.0600.010Yes
197174848T/Grs4804416−0.0570.009No
9135129086A/Crs6571520.0580.009No
1492665344A/Crs11624776−0.0640.011Yes
832535816A/Grs7825175−0.0660.001Yes
1435643769T/Crs1537424−0.0520.009Yes
6148562985T/Crs94979650.0510.009No
94257209A/Grs15715830.0570.010No

Positions given are in build 36. Tissue-specific expression information from the Genotype-Tissue Expression Consortium (www.gtexportal.org).

Data analysis

In order to identify the causal effect of TSH on thyroid cancer and benign nodular thyroid disease, we performed two-sample Mendelian randomization (MR) (Bowden et al. 2016a) using the 20 known genetic variants associated with TSH (Porcu et al. 2013). We corrected for inter-relatedness by performing a GWAS of the thyroid cancer and benign nodular thyroid disease variables using a linear mixed model in the BOLT-LMM software (Loh et al. 2015). The 20 known TSH variants were then extracted from these GWAS analyses for use in the two-sample MR. The SNP-TSH association was taken from the primary GWAS by Porcu et al., while the SNP-outcome association was taken from the BOLT-LMM GWAS of our UK Biobank outcome traits. Using the median s.d. (0.8 mIU/L) from the meta-analysis of studies used to identify genetic variants associated with TSH (Porcu et al. 2013), the coefficients from the two-sample MR were adjusted to approximate the odds ratios per unit increase in TSH.

MR relies upon the fact that the instrumental variable being used is associated with the risk factor of interest, that the instrumental variable is not subject to the confounding factors acting upon the association between the risk factor and outcome of interest and that the instrumental variable is associated with the outcome of interest only via its effect on the risk factor of interest. Figure 1 illustrates the principles of MR.

Figure 1
Figure 1

If a risk factor, for example, high TSH truly causes an outcome, for example, thyroid cancer, then the genetic variants for the risk factor should also be associated with the outcome. Unlike the observed risk factor, the genetic variants are not susceptible to confounding by other risk factors or reverse causation (dashed lines) as they are assigned at conception. Horizontal pleiotropy (dotted line), whereby the variants of interest also affect the outcome via their association with another trait is a possible limitation of MR.

Citation: Endocrine-Related Cancer 27, 10; 10.1530/ERC-20-0067

Three different methods of two-sample MR were performed. First, inverse variant weighted (IVW) instrumental variable analysis. IVW assumes that all genetic instruments are valid and is therefore susceptible to horizontal pleiotropy (variants affecting the outcome via a route other than the risk factor of interest). To reduce this potential source of bias, we also used the MR-Egger and Median MR techniques (Bowden et al. 2016a,b) which are more robust to pleiotropy. In MR-Egger analysis, the intercept is unconstrained to allow a weighted regression, thus removing the assumption that all variants are valid instrumental variables. This reduces the possibility of variants having a stronger effect on the outcome than the exposure itself (actual TSH levels). Median-MR is also more resistant to pleiotropy, as it uses the median instrumental variable from all included variants and allows for up to 50% of the variants to be invalid.

In order to allow for sensitivity analyses, the effect sizes of the 20 included TSH-associated SNPs were used to produce a genetic risk score (GRS) for TSH in the smaller subset of 379,708 unrelated UK Biobank participants. This group contained 425 cases of differentiated thyroid cancer and 1812 cases of benign nodular thyroid disease. The association between these GRSs and the outcome traits of benign nodular thyroid disease and thyroid cancer was then tested using a logistic regression model with adjustment for age, sex, ancestral principal component and recruitment center. Robust s.e. were used to allow for uncertainty in the estimate. In addition, the 379,708 unrelated participants were divided into quartiles based on their GRS for TSH, and logistic regression analysis was used to test the association between GRS quartile and both disease outcomes. Finally, sensitivity analysis was performed to account for patients with a diagnosis of either hyper- or hypothyroidism as identified in the self-reported health questionnaire or the Hospital Episode Statistics data. A post hoc power calculation using a Mendelian randomization power calculator (Brion et al. 2013) confirmed the power of the study to detect a true odds ratio of 4.96 for the binary outcome of benign nodular thyroid disease per 1 s.d. increase in genetically determined TSH (Power = 1.00; α = 0.05; non-centrality parameter = 850.45; F statistic = 26959.26); and a true odds ratio of 2.00 for the binary outcome of thyroid cancer per 1 s.d. increase in genetically determined TSH (Power 1.00; α = 0.05; non-centrality parameter = 113.44; F statistic 26959.26).

Results

Table 2 displays basic information on the unrelated subgroup of participants and controls. Participants with a diagnosis of benign nodular thyroid disease were more likely than controls to be female, have a higher BMI and have co-existent type two diabetes mellitus (T2DM), hyper- or hypothyroidism. Those with a diagnosis of thyroid cancer were also more likely than controls to be female, and marginally more likely to be obese, with a higher proportion than controls having co-existent hyper- or hypothyroidism.

Table 2

Summary of demographic characteristics of participants.

