Assessment of circulating proteins in thyroid cancer: Proteome-wide Mendelian randomization and colocalization analysis.

The causality between circulating proteins and thyroid cancer (TC) remains unclear. We employed five large-scale circulating proteomic genome-wide association studies (GWASs) with up to 100,000 participants and a TC meta-GWAS (nCase = 3,418, nControl = 292,703) to conduct proteome-wide Mendelian randomization (MR) and Bayesian colocalization analysis. Protein and gene expressions were validated in thyroid tissue. Through MR analysis, we identified 26 circulating proteins with a putative causal relationship with TCs, among which NANS protein passed multiple corrections (P BH = 3.28e-5, 0.05/1,525). These proteins were involved in amino acids and organic acid synthesis pathways. Colocalization analysis further identified six proteins associated with TCs (VCAM1, LGMN, NPTX1, PLEKHA7, TNFAIP3, and BMP1). Tissue validation confirmed BMP1, LGMN, and PLEKHA7's differential expression between normal and TC tissues. We found limited evidence for linking circulating proteins and the risk of TCs. Our study highlighted the contribution of proteins, particularly those involved in amino acid metabolism, to TCs.

Association Between Genetic Risk, Adherence to Healthy Lifestyle Behavior, and Thyroid Cancer Risk.

Importance: Genetic and lifestyle factors are related to thyroid cancer (TC). Whether a healthy lifestyle is associated with TC and could attenuate the influence of genetic variants in TC remains equivocal. Objectives: To examine the associations between genetics and healthy lifestyle with incident TC and whether adherence to a healthy lifestyle modifies the association between genetic variants and TC. Design, Setting, and Participants: A prospective cohort study using UK Biobank data recruited 502 505 participants aged 40 to 69 years between March 13, 2006, and October 1, 2010. A total of 307 803 participants of European descent were recruited at baseline, and 264 956 participants were available for the present study. Data analysis was conducted from November 1, 2021, to April 22, 2022. Exposures: Lifestyle behaviors were determined by diet index, physical activity, weight, smoking, and alcohol consumption. Lifestyle was categorized as unfavorable (scores 0-1), intermediate (score 2), and favorable (scores 3-5). The polygenic risk score (PRS) was derived from a meta-genome-wide association study using 3 cohorts and categorized as low, intermediate, and high. Main Outcomes and Measures: Thyroid cancer was defined using the International Classification of Diseases, Ninth Revision (code 193), International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (code C73), and self-report (code 1065). Results: Of 264 956 participants, 137 665 were women (52%). The median age was 57 (IQR, 49-62) years. During a median follow-up of 11.1 (IQR, 10.33-11.75) years (2 885 046 person-years), 423 incident TCs were ascertained (14.66 per 100 000 person-years). Higher PRSs were associated with TC (hazard ratio [HR], 2.25; 95% CI, 1.91-2.64; P = 8.65 × 10-23). An unfavorable lifestyle was also associated with a higher risk of TC (HR, 1.93; 95% CI, 1.50-2.49; P < .001). When stratified by PRS, unfavorable lifestyle was associated with TC in the higher PRS group (favorable vs unfavorable HR, 0.52; 95% CI, 0.37-0.73; P < .001). Furthermore, participants with both a high PRS and unfavorable lifestyle had the highest risk of TC (HR, 4.89; 95% CI, 3.03-7.91; P < .001). Conclusions and Relevance: In this prospective cohort study, genetic and lifestyle factors were independently associated with incident TC, which suggests that a healthier lifestyle may attenuate the deleterious influence of genetics on the risk of TC in individuals of European descent.

Appraising the Effect of Potential Risk Factors on Thyroid Cancer: A Mendelian Randomization Study.

