Thyroid function, pernicious anemia and erythropoiesis: a two-sample Mendelian randomization study.

Autoimmune thyroid disease (AITD) and pernicious anemia (PA) often coexist, but the directionality is unknown. In a two-sample Mendelian randomization (MR) analysis, using summary statistics from large genome-wide association studies (GWASs) in Europeans (N = 49 269-755 406), we examined the genetic associations between thyroid function, PA and markers of erythropoiesis. We performed inverse variance weighted random-effects MR, several sensitivity MR analyses, and bidirectional MR and MR Steiger for directionality. AITD and PA were associated bidirectionally (P ≤ 8 × 10-6). Neither euthyroid thyroid stimulating hormone (TSH) nor free thyroxine (FT4) were causally associated with PA. One standard deviation (SD) increase in euthyroid FT4 regulated by genetic variants in deiodinases 1 and 2 genes (DIO1/DIO2), corresponding to low-normal free triiodothyronine (FT3) levels, was causally associated with a pernicious/macrocytic anemia pattern, i.e. decreased erythrocyte counts (rank-based inverse normal transformed ß = -0,064 [95% confidence interval: -0,085, -0,044], P = 8 × 10-10) and hemoglobin (-0.028 [-0.051, -0.005], P = 0.02) and increased mean corpuscular hemoglobin (0.058 [0.025, 0.091], P = 5 × 10-4) and mean corpuscular volume levels (0.075 [0.052, 0.098], P = 1 × 10-8). Meanwhile, subclinical hyperthyroidism mirrored that pattern. AITD was causally associated with increased erythrocyte distribution width (P = 0.007) and decreased reticulocyte counts (P ≤ 0.02), whereas high-normal FT4 regulated by DIO1/DIO2 variants was causally associated with decreased bilirubin (-0.039 (-0.064, -0.013), P = 0.003). In conclusion, the bidirectional association between AITD and PA suggests a shared heritability for these two autoimmune diseases. AITD was causally associated with impaired erythropoiesis and not autoimmune hemolysis. Additionally, in euthyroid individuals, local regulation of thyroid hormones by deiodinases likely plays a role in erythropoiesis.

Thyroid function, sex hormones and sexual function: a Mendelian randomization study.

Hypothyroidism and hyperthyroidism are observationally associated with sex hormone concentrations and sexual dysfunction, but causality is unclear. We investigated whether TSH, fT4, hypo- and hyperthyroidism are causally associated with sex hormones and sexual function. We used publicly available summary statistics from genome-wide association studies on TSH and fT4 and hypo- and hyperthyroidism from the ThyroidOmics Consortium (N ≤ 54,288). Outcomes from UK Biobank (women ≤ 194,174/men ≤ 167,020) and ReproGen (women ≤ 252,514) were sex hormones (sex hormone binding globulin [SHBG], testosterone, estradiol, free androgen index [FAI]) and sexual function (ovulatory function in women: duration of menstrual period, age at menarche and menopause, reproductive lifespan, and erectile dysfunction in men). We performed two-sample Mendelian randomization (MR) analyses on summary level, and unweighted genetic risk score (GRS) analysis on individual level data. One SD increase in TSH was associated with a 1.332 nmol/L lower (95% CI: - 0.717,- 1.946; p = 2 × 10-5) SHBG and a 0.103 nmol/l lower (- 0.051,V0.154; p = 9 × 10-5) testosterone in two-sample MR, supported by the GRS approach. Genetic predisposition to hypothyroidism was associated with decreased and genetic predisposition to hyperthyroidism with increased SHBG and testosterone in both approaches. The GRS for fT4 was associated with increased testosterone and estradiol in women only. The GRS for TSH and hypothyroidism were associated with increased and the GRS for hyperthyroidism with decreased FAI in men only. While genetically predicted thyroid function was associated with sex hormones, we found no association with sexual function.