CharacteristicsBenign nodular thyroid diseaseControlsP-valueThyroid cancerCancer-free controlsP-value
n1812377,896425310,176
Female sex1492 (82.34)203,244 (53.78)<1 × 10−15316 (74.35)165,537 (53.37)5.6 × 10−17
Mean age at recruitment (s.d.), years58.92 (7.39)57.23 (8.01)<1 × 10−1557.72 (7.29)56.54 (8.04)0.0022
Smoking status:
 Never976 (53.86)203,242 (53.78)0.04233 (54.82)169,785 (54.74)0.40
 Former649 (35.82)133,744 (35.40)152 (35.76)107,027 (34.51)
 Current166 (9.16)35,774 (9.47)32 (7.53)29,261 (9.43)
 Missing21 (1.16)5136 (1.36)8 (1.88)4103 (1.32)
 Mean townsend deprivation index (s.d.)−1.16 (3.09)−1.48 (2.99)4.8 × 10−8−1.63 (2.94)−1.45 (2.99)0.42
 Mean units of alcohol (s.d.)0.20 (1.07)0.57 (1.04)2.5 × 10−60.37 (1.00)0.57 (1.04)0.48
 Mean BMI (s.d.), kg/m227.96 (5.23)27.38 (4.78)4.1 × 10−1227.55 (5.34)27.38 (4.77)0.16
 Obese: BMI 30–40 kg/m2471 (25.99)83,503 (22.10)1.6 × 10−9111 (26.12)68,563 (22.10)0.068
 Type 2 diabetes70 (3.86)11,996 (3.17)0.003716 (3.76)9290 (3.0)0.16
 Hypothyroidism182 (10.04)18,600 (4.92)4.8 × 10−928 (6.59)15,238 (4.91)0.12
 Hyperthyroidism59 (3.26)2897 (0.77)1.6 × 10−47 (1.65)2377 (0.77)0.35

Table represents data after exclusion of related individuals due to the difficulty in adjusting observational analyses for relatedness. Values stated are numbers (percentages), unless otherwise stated. P-values calculated using logistic regression adjusted for age and sex.

Two-sample MR

Two-sample MR provided evidence that higher TSH caused both benign nodular thyroid disease and thyroid cancer. A 1 s.d. (approximately 0.8 mIU/L) higher genetically instrumented TSH level was associated with 4.96 higher odds of benign nodular thyroid (95% CI 2.46–9.99) and 2.00 higher odds of thyroid cancer (95% CI 1.09–3.70; Fig. 2 and Table 2). This approximates to 7.39 times higher odds of benign nodular thyroid disease (95% CI 3.67–14.90) and 2.39 times higher odds of thyroid cancer (95% CI 1.29–4.40) per 1 mIU/L higher TSH. The more pleiotropy-resistant two-sample analyses were directionally consistent and MR-Egger provided no evidence of horizontal pleiotropy for either outcome trait (Table 3).

Figure 2
Figure 2

Forest plot showing two sample MR (instrumental variable analysis) associations between genetically instrumented TSH and thyroid cancer and benign nodular thyroid disease. Odds ratios of outcome per s.d. higher genetically instrumented TSH and 95% CIs are shown.

Citation: Endocrine-Related Cancer 27, 10; 10.1530/ERC-20-0067

Table 3

Results of two-sample MR analysis for benign nodular thyroid disease and thyroid cancer.

TraitIVWEggerWMPWM
OR (95% CI)P-valueOR (95% CI)P-valueInt POR (95% CI)P-valueOR (95% CI)P-value
Thyroid cancer2.00 (1.09–3.70)0.0391.71 (0.23–12.72)0.600.871.88 (1.04–3.39)0.0371.50 (0.83–2.73)0.18
Benign nodular thyroid disease4.96 (2.46–9.99)2.59 × 10−41.46 (0.16–13.43)0.740.273.84 (2.27–6.49)5.54 × 10−75.44 (2.90–10.21)1.37 × 10−7

Beta coefficients and P values for the inverse variant weighted (IVW), Egger, weighted median (WM) and penalised weighted median (PWM) analyses are displayed. Int P represents the P-intercept of Egger analysis, which is a measure of horizontal pleiotropy. s.e. are displayed in parentheses.

Sensitivity analyses

The GRS for TSH was associated with both benign nodular thyroid disease and thyroid cancer in the subgroup of unrelated participants. Using logistic regression adjusted for age, sex, ancestral principal component and assessment center with the GRS for TSH as the dependent variable, we found a positive association with benign nodular thyroid disease, with each weighted allele increase in the TSH GRS resulting in 1.11-fold higher odds of benign nodular thyroid disease (95% CI 1.10–1.13; Fig. 3). Similarly, there was a positive association with thyroid cancer, with an odds ratio of 1.05 (95% CI 1.02–1.09; Fig. 3). Furthermore, individuals in the top 25% of the TSH GRS were at 1.34 higher odds of thyroid cancer (95% CI 1.14–1.50; Fig. 4) and 2.23 higher odds of benign nodular thyroid disease (95% CI 1.89–2.63) than those in the bottom 25%. Results of the sensitivity analysis after excluding participants with hypothyroidism or hyperthyroidism, which did not affect the associations, are shown in Table 4. Finally, the analysis using TSH GRS in the unrelated subgroup was repeated separately in male and female participants (Table 5) with the associations with both benign nodular disease and thyroid cancer remaining stable in females, but the association with thyroid cancer weakening in males.

Figure 3
Figure 3

Forest plot showing associations between genetically instrumented TSH and thyroid cancer and benign nodular thyroid disease. Odds ratios of outcome per s.d. higher genetically instrumented TSH and 95% CIs are shown.

