Identification of Novel Genetic Loci Associated with Thyroid Peroxidase Antibodies and Clinical Thyroid Disease

Peer reviewe

<b><i>RAP1GAP</i></b> Functions as a Tumor Suppressor Gene and Is Regulated by DNA Methylation in Differentiated Thyroid Cancer

Inactivation of tumor suppressor genes, such as &lt;i&gt;RAP1GAP&lt;/i&gt;, by hypermethylation of their regulatory region can give rise to thyroid tumors. The aim of this study was to investigate the expression of the &lt;i&gt;RAP1GAP&lt;/i&gt; gene and the DNA methylation patterns of its CpG74&lt;sub&gt;a&lt;/sub&gt;, CpG74&lt;sub&gt;b&lt;/sub&gt;, and CpG24 in an Iranian population with differentiated thyroid cancer (DTC). In this study, 160 individuals who underwent thyroidectomy in the Tehran Erfan Hospital between 2018 and 2020 were selected. DNA methylation patterns of selected CpG islands (CpG74&lt;sub&gt;a&lt;/sub&gt;, CpG74&lt;sub&gt;b&lt;/sub&gt;, and CpG24) were determined using methylation-specific PCR. The mRNA expression and protein level of ­RAP1GAP were also evaluated. SW1736 and B-CPAP cells were treated with 5-aza-2′-deoxycytidine (5-Aza) to demethylate these regions. The hypermethylation rates of CpG74&lt;sub&gt;a&lt;/sub&gt; and CpG24 in DTC samples were significantly higher than in the control. The mRNA expression and protein level of ­RAP1GAP were significantly decreased in the DTC group. In the DTC group, hypermethylation in CpG74&lt;sub&gt;a&lt;/sub&gt; was correlated with decreasing &lt;i&gt;RAP1GAP&lt;/i&gt; expression (&lt;i&gt;R&lt;/i&gt;&lt;sup&gt;2&lt;/sup&gt;: 0.34; &lt;i&gt;p&lt;/i&gt; = 0.043). CpG74&lt;sub&gt;a&lt;/sub&gt; with a specificity of 86.4% has significant prediction power to distinguish between DTC and normal thyroid tissues. Additionally, hypermethylation of CpG74&lt;sub&gt;a&lt;/sub&gt; was significantly associated with higher tumor stages (stage III-IV: 77%; stage I-II: 23%; &lt;i&gt;p&lt;/i&gt; = 0.012). Increasing expression of &lt;i&gt;RAP1GAP&lt;/i&gt; after demethylation with 15 µM of 5-Aza was observed in both cell lines. These results indicate that DNA hypermethylation in CpG74&lt;sub&gt;a&lt;/sub&gt; can be considered as an epigenetic biomarker in DTC. </jats:p

Pulmonary function and CT biomarkers as risk factors for cardiovascular events in male lung cancer screening participants: the NELSON study

Objective The objective of this study was to investigate the association of spirometry and pulmonary CT biomarkers with cardiovascular events. Methods In this lung cancer screening trial 3,080 male participants without a prior cardiovascular event were analysed. Fatal and non-fatal cardiovascular events were included. Spirometry included forced expiratory volume measured in units of one-second percent predicted (FEV1% predicted) and FEV1 divided by forced vital capacity (FVC; FEV1/FVC). CT examinations were quantified for coronary artery calcium volume, pulmonary emphysema (perc15) and bronchial wall thickness (pi10). Data were analysed via a Cox proportional hazard analysis, net reclassification improvement (NRI) and C-indices. Results 184 participants experienced a cardiovascular event during a median follow-up of 2.9 years. Age, pack-years and smoking status adjusted hazard ratios were 0.992 (95 % confidence interval (CI) 0.985-0.999) for FEV1% predicted, 1.000 (95% CI 0.986-1.015) for FEV1/FVC, 1.014 (95% CI 1.005-1.023) for perc15 per 10 HU, and 1.269 (95% CI 1.024-1.573) for pi10 per 1 mm. The incremental C-index (<0.015) and NRI (<2.8 %) were minimal. Coronary artery calcium volume had a hazard ratio of 1.046 (95% CI 1.034-1.058) per 100 mm(3), an increase in C-index of 0.076 and an NRI of 16.9 % (P< 0.0001). Conclusions Pulmonary CT biomarkers and spirometry measurements were significantly associated with cardiovascular events, but did not contain clinically relevant independent prognostic information for cardiovascular events