Paediatric-onset and adult-onset Graves' disease share multiple genetic risk factors.

BACKGROUND: Graves' disease (GD) is an autoimmune thyroid disease (AITD) with a peak incidence between 30 and 50 years of age. Although children and adolescents may also develop the disease, the genetic background of paediatric-onset GD (POGD) remains largely unknown. Here, we looked for similarities and differences in the genetic risk factors for POGD and adult-onset GD (AOGD) as well as for variants associated with age of GD onset. MATERIALS AND METHODS: A total of 1267 GD patients and 1054 healthy controls were included in the study. Allele frequencies of 40 established and suggested GD/AITD genetic risk variants (39 SNPs and HLA-DRB1*03) were compared between POGD (N = 179), AOGD (N = 1088) and healthy controls. Subsequently, multiple linear regression was used to explore the relationship between age of GD onset and genotype for each locus. RESULTS: We identified six POGD risk loci, all of them were also strongly associated with AOGD. Although for some of the analysed variants, including HCP5 (rs3094228), PRICKLE1 (rs4768412) and SCGB3A2 (rs1368408), allele frequencies differed nominally between POGD and AOGD patients, these differences were not significant after applying multiple testing correction (Pcor  = 0.05/40 = 1.25 × 10-3 ). Regression analysis showed that patients with higher number of HCP5 risk alleles tend to have a significantly earlier onset of GD (P = 6.9 × 10-5 ). CONCLUSIONS: The results of our study revealed that POGD and AOGD share multiple common genetic risk variants. Moreover, we demonstrated for the first time that HCP5 polymorphism is associated with an earlier age of GD onset in a dose-dependent manner.

Gender-dependent and age-of-onset-specific association of the rs11675434 single-nucleotide polymorphism near TPO with susceptibility to Graves' ophthalmopathy.

The role of TPO gene polymorphism in the susceptibility to Graves' disease (GD) remains unclear. However, single-nucleotide polymorphisms (SNPs) near TPO have been recently associated with serum levels of thyroid peroxidase (TPO) antibody in two independent genome-wide association studies. Moreover, we have observed a strong association between the rs11675434 SNP located near TPO and the presence of clinically evident Graves' ophthalmopathy (GO). The aim of the current study was to reevaluate and dissect this association in an extended group of 1231 well-characterized patients with GD (1043 adults and 188 children) and 1130 healthy controls from the Polish Caucasian population, considering possible gender-dependent and age-of-onset-specific effects of the studied SNP. We found that the T allele of rs11675434 was significantly more frequent in GD patients with than without GO (odds ratio (OR)=1.26, 95% confidence interval (CI)=1.05-1.51, P=0.012), which was consistent with our previous findings. Further analyses performed in subgroups of patients showed that the association with GO was significant in adult patients with age of GD onset ⩾45 years (OR=1.34, 95% CI=1.03-1.75, P=0.031), but not in children and adolescents or adult patients with earlier onset of the disease (OR=1.72, 95% CI=0.77-3.84, P=0.18 and OR=1.05, 95% CI=0.79-1.40, P=0.75, respectively). Moreover, a strong association with GO was present in males (OR=2.06, 95% CI=1.40-3.02, P=0.0002), whereas it was absent in females (OR=1.10, 95% CI=0.90-1.35, P=0.35). The results of our study further suggest that rs11675434 SNP located near TPO is associated with the development of GO, especially in males and patients with later age of GD onset.

The association of thyroid peroxidase antibody risk loci with susceptibility to and phenotype of Graves' disease.