Citation: Endocrine-Related Cancer 27, 10; 10.1530/ERC-20-0067

Figure 4
Figure 4

Forest plot showing associations between quartiles for TSH genetic risk and thyroid cancer and benign nodular thyroid disease. Odds ratios and 95% CIs are shown for each quartile as compared to those in the lowest quartile.

Citation: Endocrine-Related Cancer 27, 10; 10.1530/ERC-20-0067

Table 4

Results of sensitivity analysis for both thyroid cancer and benign nodular thyroid disease after exclusion of participants with co-existing diagnoses of hypothyroidism or hyperthyroidism.

AnalysisExposureOR thyroid cancern = cases (controls)95% CIOR Benign nodular thyroid diseasen = cases (controls)95% CI
Primary analysisTSH1.05425 (310,176)1.02–1.091.111812 (377,896)1.10–1.13
Sensitivity analysisTSH1.05423 (309,526)1.02–1.091.131803 (377,110)1.11–1.14
Table 5

Results of sensitivity analysis for both thyroid cancer and benign nodular thyroid disease according to sex.

AnalysisExposureOR thyroid cancern = cases (controls)95% CIOR Benign nodular thyroid diseasen = cases (controls)95% CI
Primary analysisTSH1.05462 (391,458)1.02–1.091.111812 (377,896)1.10–1.13
Male sexTSH1.01109 (144,639)0.94–1.081.12320 (174,652)1.08–1.15
Female sexTSH1.07316 (165,537)1.03–1.111.131492 (203,244)1.11–1.15

Discussion

Principal findings

This study investigated the causal relationship between serum TSH levels and thyroid cancer risk and benign nodular thyroid disease risk. Our results reveal a significant association between genetic variants predicting higher serum TSH and both diagnoses. Furthermore, these results were consistent when using different approaches.

The first study to identify an association between serum TSH levels and risk of thyroid cancer was published by Boelaert et al. (2006) and since then many authors have reported similar findings, with two meta-analyses reporting positive associations (McLeod et al. 2012, Zheng et al. 2016). However, the majority of included studies were retrospective, resulting in bias and difficulty in adjusting for all confounders. There is also some controversy on the subject, with the EPIC case-control study reporting a negative association among its 357 cases and 767 matched controls (Rinaldi et al. 2014), and a more recent case-control study on papillary thyroid carcinoma identifying a positive association in men and a negative association in women (Huang et al. 2017). Furthermore, differentiated thyroid cancer has been reported even in patients with completely suppressed TSH levels (Satta et al. 1993), although the authors note that tumors may have arisen prior to development of thyrotoxicosis. Here, we demonstrated stronger evidence of a role for TSH in thyroid cancer in women than in men. However, these analyses were limited by the low numbers of male participants with thyroid cancer in the UK Biobank study. When testing the role of TSH on benign thyroid nodules, results were similar in men and women.

The widely proposed mechanism explaining the positive association between serum TSH levels and both benign thyroid nodules and thyroid cancer reported by most studies is the thyrotropic effect of TSH. TSH is known to induce proliferation of thyrocytes and both benign and malignant thyroid tumors have long been known to express TSH receptors (Ichikawa et al. 1976). Furthermore, suppression of TSH is a well-established adjunct to the management of differentiated thyroid carcinoma (Perros et al. 2014) and has in the past been used in the treatment of benign nodular thyroid disease although has now largely been abandoned in this setting due to long-term adverse effects (Wémeau et al. 2002). Animal studies have demonstrated a convincing role for TSH in thyroid tumorigenesis (Lu et al. 2010) however the cause-effect relationship between high TSH and thyroid cancer in humans is unclear due to the difficulty in accounting for known and unknown confounders.

The aim of this study was to test the hypothesis that TSH has a causal role in the development of thyroid cancer, using genetic techniques. Our findings while positive, are not sufficient to change clinical practice. They do, however, add to the debate on the topic and represent evidence using a novel technique that higher TSH does increase the risk of both benign nodular thyroid disease and thyroid cancer. It is vital that this causal relationship is understood when considering previously published observational and clinical studies on the link between TSH and thyroid cancer. Furthermore, our findings help pave the way for future research on the ability of genetic instruments to distinguish between benign and malignant thyroid nodules, with the advantage that they are not confounded by environmental factors. This information may eventually be used along with other genetic instruments to formulate pre-diagnostic screening or stratification tools to aid clinical decision making in patients with thyroid nodules.

Strengths and limitations

The advantage of the present study is the ability to limit the effect of environmental confounders by using genetic predictors of TSH levels, which are fixed at conception. This is the first study using Mendelian randomization to investigate the link between TSH levels and benign nodular thyroid disease and thyroid cancer. The main limitation of the study is the lack of an observational measure of TSH in the UK Biobank cohort. This problem is partially overcome by using data from large genome wide association studies to confirm robust associations between the TSH SNPs we used and TSH levels in European subjects; however, the UK Biobank participants are inevitably not completely comparable to those cohorts. Secondly, the power of our MR analyses is somewhat limited by the small number (462) of thyroid cancers amongst the UK Biobank participants. Finally, the UK Biobank is not representative of the wider population, including only UK residents aged between 40 and 69 at enrolment. There is some evidence of healthy volunteer bias within the UK Biobank, with lower rates of cancer incidence than the age and sex matched general population (Fry et al. 2017).

