Genetic epidemiology of thalassemia in couples of childbearing age: over 6 years of a thalassemia intervention project.

BACKGROUND: Shenzhen is one of the most populated metropolises in southern China where thalassemia is highly prevalent. The prevention of thalassemia inheritance is an ambition of child-bearing couples. METHODS AND RESULTS: A total of 22,098 peripheral blood samples were collected from 11,049 potentially at-risk couples of childbearing age from Shenzhen. Thalassemia mutations were determined by PCR-based flow-through hybridization. The results identified 45.02% of the participants (9948 out of 22,098) as harboring globin gene mutations, distributed into 18 α-thalassemia alleles detected in 71.48% (7111 out of 9948) and 15 ß-thalassemia alleles detected in 32.68% (3252 out of 9948) of all mutant individuals, among which 415 individuals carried both α- and ß-thalassemia alleles. The most frequent phenotypes for α-globin variations were --SEA/αα (63.37%), -α3.7/αα (18.66%), and -α4.2/αα (7.31%), and those for ß-globin variations were ß41-42/ßN (34.96%), ß654/ßN (28.11%), and ß17/ßN (13.84%). A total of 970 high-risk couples who could possibly give birth to offspring with thalassemia intermedia or major were identified. In addition, the hematological indices were compared among thalassemia genotypes. Significant differences in MCH, MCV, Hb A, and Hb A2 levels among α-thalassemia minor (α+), trait (α0), and intermediate phenotypes (P < 0.05) and between ßE/ßN and the other ß-thalassemia phenotypes (P < 0.05) were found. Moreover, GAP-PCR and next-generation sequencing further identified 42 rare mutations, 13 of which were first reported in the Chinese population. A novel mutation in the ß-globin gene (HBB: c.246 C > A (rs145669504)) was also discovered. CONCLUSIONS: This study presented a comprehensive analysis of thalassemia variations in a population from Shenzhen and may offer valuable insights for thalassemia control and intervention strategies in this area.

Association of sleep traits with risk of hypertensive disorders of pregnancy: a mendelian randomization study.

BACKGROUND: Unhealthy sleep patterns are common during pregnancy and have been associated with an increased risk of developing hypertensive disorders of pregnancy (HDPs) in observational studies. However, the causality underlying these associations remains uncertain. This study aimed to evaluate the potential causal association between seven sleep traits and the risk of HDPs using a two-sample Mendelian randomization study. METHODS: Genome-wide association study (GWAS) summary statistics were obtained from the FinnGen consortium, UK Biobank, and other prominent consortia, with a focus on individuals of European ancestry. The primary analysis utilized an inverse-variance-weighted MR approach supplemented by sensitivity analyses to mitigate potential biases introduced by pleiotropy. Furthermore, a two-step MR framework was employed for mediation analyses. RESULTS: The data analyzed included 200 000-500 000 individuals for each sleep trait, along with approximately 15 000 cases of HDPs. Genetically predicted excessive daytime sleepiness (EDS) exhibited a significant association with an increased risk of HDPs [odds ratio (OR) 2.96, 95% confidence interval (95% CI) 1.40-6.26], and the specific subtype of preeclampsia/eclampsia (OR 2.97, 95% CI 1.06-8.3). Similarly, genetically predicted obstructive sleep apnea (OSA) was associated with a higher risk of HDPs (OR 1.27, 95% CI 1.09-1.47). Sensitivity analysis validated the robustness of these associations. Mediation analysis showed that BMI mediated approximately 25% of the association between EDS and HDPs, while mediating up to approximately 60% of the association between OSA and the outcomes. No statistically significant associations were observed between other genetically predicted sleep traits, such as chronotype, daytime napping, sleep duration, insomnia, snoring, and the risk of HDPs. CONCLUSION: Our findings suggest a causal association between two sleep disorders, EDS and OSA, and the risk of HDPs, with BMI acting as a crucial mediator. EDS and OSA demonstrate promise as potentially preventable risk factors for HDPs, and targeting BMI may represent an alternative treatment strategy to mitigate the adverse impact of sleep disorders.

A hidden proteome encoded by circRNAs in human placentas: Implications for uncovering preeclampsia pathogenesis.

BACKGROUND: CircRNA-encoded proteins (CEPs) are emerging as new players in health and disease, and function as baits for the common partners of their cognate linear-spliced RNA encoded proteins (LEPs). However, their prevalence across human tissues and biological roles remain largely unexplored. The placenta is an ideal model for identifying CEPs due to its considerable protein diversity that is required to sustain fetal development during pregnancy. The aim of this study was to evaluate circRNA translation in the human placenta, and the potential roles of the CEPs in placental development and dysfunction. METHODS: Multiomics approaches, including RNA sequencing, ribosome profiling, and LC-MS/MS analysis, were utilised to identify novel translational events of circRNAs in human placentas. Bioinformatics methods and the protein bait hypothesis were employed to evaluate the roles of these newly discovered CEPs in placentation and associated disorders. The pathogenic role of a recently identified CEP circPRKCB119aa in preeclampsia was investigated through qRT-PCR, Western blotting, immunofluorescence imaging and phenotypic analyses. RESULTS: We found that 528 placental circRNAs bound to ribosomes with active translational elongation, and 139 were translated to proteins. The CEPs showed considerable structural homology with their cognate LEPs, but are more stable, hydrophobic and have a lower molecular-weight than the latter, all of which are conducive to their function as baits. On this basis, CEPs are deduced to be closely involved in placental function. Furthermore, we focused on a novel CEP circPRKCB119aa, and illuminated its pathogenic role in preeclampsia; it enhanced trophoblast autophagy by acting as a bait to inhibit phosphorylation of the cognate linear isoform PKCß. CONCLUSIONS: We discovered a hidden circRNA-encoded proteome in the human placenta, which offers new insights into the mechanisms underlying placental development, as well as placental disorders such as preeclampsia. Key points A hidden circRNA-encoded proteome in the human placenta was extensively identified and systematically characterised. The circRNA-encoded proteins (CEPs) are potentially related to placental development and associated disorders. A novel conserved CEP circPRKCB119aa enhanced trophoblast autophagy by inhibiting phosphorylation of its cognate linear-spliced isoform protein kinase C (PKC) ß in preeclampsia.