BACKGROUND: Despite great progress, the genetic basis of Graves' disease (GD) remains poorly understood. Recently, a population-based genomewide association study (GWAS) identified five novel loci (ATXN2/SH2B3, MAGI3, BACH2, TPO and KALRN) as significantly associated with the presence of thyroid peroxidase autoantibodies (TPOAbs), whereas several other loci showed suggestive association. METHODS: In this study, we investigated 16 single nucleotide polymorphisms (SNPs) associated with TPOAbs for the association with susceptibility to and phenotype of GD in a cohort of 647 patients with GD and 769 controls from a Polish Caucasian population. RESULTS: SNPs within/near HCP5 (rs3094228, P = 1·6 × 10(-12) , OR = 1·88), MAGI3 (rs1230666, P = 1·9 × 10(-5) , OR = 1·51) and ATXN2/SH2B3 (rs653178, P = 0·0015, OR = 1·28) loci were significantly associated with susceptibility to GD. Allele frequencies differed significantly in subgroups of patients with GD stratified by age of GD onset for HCP5 (P = 0·0014, OR = 1·50) and showed a suggestive difference for MAGI3 (P = 0·0035, OR = 1·50) SNPs. Although rs11675434 located near TPO showed no association with GD susceptibility, it was significantly associated with the presence of clinically evident Graves' ophthalmopathy (GO, P = 5·2 × 10(-5) , OR = 1·64), and this effect was independent from smoking status, age of GD onset and gender. CONCLUSIONS: This is the first study showing an association of the ATXN2/SH2B3 locus with susceptibility to GD. Furthermore, we observed a novel significant association within the HLA region at a SNP located near HCP5 and confirmed the association of the MAGI3 locus with GD susceptibility. HCP5 and MAGI3 SNPs were further correlated with age of GD onset. Finally, we identified TPO as a new susceptibility locus for GO.

Increased concentration of T-cell receptor rearrangement excision circles (TREC) in peripheral blood in Graves' disease.

BACKGROUND: T-cell receptor rearrangement excision circles (TREC) are circular DNA molecules generated during T-cell maturation in the thymus. Recent studies suggested that a decreased TREC concentration in peripheral blood may be a general feature of autoimmunity. Our purpose was to assess the TREC concentration in Graves' disease (GD). METHODS: TREC concentration was assessed by real time PCR in DNA samples isolated from peripheral blood leucocytes among younger (n = 94, age range 6-29 years) and older patients with GD (n = 93, age range 57-80 years) and age-matched controls (n = 206). RESULTS: TREC concentration decreased with age in all subjects, but it was significantly higher in GD compared with controls (P = 9·4 × 10(-10) ). TREC concentration was higher (P = 0·0038) in hyperthyroid (n = 78) than euthyroid (n = 82) patients with GD, but in both groups, it remained increased relative to controls (P = 2·2 × 10(-11) and P = 4·4 ×10(-7) , respectively). CONCLUSIONS: Patients with GD, particularly those with hyperthyroidism, have increased concentration of TREC which may suggest increased rather than decreased thymic activity. Thus, GD does not follow the paradigm suggested for other autoimmune disorders which links autoimmunity with thymic senescence.

Long-term remission of corticosteroid-resistant Graves' orbitopathy after therapy with tocilizumab.

Not required for Clinical Vignettes.

Towards Personalized TSH Reference Ranges: A Genetic and Population-Based Approach in Three Independent Cohorts.