Conclusions

Using MR, we have demonstrated a causal role for TSH in both benign nodular thyroid disease and differentiated thyroid cancer. This supports the associations reported by many observational studies. Further research is required to test the applicability of these findings to the wider population and investigate their clinical applicability in patients with thyroid nodules.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

J T is supported by an Academy of Medical Sciences (AMS) Springboard award, which is supported by the AMS, the Wellcome Trust, GCRF, the Government Department of Business, Energy and Industrial strategy, the British Heart Foundation and Diabetes UK (SBF004/1079). R N B is supported by a Wellcome Trust and Royal Society grant (WT104150).

Acknowledgement

This work was conducted using the UK Biobank Resource under application number 9072.

References

  • Boelaert K, Horacek J, Holder RL, Watkinson JC, Sheppard MC & Franklyn JA 2006 Serum thyrotropin concentration as a novel predictor of malignancy in thyroid nodules investigated by fine-needle aspiration. Journal of Clinical Endocrinology and Metabolism 91 42954301. (https://doi.org/10.1210/jc.2006-0527)

    • Search Google Scholar
    • Export Citation
  • Bongiovanni M, Spitale A, Faquin WC, Mazzucchelli L & Baloch ZW 2012 The Bethesda system for reporting thyroid cytopathology: a meta-analysis. Acta Cytologica 56 333339. (https://doi.org/10.1159/000339959)

    • Search Google Scholar
    • Export Citation
  • Bowden J, Del Greco F, Minelli C, Davey Smith G, Sheehan NA & Thompson JR 2016a Assessing the suitability of summary data for two-sample Mendelian randomization analyses using MR-Egger regression: the role of the I2 statistic. International Journal of Epidemiology 45 19611974. (https://doi.org/10.1093/ije/dyw220)

    • Search Google Scholar
    • Export Citation
  • Bowden J, Davey Smith G, Haycock PC & Burgess S 2016b Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genetic Epidemiology 40 304314. (https://doi.org/10.1002/gepi.21965)

    • Search Google Scholar
    • Export Citation
  • Brion MJ, Shakhbazov K & Visscher PM 2013 Calculating statistical power in Mendelian randomization studies. International Journal of Epidemiology 42 14971501. (https://doi.org/10.1093/ije/dyt179)

    • Search Google Scholar
    • Export Citation
  • Bycroft C, Freeman C, Petkova D, Band G, Elliott LT, Sharp K, Motyer A, Vukcevic D, Delaneau O, O’Connell J, 2018 The UK Biobank resource with deep phenotyping and genomic data. Nature 562 203209. (https://doi.org/10.1038/s41586-018-0579-z)

    • Search Google Scholar
    • Export Citation
  • Cho A, Chang Y, Ahn J, Shin H & Ryu S 2018 Cigarette smoking and thyroid cancer risk: a cohort study. British Journal of Cancer 119 638645. (https://doi.org/10.1038/s41416-018-0224-5)

    • Search Google Scholar
    • Export Citation
  • Collins R 2012 What makes UK Biobank special? Lancet 379 11731174. (https://doi.org/10.1016/S0140-6736(12)60404-8)

  • Fighera TM, Perez CL, Faris N, Scarabotto PC, da Silva TT, Cavalcanti TC, Junior CO, Miasaki F, da Paz Filho GJ & de Carvalho GA 2015 TSH levels are associated with increased risk of thyroid carcinoma in patients with nodular disease. Endokrynologia Polska 66 480485. (https://doi.org/10.5603/EP.a2015.0059)

    • Search Google Scholar
    • Export Citation
  • Fry A, Littlejohns TJ, Sudlow C, Doherty N, Adamska L, Sprosen T, Collins R & Allen NE 2017 Comparison of sociodemographic and health-related characteristics of UK Biobank participants with those of the general population. American Journal of Epidemiology 186 10261034. (https://doi.org/10.1093/aje/kwx246)

    • Search Google Scholar
    • Export Citation
  • Golbert L, de Cristo AP, Faccin CS, Farenzena M, Folgierini H, Graudenz MS & Maia AL 2017 Serum TSH levels as a predictor of malignancy in thyroid nodules: a prospective study. PLoS ONE 12 e0188123. (https://doi.org/10.1371/journal.pone.0188123)

    • Search Google Scholar
    • Export Citation
  • Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, Pacini F, Randolph GW, Sawka AM & Schlumberger 2016 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association guidelines task force on thyroid nodules and differentiated thyroid cancer. Thyroid 26 133. (https://doi.org/10.1089/thy.2015.0020)

    • Search Google Scholar
    • Export Citation
  • Haymart MR, Repplinger DJ, Leverson GE, Elson DF, Sippel RS, Jaume JC & Chen H 2008 Higher serum thyroid stimulating hormone level in thyroid nodule patients is associated with greater risks of differentiated thyroid cancer and advanced tumor stage. Journal of Clinical Endocrinology and Metabolism 93 809814. (https://doi.org/10.1210/jc.2007-2215)

    • Search Google Scholar
    • Export Citation
  • Haymart MR, Glinberg SL, Liu J, Sippel RS, Jaume JC & Chen H 2009 Higher serum TSH in thyroid cancer patients occurs independent of age and correlates with extrathyroidal extension. Clinical Endocrinology 71 434439. (https://doi.org/10.1111/j.1365-2265.2008.03489.x)