The association between the rs4987105 of 5-lipoxygenase (ALOX5) gene and gestational glucose metabolism in Chinese population.

OBJECTIVE: The arachidonate 5-lipoxygenase (ALOX5) pathway has been investigated in diverse chronic inflammatory diseases including metabolic disorders. Recently, the ALOX5 polymorphism rs4987105 was identified to confer susceptibility to type 2 diabetes mellitus (T2DM), implicating its role in regulating glucose homeostasis. Gestational diabetes mellitus (GDM) shares similar pathogenic mechanism with T2DM. Thus, we aimed to evaluate the association between rs4987105 and gestational glucose metabolism in Chinese pregnant women. RESULTS: A total of 380 unrelated Chinese pregnant women including 241 GDM patients and 139 controls were included in this study. The genotypes of rs4987105 were examined by the Agena MassARRAY iPLEX platform, the association between rs4987105 and fasting plasma glucose (FPG) levels at 24-28 gestational weeks was evaluated using different statistical methods. We found that carriers of rs4987105 CT/TT genotypes exhibited significantly lower FPG levels (P = 0.011). In addition, we observed a significant association between rs4987105 and FPG levels after adjusting confounding variables in the linear regression analysis using dominant genetic model (b = - 0.218; P = 0.01). The present study for the first time reported that the rs4987105 of 5-lipoxygenase (ALOX5) gene was associated with gestational glucose metabolism in Chinese pregnant women.

Comprehensive analysis of spectral distribution of a large cohort of Chinese patients with non-syndromic oculocutaneous albinism facilitates genetic diagnosis.

Non-syndromic oculocutaneous albinism (nsOCA) is a group of genetically heterogeneous autosomal recessive disorders with complete lack or decrease pigmentation in skin, hair, and eyes. TYR, OCA2, TYRP1, SLC45A2, SLC24A5, and LRMDA were reported to cause OCA1-4 and OCA6-7, respectively. By sequencing all the known nsOCA genes in 114 unrelated Chinese nsOCA patients combined with In silico analyses, splicing assay, and classification of variants according to the standards and guidelines of American College of Medical Genetics and Genomics, we detected seventy-one different OCA-causing variants separately in TYR, OCA2, SLC45A2, and SLC24A5, including thirty-one novel variants (13 in TYR, 11 in OCA2, and 7 in SLC45A2). This study shows that OCA1 is the most common (75/114) and OCA2 ranks the second most common (16/114) in Chinese. 99 patients of our cohort were caused by variants of all the known nsOCA genes. Cutaneous phenotypes of OCA1, OCA2, and OCA4 patients were shown in this study. The second OCA6 case in China was identified here. These data expand the spectrum of OCA variants as well phenotype and facilitate clinical implement of Chinese OCA patients.

PITX3 mutations associated with autosomal dominant congenital cataract in the Chinese population.

The present study aimed to identify the disease­causing gene of a four­generation Chinese family affected with congenital posterior subcapsular cataracts (CPSC), to additionally investigate the frequency of paired like homeodomain 3 (PITX3) mutations in Chinese patients with autosomal dominant congenital cataract (ADCC) and to analyze the pathogenesis of the mutations identified in the present study. Whole exome sequencing (WES) was utilized to identify the genetic cause of CPSC in the four­generation family. Sanger sequencing was performed to verify the WES results and to screen for mutations of the PITX3 gene in probands of an additional 194 Chinese ADCC families. Co­segregation analysis was performed in the family members with available DNA. Subcellular localization analyses and transactivation assays were performed for the PITX3 mutations identified. From the WES data, the c.608delC (p.A203GfsX106) mutation of PITX3 was identified in the four­generation family with CPSC. A second PITX3 mutation c.640_656del (p.A214RfsX42) was detected in two of the additional 194 ADCC families and one of these two families exhibited incomplete penetrance. Functional studies indicated that these 2 PITX3 mutant proteins retained a nuclear localization pattern, but resulted in decreased transactivation activity, similar to other previously identified PITX3 mutations. In the present study, 2 different mutations (p.A203GfsX106 and p.A214RfsX42) in PITX3 were identified as the causative defect in a four­generation family with CPSC and two ADCC families, respectively. The prevalence of PITX3 gene­associated cataract was 1.54% (3/195) in the Chinese congenital cataract (CC) family cohort. In vitro functional analyses of these 2 PITX3 mutations were performed, in order to enhance understanding of the pathogenesis of CC caused by PITX3 mutations.