Background: Serum thyroid-stimulating hormone (TSH) measurement is the diagnostic cornerstone for primary thyroid dysfunction. There is high inter-individual but limited intra-individual variation in TSH concentrations, largely due to genetic factors. The currently used wide population-based reference intervals may lead to inappropriate management decisions. Methods: A polygenic score (PGS) including 59 genetic variants was used to calculate genetically determined TSH reference ranges in a thyroid disease-free cohort (n = 6,834). Its effect on reclassification of diagnoses was investigated when compared to using population-based reference ranges. Next, results were validated in a second independent population-based thyroid disease-free cohort (n = 3,800). Potential clinical implications were assessed in a third independent population-based cohort including individuals without thyroid disease (n = 26,321) as well as individuals on levothyroxine (LT4) treatment (n = 1,132). Results: PGS was a much stronger predictor of individual TSH concentrations than FT4 (total variance in TSH concentrations explained 9.2-11.1% vs. 2.4-2.7%, respectively) or any other nongenetic factor (total variance in TSH concentrations explained 0.2-1.8%). Genetically determined TSH reference ranges differed significantly between PGS quartiles in all cohorts, while the differences in FT4 concentrations were absent or only minor. Up to 24.7-30.1% of individuals, previously classified as having subclinical hypo- and hyperthyroidism when using population-based TSH reference ranges, were reclassified as euthyroid when genetically determined TSH reference ranges were applied. Individuals in the higher PGS quartiles had a higher probability of being prescribed LT4 treatment compared to individuals from the lower PGS quartiles (3.3% in Q1 vs. 5.2% in Q4, Pfor trend =1.7 × 10-8). Conclusions: Individual genetic profiles have the potential to personalize TSH reference ranges, with large effects on reclassification of diagnosis and LT4 prescriptions. As the currently used PGS can only predict approximately 10% of inter-individual variation in TSH concentrations, it should be further improved when more genetic variants determining TSH concentrations are identified in future studies.

The role of thyroid function in borderline personality disorder and schizophrenia: a Mendelian Randomisation study.

BACKGROUND: Genome-wide association studies have reported a genetic overlap between borderline personality disorder (BPD) and schizophrenia (SCZ). Epidemiologically, the direction and causality of the association between thyroid function and risk of BPD and SCZ are unclear. We aim to test whether genetically predicted variations in TSH and FT4 levels or hypothyroidism are associated with the risk of BPD and SCZ. METHODS: We employed Mendelian Randomisation (MR) analyses using genetic instruments associated with TSH and FT4 levels as well as hypothyroidism to examine the effects of genetically predicted thyroid function on BPD and SCZ risk. Bidirectional MR analyses were employed to investigate a potential reverse causal association. RESULTS: Genetically predicted higher FT4 was not associated with the risk of BPD (OR: 1.18; P = 0.60, IVW) or the risk of SCZ (OR: 0.93; P = 0.19, IVW). Genetically predicted higher TSH was not associated with the risk of BPD (OR: 1.11; P = 0.51, IVW) or SCZ (OR: 0.98, P = 0.55, IVW). Genetically predicted hypothyroidism was not associated with BPD or SCZ. We found no evidence for a reverse causal effect between BPD or SCZ on thyroid function. CONCLUSIONS: We report evidence for a null association between genetically predicted FT4, TSH or hypothyroidism with BPD or SCZ risk. There was no evidence for reverse causality.

Genotype-phenotype correlations in Graves' disease.

Graves' disease (GD) is a heterogeneous autoimmune disease affecting with varying degrees of severity the thyroid gland, orbital tissues and skin. The pathogenesis of GD involves a complex interplay between multiple genetic, environmental and endogenous factors. Although the genetic predisposition to GD is well established, the significance of genotype-phenotype correlations and the role of epigenetic modifications in the disease pathogenesis remains largely unknown. In this review, we provide an up-to-date overview of genotype-phenotype correlations and summarize possible clinical implications of genetic and epigenetic markers in GD patients. We will specifically discuss the association of genetic markers and epigenetic modifications with age of GD onset, severity of Graves' hyperthyroidism and the development of clinically evident Graves' orbitopathy.

Height, Autoimmune Thyroid Disease, and Thyroid Cancer: A Mendelian Randomization Study.