    • Search Google Scholar
    • Export Citation
  • Hegedüs L 2004 Clinical practice. The thyroid nodule. New England Journal of Medicine 351 17641771. (https://doi.org/10.1056/NEJMcp031436)

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  • Huang H, Rusiecki J, Zhao N, Chen Y, Ma S, Yu H, Ward MH, Udelsman R & Zhang Y 2017 Thyroid-stimulating hormone, thyroid hormones and risk of papillary thyroid cancer: a nested case-control study. Cancer Epidemiology, Biomarkers and Prevention 26 12091218. (https://doi.org/10.1158/1055-9965.EPI-16-0845)

    • Search Google Scholar
    • Export Citation
  • Ichikawa Y, Saito E, Abe Y, Homma M & Muraki T 1976 Presence of TSH receptor in thyroid neoplasms. Journal of Clinical Endocrinology and Metabolism 42 395398. (https://doi.org/10.1210/jcem-42-2-395)

    • Search Google Scholar
    • Export Citation
  • Kitahara CM & Sosa JA 2016 The changing incidence of thyroid cancer. Nature Reviews: Endocrinology 12 646653. (https://doi.org/10.1038/nrendo.2016.110)

    • Search Google Scholar
    • Export Citation
  • Loh PR, Tucker G, Bulik-Sullivan BK, Vilhjálmsson BJ, Finucane HK, Salem RM, Chasman DI, Ridker PM, Neale BM, Berger B, 2015 Efficient Bayesian mixed-model analysis increases association power in large cohorts. Nature Genetics 47 284290. (https://doi.org/10.1038/ng.3190)

    • Search Google Scholar
    • Export Citation
  • Lu C, Zhao L, Ying H, Willingham MC & Cheng SY 2010 Growth activation alone is not sufficient to cause metastatic thyroid cancer in a mouse model of follicular thyroid carcinoma. Endocrinology 151 19291939. (https://doi.org/10.1210/en.2009-1017)

    • Search Google Scholar
    • Export Citation
  • Machiela MJ & Chanock SJ 2015 LDlink: a web-based application for exploring population-specific haplotype structure and linking correlated alleles of possible functional variants. Bioinformatics 31 35553557. (https://doi.org/10.1093/bioinformatics/btv402)

    • Search Google Scholar
    • Export Citation
  • McLeod DS, Watters KF, Carpenter AD, Ladenson PW, Cooper DS & Ding EL 2012 Thyrotropin and thyroid cancer diagnosis: a systematic review and dose-response meta-analysis. Journal of Clinical Endocrinology and Metabolism 97 26822692. (https://doi.org/10.1210/jc.2012-1083)

    • Search Google Scholar
    • Export Citation
  • McLeod DS, Cooper DS, Ladenson PW, Ain KB, Brierley JD, Fein HG, Haugen BR, Jonklaas J, Magner J, Ross DS, 2014 Prognosis of differentiated thyroid cancer in relation to serum thyrotropin and thyroglobulin antibody status at time of diagnosis. Thyroid 24 3542. (https://doi.org/10.1089/thy.2013.0062)

    • Search Google Scholar
    • Export Citation
  • Moon JH, Hyun MK, Lee JY, Shim JI, Kim TH, Choi HS, Ahn HY, Kim KW, Park DJ, Park YJ, 2018 Prevalence of thyroid nodules and their associated clinical parameters: a large-scale, multicenter-based health checkup study. Korean Journal of Internal Medicine 33 753762. (https://doi.org/10.3904/kjim.2015.273)

    • Search Google Scholar
    • Export Citation
  • Nikiforov YE & Baloch ZW 2019 Clinical validation of the ThyroSeq v3 genomic classifier in thyroid nodules with indeterminate FNA cytology. Cancer Cytopathology 127 225230. (https://doi.org/10.1002/cncy.22112)

    • Search Google Scholar
    • Export Citation
  • Perros P, Boelaert K, Colley S, Evans C, Evans RM, Gerrard Ba G, Gilbert J, Harrison B, Johnson SJ, Giles TE, 2014 Guidelines for the management of thyroid cancer. Clinical Endocrinology 81 (Supplement 1) 1122. (https://doi.org/10.1111/cen.12515)

    • Search Google Scholar
    • Export Citation
  • Porcu E, Medici M, Pistis G, Volpato CB, Wilson SG, Cappola AR, Bos SD, Deelen J, den Heijer M, Freathy RM, 2013 A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function. PLoS Genetics 9 e1003266. (https://doi.org/10.1371/journal.pgen.1003266)

    • Search Google Scholar
    • Export Citation
  • Rinaldi S, Plummer M, Biessy C, Tsilidis KK, Østergaard JN, Overvad K, Tjønneland A, Halkjær J, Boutron-Ruault MC, Clavel-Chapelon F, 2014 Thyroid-stimulating hormone, thyroglobulin, and thyroid hormones and risk of differentiated thyroid carcinoma: the EPIC study. Journal of the National Cancer Institute 106 dju097. (https://doi.org/10.1093/jnci/dju097)

    • Search Google Scholar
    • Export Citation
  • Satta MA, De Rosa G, Testa A, Maussier ML, Valenza V, Saletnich I, Rabitti C, D’Ugo D & Picciocchi A 1993 Thyroid cancer in suppressed contralateral lobe of patients with hot thyroid nodule. European Journal of Cancer 29A 11901192. (https://doi.org/10.1016/s0959-8049(05)80313-2)