CONTEXT: Various risk factors have been associated with the risk of thyroid cancer in observational studies. However, the causality of the risk factors is not clear given the susceptibility of confounding and reverse causation. OBJECTIVE: A 2-sample Mendelian randomization approach was used to estimate the effect of potential risk factors on thyroid cancer risk. METHODS: Genetic instruments to proxy 55 risk factors were identified by genome-wide association studies (GWAS). Associations of these genetic variants with thyroid cancer risk were estimated in GWAS of the FinnGen Study (989 cases and 217 803 controls). A Bonferroni-corrected threshold of P = 9.09 × 10-4 was considered significant, and P < 0.05 was considered to be suggestive of an association. RESULTS: Telomere length was significantly associated with increased thyroid cancer risk after correction for multiple testing (OR 4.68; 95% CI, 2.35-9.31; P = 1.12 × 10-5). Suggestive associations with increased risk were noted for waist-to-hip ratio (OR 1.85; 95% CI, 1.02-3.35; P = 0.042) and diastolic blood pressure (OR 1.60; 95% CI, 1.08-2.38; P = 0.019). Suggestive associations were noted between hemoglobin A1c (HbA1c) (OR 0.20; 95% CI, 0.05-0.82; P = 0.025) and decreased risk of thyroid cancer. Risk of thyroid cancer was not associated with sex hormones and reproduction, developmental and growth, lipids, diet and lifestyle, or inflammatory factors (All P > 0.05). CONCLUSION: Our study identified several potential targets for primary prevention of thyroid cancer, including central obesity, diastolic blood pressure, HbA1c, and telomere length, which should inform public health policy.

Causal relationships between blood calcium, iron, magnesium, zinc, selenium, phosphorus, copper, and lead levels and multisystem disease outcomes in over 400,000 Caucasian participants.

BACKGROUND & AIMS: Metal elements have been associated with a wide range of clinical outcomes. The available epidemiological evidence for these associations is often inconsistent and suffers from confounding and reverse causation. We aimed to explore the broad clinical effects of varying blood metal element levels and possible underlying mechanisms. METHODS: We performed a two-sample Mendelian randomization (MR) analysis by using metal element-associated genetic loci as instrumental variable to evaluate the causal associations between blood metal element levels and 1050 disease outcomes in a UK Biobank cohort. A total of 408,910 White British participants were enrolled in the analysis. We further used the metal element-related genes and disease-related genes to construct a protein-protein interaction (PPI) network. RESULTS: Eight metal elements were associated with 63 diseases in total. Notably, we found nine pairs of suggestive evidence between two different metal elements for the same disease. Selenium and lead share some of the associated clinical outcomes, including diabetes mellitus, type 2 diabetes, lymphoid leukemia, and acute pharyngitis. Lead and zinc share the associated disease of acquired hypothyroidism. Iron and copper share the associated disease of arthropathies. Copper and zinc share the associated disease of occlusion of cerebral arteries. Calcium and zinc share the associated disease of arthropathies. In addition, the PPI network provided potential links between metal elements and disease outcomes at the genetic level. CONCLUSIONS: Our MR study of eight metal elements comprehensively characterized their shared and unique clinical effects, highlighting their potential causal roles in multiple diseases. Given the modifiable nature of blood metal elements and the potential for clinical interventions, these findings warrant further investigation.

Causal Effect of Genetically Determined Blood Copper Concentrations on Multiple Diseases: A Mendelian Randomization and Phenome-Wide Association Study.

Exposures to copper have become a health concern. We aim to explore the broad clinical effects of blood copper concentrations. A total of 376,346 Caucasian subjects were enrolled. We performed a Mendelian randomization and phenome-wide association study (MR-PheWAS) to evaluate the causal association between copper and a wide range of outcomes in UK Biobank, and we constructed a protein-protein interaction network. We found association between blood copper concentrations and five diseases in the overall population and nine diseases in male. MR analysis implicated a causal role of blood copper in five diseases (overall population), including prostate cancer (OR = 0.87, 95% CI 0.77-0.98), malignant and unknown neoplasms of the brain and nervous system (OR = 0.58, 95% CI 0.38-0.89), and hypertension (OR = 0.94, 95% CI 0.90-0.98), essential hypertension (OR = 0.94, 95% CI 0.90-0.98) and cancer of brain and nervous system (OR = 0.63, 95% CI 0.41-0.98). For male, except for dysphagia being newly associated with blood copper (OR = 1.39, 95% CI 1.18-1.63), other MR results were consistent with the overall population. In addition, the PPI network showed possible relationship between blood copper and four outcomes, namely brain cancer, prostate cancer, hypertension, and dysphagia. Blood copper may have causal association with prostate cancer, malignant and unknown neoplasms of the brain and nervous system, hypertension, and dysphagia. Considering that copper is modifiable, exploring whether regulation of copper levels can be used to optimize health outcomes might have public health importance. Supplementary Information: The online version contains supplementary material available at 10.1007/s43657-022-00052-3.