Background: Increased height has been associated with increased risk of hypothyroidism or thyroid cancer in epidemiological studies. However, the potential causal association between height and hypothyroidism or thyroid cancer has not been thoroughly explored. Autoimmune thyroid disease (AITD) mainly presents as hypothyroidism, thus we aim to evaluate the causal relationship between height as exposure and its association with AITD or thyroid cancer. Methods: Mendelian randomization (MR) analyses were performed by using genetic instruments associated with height, which were selected from the largest genome-wide association meta-analysis for height in up to 5.4 million individuals. Summary-level data for AITD and thyroid cancer (including 30,234 and 3001 cases, respectively) were collected from the large number of available genome-wide association studies. Bidirectional MR was performed to test for reverse causal association between AITD and adult height. Results: MR analyses showed that increased genetically predicted height was associated with a 4% increased risk of AITD ([CI 1.02 to 1.07], p-value = 1.99E-03) per 1-standard deviation (SD) increase in genetically predicted height. The bidirectional MR did not show any causal association between AITD and adult height. Additionally, increased genetically predicted height was associated with 15% increased risk of thyroid cancer ([CI 1.07 to 1.23], p-value = 2.32E-04) per 1-SD increase in height. Sensitivity analysis confirmed the main results. Conclusions: This MR study showed that 1-SD increase in genetically predicted height was associated with increased risk of AITD and thyroid cancer. In contrast, there was no evidence of a causal association of genetically predicted AITD with height. These results could further aid in investigation of height-related pathways as a means of gaining new mechanistic insights into AITD and thyroid cancer.

Variation in Normal Range Thyroid Function Affects Serum Cholesterol Levels, Blood Pressure, and Type 2 Diabetes Risk: A Mendelian Randomization Study.

Background: Observational studies have demonstrated that variation in normal range thyroid function is associated with major cardiovascular risk factors, including dyslipidemia, hypertension, type 2 diabetes (T2D), and obesity. As observational studies are prone to residual confounding, reverse causality, and selection bias, we used a Mendelian randomization (MR) approach to investigate whether these associations are causal or not. Methods: Two-sample MR analysis using data from the largest available genome-wide association studies on normal range thyrotropin (TSH) and free thyroxine (fT4) levels, serum lipid levels, blood pressure measurements, T2D, and obesity traits (body mass index [BMI] and waist/hip ratio). Results: A one standard deviation (SD) increase in genetically predicted TSH levels was associated with a 0.037 SD increase in total cholesterol levels (p = 3.0 × 10-4). After excluding pleiotropic instruments, we also observed significant associations between TSH levels and low-density lipoprotein levels (ß = 0.026 SD, p = 1.9 × 10-3), pulse pressure (ß = -0.477 mmHg, p = 7.5 × 10-10), and T2D risk (odds ratio = 0.95, p = 2.5 × 10-3). While we found no evidence of causal associations between TSH or fT4 levels and obesity traits, we found that a one SD increase in genetically predicted BMI was associated with a 0.075 SD decrease in fT4 levels (p = 3.6 × 10-4). Conclusions: Variation in normal range thyroid function affects serum cholesterol levels, blood pressure, and T2D risk.

Thyroid Function and the Risk of Alzheimer's Disease: A Mendelian Randomization Study.

Background: Observational studies suggest an association between thyroid function and risk of dementia, but the causality and direction of these effects are unclear. We aim to test whether genetically predicted variation within the normal range of thyroid function and hypothyroidism is causally associated with the risk of Alzheimer's disease (AD). Methods: Mendelian randomization (MR) analyses using genetic instruments are associated with normal range thyrotropin (TSH) and free thyroxine (fT4) levels. Secondary analyses included investigation of the role of hypothyroidism. Bidirectional MR was conducted to address the presence of a potential reverse causal association. Summary statistics were obtained from the ThyroidOmics Consortium involving up to 119,715 individuals and the latest AD genome-wide association study data including up to 71,880 cases. Results: MR analyses show an association between increased genetically predicted normal range TSH levels and a decreased risk of AD (p = 0.02). One standard deviation increased normal range TSH levels were associated with a decreased risk of AD in individuals younger than 50 years old (p = 0.04). There was no evidence for a causal association between fT4 (p = 0.54) and AD. We did not identify any effect of the genetically predicted full range TSH levels (p = 0.06) or hypothyroidism (p = 0.23) with AD. Bidirectional MR did not show any effect of genetic predisposition to AD on TSH or fT4 levels. Conclusions: This MR study shows that increased levels of genetically predicted TSH within the normal range and in younger individuals are associated with a decreased risk of AD. We observed a marginal association between genetically predicted full range TSH and AD risk. There was no evidence for an effect between genetically predicted fT4 or hypothyroidism on AD. Future studies should clarify the underlying pathophysiological mechanisms.