    • Search Google Scholar
    • Export Citation
  • Singh B, Shaha AR, Trivedi H, Carew JF, Poluri A & Shah JP 1999 Coexistent Hashimoto's thyroiditis with papillary thyroid carcinoma: impact on presentation, management, and outcome. Surgery 126 10701076; discussion 1076. (https://doi.org/10.1067/msy.2099.101431)

    • Search Google Scholar
    • Export Citation
  • Sudlow C, Gallacher J, Allen N, Beral V, Burton P, Danesh J, Downey P, Elliott P, Green J, Landray M, 2015 UK Biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Medicine 12 e1001779. (https://doi.org/10.1371/journal.pmed.1001779)

    • Search Google Scholar
    • Export Citation
  • Welsh S, Peakman T, Sheard S & Almond R 2017 Comparison of DNA quantification methodology used in the DNA extraction protocol for the UK Biobank cohort. BMC Genomics 18 26. (https://doi.org/10.1186/s12864-016-3391-x)

    • Search Google Scholar
    • Export Citation
  • Wémeau JL, Caron P, Schvartz C, Schlienger JL, Orgiazzi J, Cousty C & Vlaeminck-Guillem V 2002 Effects of thyroid-stimulating hormone suppression with levothyroxine in reducing the volume of solitary thyroid nodules and improving extranodular nonpalpable changes: a randomized, double-blind, placebo-controlled trial by the French Thyroid Research Group. Journal of Clinical Endocrinology and Metabolism 87 49284934. (https://doi.org/10.1210/jc.2002-020365)

    • Search Google Scholar
    • Export Citation
  • Zafón C, Obiols G & Mesa J 2015 Preoperative TSH level and risk of thyroid cancer in patients with nodular thyroid disease: nodule size contribution. Endocrinología Y Nutrición 62 2428. (https://doi.org/10.1016/j.endonu.2014.06.002)

    • Search Google Scholar
    • Export Citation
  • Zheng J, Li C, Lu W, Wang C & Ai Z 2016 Quantitative assessment of preoperative serum thyrotropin level and thyroid cancer. Oncotarget 7 3491834929. (https://doi.org/10.18632/oncotarget.9201)

    • Search Google Scholar
    • Export Citation
  • Zimmermann MB & Galetti V 2015 Iodine intake as a risk factor for thyroid cancer: a comprehensive review of animal and human studies. Thyroid Research 8 8. (https://doi.org/10.1186/s13044-015-0020-8)

    • Search Google Scholar
    • Export Citation

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    If a risk factor, for example, high TSH truly causes an outcome, for example, thyroid cancer, then the genetic variants for the risk factor should also be associated with the outcome. Unlike the observed risk factor, the genetic variants are not susceptible to confounding by other risk factors or reverse causation (dashed lines) as they are assigned at conception. Horizontal pleiotropy (dotted line), whereby the variants of interest also affect the outcome via their association with another trait is a possible limitation of MR.

  • View in gallery

    Forest plot showing two sample MR (instrumental variable analysis) associations between genetically instrumented TSH and thyroid cancer and benign nodular thyroid disease. Odds ratios of outcome per s.d. higher genetically instrumented TSH and 95% CIs are shown.

  • View in gallery

    Forest plot showing associations between genetically instrumented TSH and thyroid cancer and benign nodular thyroid disease. Odds ratios of outcome per s.d. higher genetically instrumented TSH and 95% CIs are shown.

  • View in gallery

    Forest plot showing associations between quartiles for TSH genetic risk and thyroid cancer and benign nodular thyroid disease. Odds ratios and 95% CIs are shown for each quartile as compared to those in the lowest quartile.

  • Boelaert K, Horacek J, Holder RL, Watkinson JC, Sheppard MC & Franklyn JA 2006 Serum thyrotropin concentration as a novel predictor of malignancy in thyroid nodules investigated by fine-needle aspiration. Journal of Clinical Endocrinology and Metabolism 91 42954301. (https://doi.org/10.1210/jc.2006-0527)

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    • Export Citation
  • Bongiovanni M, Spitale A, Faquin WC, Mazzucchelli L & Baloch ZW 2012 The Bethesda system for reporting thyroid cytopathology: a meta-analysis. Acta Cytologica 56 333339. (https://doi.org/10.1159/000339959)

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    • Export Citation
  • Bowden J, Del Greco F, Minelli C, Davey Smith G, Sheehan NA & Thompson JR 2016a Assessing the suitability of summary data for two-sample Mendelian randomization analyses using MR-Egger regression: the role of the I2 statistic. International Journal of Epidemiology 45 19611974. (https://doi.org/10.1093/ije/dyw220)

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  • Bowden J, Davey Smith G, Haycock PC & Burgess S 2016b Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genetic Epidemiology 40 304314. (https://doi.org/10.1002/gepi.21965)

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  • Brion MJ, Shakhbazov K & Visscher PM 2013 Calculating statistical power in Mendelian randomization studies. International Journal of Epidemiology 42 14971501. (https://doi.org/10.1093/ije/dyt179)

