The Mechanism Underlying the Regulation of LncRNA-ASLNC18810 Involved in the Abnormal Function of Vascular Endothelial Cell in Atherosclerosis: Its Function as a microRNA (miRNA) Sponge for miR-559.

Abnormal function of endothelial cells (ECs) is an important reason for vascular endothelial remodeling and atherosclerotic plaque formation in patients with atherosclerosis (AS). Here, we report for the first time that the vascular ECs with apoptosis resistance phenotype (ARECs) exist in peripheral blood of AS patients. Our research data showed that the switch of regulation modes between HIF-1α and Bax operated by lncRNA-ASLNC18810 is the direct cause for the formation of ARECs. When ASLNC18810 is low or missing, HIF-1α indirectly negatively regulates the Bax in post-transcription through HIF-1α/miR-559/Bax pathway which makes ECs acquire apoptosis resistance and form ARECs. The functional experiments results showed that ASLNC18810 could effectively eliminate the anti-apoptotic properties of ARECs by blocking the HIF-1α/miR559/Bax pathway and maintaining HIF-1α/Bax pathway. In a word, our study shows that ASLNC18810 has full potential to become a biological target for the prevention and treatment of atherosclerotic plaques by regulating ARECs. ASLNC18810 was significantly upregulated in ECs compared to ARECs. With high level of ASLNC18810 in ECs, ASLNC18810 binds to miR-559 as a miRNA sponge and suppresses the inhibition effect of miR-559 on Bax protein, this direct positive transcriptional regulation between HIF-1α and Bax endows the apoptotic property in ECs induced by Ox-LDL. However, with low expression of ASLNC18810 in ARECs, the post-transcriptional regulation of Bax by miR-559 dominates and the indirect negative regulation between HIF-1α and Bax endows the anti-apoptotic property of ARECs. To sum up, low ASLNC18810 expression-mediated switching of HIF-1α/Bax pathway to HIF-1α/miR-559/Bax pathway is the internal reason for ECs to obtain apoptosis resistance and the formation of ARECs under the ox-LDL induction.

A Weighted Genetic Risk Score Using Known Susceptibility Variants to Predict Graves Disease Risk.

CONTEXT: Graves disease (GD) is a common thyroid-specific autoimmune disease and one of the most heritable diseases in the population. We present a risk-prediction model, including confirmed, known genetic variants associated with GD. DESIGN: To construct a stable-prediction model, we used known GD susceptibility single nucleotide polymorphisms (SNPs) as markers and trained and tested our model in a cohort of 4897 patients with GD and 5098 healthy controls. We weighted the contribution of each SNP to the disease to calculate the weighted genetic risk score (wGRS) for each individual. The efficiency of this model can be estimated by the area under the curve (AUC) receiver operator characteristic curve and the specificity and sensitivity of each wGRS. RESULTS: With the 20 confirmed GD risk-related SNPs, our wGRS-prediction model could predict patients with GD from the general population (AUC 0.70 [95% CI: 0.69 to 0.71]) and did especially well in predicting patients with GD with persisting thyroid-stimulating hormone receptor antibody positive [pTRAb+; AUC 0.74 (95% CI: 0.72 to 0.76)]. We also evaluated how the four pTRAb+ specific risk SNPs predicted patients with GD with pTRAb+ among all patients with GD [AUC 0.62 (95% CI: 0.61 to 0.63)]. For clinical use, we partitioned subjects in each set into different risk categories to generate the wGRS cutoff of high risk for reference. CONCLUSIONS: Our study provides an approach to predict GD risk in the general population by the calculation of the wGRS of 20 known GD susceptibility variants. The wGRS-prediction model was more stable and convenient, whereas the prediction performance was still modest.

The genetic characteristics of congenital hypothyroidism in China by comprehensive screening of 21 candidate genes.

OBJECTIVE: Congenital hypothyroidism (CH), the most common neonatal metabolic disorder, is characterized by impaired neurodevelopment. Although several candidate genes have been associated with CH, comprehensive screening of causative genes has been limited. DESIGN AND METHODS: One hundred ten patients with primary CH were recruited in this study. All exons and exon-intron boundaries of 21 candidate genes for CH were analyzed by next-generation sequencing. And the inheritance pattern of causative genes was analyzed by the study of family pedigrees. RESULTS: Our results showed that 57 patients (51.82%) carried biallelic mutations (containing compound heterozygous mutations and homozygous mutations) in six genes (DUOX2, DUOXA2, DUOXA1, TG, TPO and TSHR) involved in thyroid hormone synthesis. Autosomal recessive inheritance of CH caused by mutations in DUOX2, DUOXA2, TG and TPO was confirmed by analysis of 22 family pedigrees. Notably, eight mutations in four genes (FOXE1, NKX2-1, PAX8 and HHEX) that lead to thyroid dysgenesis were identified in eight probands. These mutations were heterozygous in all cases and hypothyroidism was not observed in parents of these probands. CONCLUSIONS: Most cases of congenital hypothyroidism in China were caused by thyroid dyshormonogenesis rather than thyroid dysgenesis. This study identified previously reported causative genes for 57/110 Chinese patients and revealed DUOX2 was the most frequently mutated gene in these patients. Our study expanded the mutation spectrum of CH in Chinese patients, which was significantly different from Western countries.