Thyroid Function and Mood Disorders: A Mendelian Randomization Study.

Background: Observational studies suggest that even minor variations in thyroid function are associated with the risk of mood disorders, including major depressive disorder (MDD) and bipolar disorder (BD). However, it is unknown whether these associations are causal or not. We used a Mendelian randomization (MR) approach to investigate causal effects of minor variations in thyrotropin (TSH) and free thyroxine (fT4) levels on MDD and BD risk. Materials and Methods: We performed two-sample MR analyses using data from the largest publicly available genome-wide association studies on normal-range TSH (n = 54,288) and fT4 (n = 49,269) levels, MDD (170,756 cases, 329,443 controls) and BD (20,352 cases, 31,358 controls). Secondary MR analyses investigated the effects of TSH and fT4 levels on specific MDD and BD subtypes. Reverse MR was also performed to assess the effects of MDD and BD on TSH and fT4 levels. Results: There were no associations between genetically predicted TSH and fT4 levels and MDD risk, nor MDD subtypes and minor depressive symptoms. A one standard deviation increase in fT4 levels was nominally associated with an 11% decrease in the overall BD risk (odds ratio [OR] = 0.89, 95% confidence interval [CI] = 0.80-0.98, p = 0.022) and a 13% decrease in the BD type 1 risk (OR = 0.87, CI = 0.75-1.00, p = 0.047). In the reverse direction, genetic predisposition to MDD and BD was not associated with TSH nor fT4 levels. Conclusions: Variations in normal-range TSH and fT4 levels have no effects on the risk of MDD and its subtypes, and neither on minor depressive symptoms. This indicates that depressive symptoms should not be attributed to minor variations in thyroid function. Borderline associations with BD and BD type 1 risks suggest that further clinical studies should investigate the effect of thyroid hormone treatment in BD.

Effects of Thyroid Function on Hemostasis, Coagulation, and Fibrinolysis: A Mendelian Randomization Study.

Background: Untreated hypothyroidism is associated with acquired von Willebrand syndrome, and hyperthyroidism is associated with increased thrombosis risk. However, the causal effects of thyroid function on hemostasis, coagulation, and fibrinolysis are unknown. Methods: In a two-sample Mendelian randomization (MR) study with genome-wide association variants, we assessed causality of genetically predicted hypothyroidism (N = 134,641), normal-range thyrotropin (TSH; N = 54,288) and free thyroxine (fT4) (N = 49,269), hyperthyroidism (N = 51,823), and thyroid peroxidase antibody positivity (N = 25,821) on coagulation (activated partial thromboplastin time, von Willebrand factor [VWF], factor VIII [FVIII], prothrombin time, factor VII, fibrinogen) and fibrinolysis (D-dimer, tissue plasminogen activator [TPA], plasminogen activator inhibitor-1) from the CHARGE Hemostasis Consortium (N = 2583-120,246). Inverse-variance-weighted random effects were the main MR analysis followed by sensitivity analyses. Two-sided p < 0.05 was nominally significant, and p < 0.0011[ = 0.05/(5 exposures × 9 outcomes)] was Bonferroni significant for the main MR analysis. Results: Genetically increased TSH was associated with decreased VWF [ß(SE) = -0.020(0.006), p = 0.001] and with decreased fibrinogen [ß(SE) = -0.008(0.002), p = 0.001]. Genetically increased fT4 was associated with increased VWF [ß(SE) = 0.028(0.011), p = 0.012]. Genetically predicted hyperthyroidism was associated with increased VWF [ß(SE) = 0.012(0.004), p = 0.006] and increased FVIII [ß(SE) = 0.013(0.005), p = 0.007]. Genetically predicted hypothyroidism and hyperthyroidism were associated with decreased TPA [ß(SE) = -0.009(0.024), p = 0.024] and increased TPA [ß(SE) = 0.022(0.008), p = 0.008], respectively. MR sensitivity analyses showed similar direction but lower precision. Other coagulation and fibrinolytic factors were inconclusive. Conclusions: In the largest genetic studies currently available, genetically increased TSH and fT4 may be associated with decreased and increased synthesis of VWF, respectively. Since Bonferroni correction may be too conservative given the correlation between the analyzed traits, we cannot reject nominal associations of thyroid traits with coagulation or fibrinolytic factors.