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    • Export Citation
  • Bycroft C, Freeman C, Petkova D, Band G, Elliott LT, Sharp K, Motyer A, Vukcevic D, Delaneau O, O’Connell J, 2018 The UK Biobank resource with deep phenotyping and genomic data. Nature 562 203209. (https://doi.org/10.1038/s41586-018-0579-z)

    • Search Google Scholar
    • Export Citation
  • Cho A, Chang Y, Ahn J, Shin H & Ryu S 2018 Cigarette smoking and thyroid cancer risk: a cohort study. British Journal of Cancer 119 638645. (https://doi.org/10.1038/s41416-018-0224-5)

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    • Export Citation
  • Collins R 2012 What makes UK Biobank special? Lancet 379 11731174. (https://doi.org/10.1016/S0140-6736(12)60404-8)

  • Fighera TM, Perez CL, Faris N, Scarabotto PC, da Silva TT, Cavalcanti TC, Junior CO, Miasaki F, da Paz Filho GJ & de Carvalho GA 2015 TSH levels are associated with increased risk of thyroid carcinoma in patients with nodular disease. Endokrynologia Polska 66 480485. (https://doi.org/10.5603/EP.a2015.0059)

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  • Fry A, Littlejohns TJ, Sudlow C, Doherty N, Adamska L, Sprosen T, Collins R & Allen NE 2017 Comparison of sociodemographic and health-related characteristics of UK Biobank participants with those of the general population. American Journal of Epidemiology 186 10261034. (https://doi.org/10.1093/aje/kwx246)

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  • Golbert L, de Cristo AP, Faccin CS, Farenzena M, Folgierini H, Graudenz MS & Maia AL 2017 Serum TSH levels as a predictor of malignancy in thyroid nodules: a prospective study. PLoS ONE 12 e0188123. (https://doi.org/10.1371/journal.pone.0188123)

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  • Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, Pacini F, Randolph GW, Sawka AM & Schlumberger 2016 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association guidelines task force on thyroid nodules and differentiated thyroid cancer. Thyroid 26 133. (https://doi.org/10.1089/thy.2015.0020)

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  • Haymart MR, Repplinger DJ, Leverson GE, Elson DF, Sippel RS, Jaume JC & Chen H 2008 Higher serum thyroid stimulating hormone level in thyroid nodule patients is associated with greater risks of differentiated thyroid cancer and advanced tumor stage. Journal of Clinical Endocrinology and Metabolism 93 809814. (https://doi.org/10.1210/jc.2007-2215)

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  • Haymart MR, Glinberg SL, Liu J, Sippel RS, Jaume JC & Chen H 2009 Higher serum TSH in thyroid cancer patients occurs independent of age and correlates with extrathyroidal extension. Clinical Endocrinology 71 434439. (https://doi.org/10.1111/j.1365-2265.2008.03489.x)

    • Search Google Scholar
    • Export Citation
  • Hegedüs L 2004 Clinical practice. The thyroid nodule. New England Journal of Medicine 351 17641771. (https://doi.org/10.1056/NEJMcp031436)

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    • Export Citation
  • Huang H, Rusiecki J, Zhao N, Chen Y, Ma S, Yu H, Ward MH, Udelsman R & Zhang Y 2017 Thyroid-stimulating hormone, thyroid hormones and risk of papillary thyroid cancer: a nested case-control study. Cancer Epidemiology, Biomarkers and Prevention 26 12091218. (https://doi.org/10.1158/1055-9965.EPI-16-0845)

    • Search Google Scholar
    • Export Citation
  • Ichikawa Y, Saito E, Abe Y, Homma M & Muraki T 1976 Presence of TSH receptor in thyroid neoplasms. Journal of Clinical Endocrinology and Metabolism 42 395398. (https://doi.org/10.1210/jcem-42-2-395)

    • Search Google Scholar
    • Export Citation
  • Kitahara CM & Sosa JA 2016 The changing incidence of thyroid cancer. Nature Reviews: Endocrinology 12 646653. (https://doi.org/10.1038/nrendo.2016.110)

    • Search Google Scholar
    • Export Citation
  • Loh PR, Tucker G, Bulik-Sullivan BK, Vilhjálmsson BJ, Finucane HK, Salem RM, Chasman DI, Ridker PM, Neale BM, Berger B, 2015 Efficient Bayesian mixed-model analysis increases association power in large cohorts. Nature Genetics 47 284290. (https://doi.org/10.1038/ng.3190)

    • Search Google Scholar
    • Export Citation
  • Lu C, Zhao L, Ying H, Willingham MC & Cheng SY 2010 Growth activation alone is not sufficient to cause metastatic thyroid cancer in a mouse model of follicular thyroid carcinoma. Endocrinology 151 19291939. (https://doi.org/10.1210/en.2009-1017)

    • Search Google Scholar
    • Export Citation
  • Machiela MJ & Chanock SJ 2015 LDlink: a web-based application for exploring population-specific haplotype structure and linking correlated alleles of possible functional variants. Bioinformatics 31 35553557. (https://doi.org/10.1093/bioinformatics/btv402)

    • Search Google Scholar
    • Export Citation
  • McLeod DS, Watters KF, Carpenter AD, Ladenson PW, Cooper DS & Ding EL 2012 Thyrotropin and thyroid cancer diagnosis: a systematic review and dose-response meta-analysis. Journal of Clinical Endocrinology and Metabolism 97 26822692. (https://doi.org/10.1210/jc.2012-1083)