The Genetic Basis of Thyroid Function: Novel Findings and New Approaches.

CONTEXT: Genetic factors are major determinants of thyroid function. Over the last two decades, multiple genetic variants have been associated with variations in normal range thyroid function tests. Most recently, a large-scale genome-wide association study (GWAS) doubled the number of known variants associated with normal range thyrotropin (TSH) and free thyroxine (FT4) levels. EVIDENCE ACQUISITION: This review summarizes the results of genetic association studies on normal range thyroid function and explores how these genetic variants can be used in future studies to improve our understanding of thyroid hormone regulation and disease. EVIDENCE SYNTHESIS: Serum TSH and FT4 levels are determined by multiple genetic variants on virtually all levels of the hypothalamus-pituitary-thyroid (HPT) axis. Functional follow-up studies on top of GWAS hits has the potential to discover new key players in thyroid hormone regulation, as exemplified by the identification of the thyroid hormone transporter SLC17A4 and the metabolizing enzyme AADAT. Translational studies may use these genetic variants to investigate causal associations between thyroid function and various outcomes in Mendelian Randomization (MR) studies, to identify individuals with an increased risk of thyroid dysfunction, and to predict the individual HPT axis setpoint. CONCLUSIONS: Recent genetic studies have greatly improved our understanding of the genetic basis of thyroid function, and have revealed novel pathways involved in its regulation. In addition, these findings have paved the way for various lines of research that can improve our understanding of thyroid hormone regulation and thyroid diseases, as well as the potential use of these markers in future clinical practice.

Thyroid Function Affects the Risk of Stroke via Atrial Fibrillation: A Mendelian Randomization Study.

CONTEXT: Observational studies suggest that variations in normal range thyroid function are associated with cardiovascular diseases. However, it remains to be determined whether these associations are causal or not. OBJECTIVE: To test whether genetically determined variation in normal range thyroid function is causally associated with the risk of stroke and coronary artery disease (CAD) and investigate via which pathways these relations may be mediated. DESIGN, SETTING, AND PARTICIPANTS: Mendelian randomization analyses for stroke and CAD using genetic instruments associated with normal range thyrotropin (TSH) and free thyroxine levels or Hashimoto's thyroiditis and Graves' disease. The potential mediating role of known stroke and CAD risk factors was examined. Publicly available summary statistics data were used. MAIN OUTCOME MEASURES: Stroke or CAD risk per genetically predicted increase in TSH or FT4 levels. RESULTS: A 1 standard deviation increase in TSH was associated with a 5% decrease in the risk of stroke (odds ratio [OR], 0.95; 95% confidence interval [CI], 0.91-0.99; P = 0.008). Multivariable MR analyses indicated that this effect is mainly mediated via atrial fibrillation. MR analyses did not show a causal association between normal range thyroid function and CAD. Secondary analyses showed a causal relationship between Hashimoto's thyroiditis and a 7% increased risk of CAD (OR, 1.07; 95% CI, 1.01-1.13; P = 0.026), which was mainly mediated via body mass index. CONCLUSION: These results provide important new insights into the causal relationships and mediating pathways between thyroid function, stroke, and CAD. We identify variation in normal range thyroid function and Hashimoto's thyroiditis as risk factors for stroke and CAD, respectively.

An Intronic HCP5 Variant Is Associated With Age of Onset and Susceptibility to Graves Disease in UK and Polish Cohorts.

CONTEXT: The genetic background of young-onset Graves disease (GD) remains largely unknown. An intronic variant in human leukocyte antigen (HLA) complex P5 (HCP5) has previously been associated with GD susceptibility and age of onset in a cohort of Polish patients. OBJECTIVE: We aimed to investigate the association of the HCP5 variant rs3094228 with GD susceptibility and age of onset in a UK cohort and conduct a meta-analysis of UK and Polish data. DESIGN AND PARTICIPANTS: rs3094228 was genotyped in 469 UK patients with GD using Taqman chemistry. Genotype frequencies were compared with genotypic data available from the Wellcome Trust case-control consortium using logistic regression analysis. To determine whether rs3094228 is independently associated with age of GD onset, the HLA DRB1*0301 tagging variant, rs535777, was also genotyped. RESULTS: The C allele of rs3094228 was overrepresented in the UK GD cohort compared with controls (P allele=5.08 × 10-9, odds ratio 1.76; [95% confidence interval, 1.46-2.13]). This association was more marked in young-onset GD (<30 years) (P allele=1.70 × 10-10 vs P allele=0.0008). The meta-analysis of UK and Polish data supported the association of the C allele with GD susceptibility (P allele=1.79 × 10-5) and age of onset (P allele=5.63 × 10-8). Haplotype analysis demonstrated that rs3094228 is associated with age of GD onset (P = 2.39 × 10-6) independent of linkage disequilibrium with HLA DRB1*0301. CONCLUSION: The rs3094228 HCP5 polymorphism is independently associated with GD susceptibility and age of onset in a UK GD cohort. Our findings indicate a potential role of long noncoding ribonucleic acids, including HCP5, in GD pathogenesis, particularly in the younger population.

Genetic Risk Factors for Autoimmune Thyroid Disease might Affect the Susceptibility to and Modulate the Progression of Primary Biliary Cholangitis.

BACKGROUND AND AIMS: Patients with primary biliary cholangitis (PBC) frequently suffer from extrahepatic autoimmune conditions, of which autoimmune thyroid disease (AITD) is one of the most common. Previous studies identified several genetic variants increasing the odds of developing AITD. Here we investigate whether AITD-associated polymorphisms might also play a role in the development and clinical course of PBC and PBC associated with AITD (PBC-AITD). METHODS: To this end, we prospectively recruited 230 patients with PBC and 421 healthy controls. Among recruited patients, 64 (30.9%) had PBC-AITD as diagnosed by elevated serum TPO-antibodies. In all subjects we genotyped 10 variants previously associated with AITD. RESULTS: We detected significant associations between the PTPN22 polymorphism and risk of developing PBC (rs2476601, OR=1.43, P=0.035) as well as PBC-AITD (OR=1.74, P=0.028). The IL2RA polymorphism was associated with liver cirrhosis (rs41295061, OR=1.76, P=0.033) whereas the MMEL1 polymorphism increased the risk of requiring liver transplantation (rs2843403, OR=1.70, P=0.023). Although no significant differences in clinical or biochemical characteristics between patients with PBC and PBC-AITD were seen (all P>0.05), liver function tests and metabolic traits in PBC patients were significantly (all P<0.05) affected by the CTLA4 (rs3087243), MMEL1 (rs2843403), PTPN22 (rs2476601) and RNASET2 (rs9355610) variants. CONCLUSION: Our study demonstrates the existence of a genetic overlap between PBC and AITD. Apparently, genetic variants known to increase the AITD risk might affect the clinical course of PBC. On the other hand, AITD per se does not seem to significantly influence the natural history of PBC.