    • Search Google Scholar
    • Export Citation
  • McLeod DS, Cooper DS, Ladenson PW, Ain KB, Brierley JD, Fein HG, Haugen BR, Jonklaas J, Magner J, Ross DS, 2014 Prognosis of differentiated thyroid cancer in relation to serum thyrotropin and thyroglobulin antibody status at time of diagnosis. Thyroid 24 3542. (https://doi.org/10.1089/thy.2013.0062)

    • Search Google Scholar
    • Export Citation
  • Moon JH, Hyun MK, Lee JY, Shim JI, Kim TH, Choi HS, Ahn HY, Kim KW, Park DJ, Park YJ, 2018 Prevalence of thyroid nodules and their associated clinical parameters: a large-scale, multicenter-based health checkup study. Korean Journal of Internal Medicine 33 753762. (https://doi.org/10.3904/kjim.2015.273)

    • Search Google Scholar
    • Export Citation
  • Nikiforov YE & Baloch ZW 2019 Clinical validation of the ThyroSeq v3 genomic classifier in thyroid nodules with indeterminate FNA cytology. Cancer Cytopathology 127 225230. (https://doi.org/10.1002/cncy.22112)

    • Search Google Scholar
    • Export Citation
  • Perros P, Boelaert K, Colley S, Evans C, Evans RM, Gerrard Ba G, Gilbert J, Harrison B, Johnson SJ, Giles TE, 2014 Guidelines for the management of thyroid cancer. Clinical Endocrinology 81 (Supplement 1) 1122. (https://doi.org/10.1111/cen.12515)

    • Search Google Scholar
    • Export Citation
  • Porcu E, Medici M, Pistis G, Volpato CB, Wilson SG, Cappola AR, Bos SD, Deelen J, den Heijer M, Freathy RM, 2013 A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function. PLoS Genetics 9 e1003266. (https://doi.org/10.1371/journal.pgen.1003266)

    • Search Google Scholar
    • Export Citation
  • Rinaldi S, Plummer M, Biessy C, Tsilidis KK, Østergaard JN, Overvad K, Tjønneland A, Halkjær J, Boutron-Ruault MC, Clavel-Chapelon F, 2014 Thyroid-stimulating hormone, thyroglobulin, and thyroid hormones and risk of differentiated thyroid carcinoma: the EPIC study. Journal of the National Cancer Institute 106 dju097. (https://doi.org/10.1093/jnci/dju097)

    • Search Google Scholar
    • Export Citation
  • Satta MA, De Rosa G, Testa A, Maussier ML, Valenza V, Saletnich I, Rabitti C, D’Ugo D & Picciocchi A 1993 Thyroid cancer in suppressed contralateral lobe of patients with hot thyroid nodule. European Journal of Cancer 29A 11901192. (https://doi.org/10.1016/s0959-8049(05)80313-2)

    • Search Google Scholar
    • Export Citation
  • Singh B, Shaha AR, Trivedi H, Carew JF, Poluri A & Shah JP 1999 Coexistent Hashimoto's thyroiditis with papillary thyroid carcinoma: impact on presentation, management, and outcome. Surgery 126 10701076; discussion 1076. (https://doi.org/10.1067/msy.2099.101431)

    • Search Google Scholar
    • Export Citation
  • Sudlow C, Gallacher J, Allen N, Beral V, Burton P, Danesh J, Downey P, Elliott P, Green J, Landray M, 2015 UK Biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Medicine 12 e1001779. (https://doi.org/10.1371/journal.pmed.1001779)

    • Search Google Scholar
    • Export Citation
  • Welsh S, Peakman T, Sheard S & Almond R 2017 Comparison of DNA quantification methodology used in the DNA extraction protocol for the UK Biobank cohort. BMC Genomics 18 26. (https://doi.org/10.1186/s12864-016-3391-x)

    • Search Google Scholar
    • Export Citation
  • Wémeau JL, Caron P, Schvartz C, Schlienger JL, Orgiazzi J, Cousty C & Vlaeminck-Guillem V 2002 Effects of thyroid-stimulating hormone suppression with levothyroxine in reducing the volume of solitary thyroid nodules and improving extranodular nonpalpable changes: a randomized, double-blind, placebo-controlled trial by the French Thyroid Research Group. Journal of Clinical Endocrinology and Metabolism 87 49284934. (https://doi.org/10.1210/jc.2002-020365)

    • Search Google Scholar
    • Export Citation
  • Zafón C, Obiols G & Mesa J 2015 Preoperative TSH level and risk of thyroid cancer in patients with nodular thyroid disease: nodule size contribution. Endocrinología Y Nutrición 62 2428. (https://doi.org/10.1016/j.endonu.2014.06.002)

    • Search Google Scholar
    • Export Citation
  • Zheng J, Li C, Lu W, Wang C & Ai Z 2016 Quantitative assessment of preoperative serum thyrotropin level and thyroid cancer. Oncotarget 7 3491834929. (https://doi.org/10.18632/oncotarget.9201)

    • Search Google Scholar
    • Export Citation
  • Zimmermann MB & Galetti V 2015 Iodine intake as a risk factor for thyroid cancer: a comprehensive review of animal and human studies. Thyroid Research 8 8. (https://doi.org/10.1186/s13044-015-0020-8)

    • Search Google Scholar
    • Export Citation