Exploring the impact of prenatal perfluoroalkyl and polyfluoroalkyl substances exposure on blood pressure in early childhood: A longitudinal analysis.

Previous research investigating the correlation between prenatal exposure to per- and polyfluoroalkyl substances (PFAS) and subsequent blood pressure (BP) in offspring has yielded limited and contradictory findings. This study was conducted to investigate the potential relationship between maternal PFAS levels during pregnancy and subsequent BP in early childhood. A total of 129 expectant mothers from the Shanghai Birth Cohort were included in the study. Using high-performance liquid chromatography/tandem mass spectrometry, we measured ten PFAS compounds in maternal plasma throughout the pregnancy. When the children reached the age of 4, we examined their systolic BP (SBP) and diastolic BP (DBP), along with mean arterial pressure (MAP) and pulse pressure (PP). Data interpretation employed multiple linear and logistic regression models, complemented by Bayesian kernel machine regression (BKMR).We found that the majority of PFAS concentrations remained stable during pregnancy. The linear and BKMR models indicated a positive relationship between the PFAS mixture in maternal plasma and offspring's DBP and MAP, with perfluorohexanesulphonic acid (PFHxS) having the most significant influence (PFHxS and DBP [first trimester:ß=3.03, 95%CI: (1.01,5.05); second trimester: ß=2.35, 95%CI: (0.94,3.75); third trimester: ß=2.57, 95%CI:(0.80,4.34)]; MAP [first trimester:ß=2.55, 95%CI: (0.64,4.45); second trimester: ß=2.28, 95%CI: (0.95,3.61); third trimester: ß=2.35, 95%CI:(0.68,4.01)]). Logistic regression highlighted an increased risk of prehypertension and hypertension in offspring with higher maternal PFHxS concentrations during all three trimesters [first trimester: OR=2.53, 95%CI:(1.11,5.79), second trimester: OR=2.05, 95%CI:(1.11,3.78), third trimester: OR=3.08, 95%CI:(1.40,6.79)]. A positive correlation was identified between the half-lives of PFAS and the odds ratio (OR) of prehypertension and hypertension in childhood (ß=0.139, P=0.010). In conclusion, this research found maternal plasma PFAS concentrations to be positively associated with BP in offspring, with PFHxS showing the most significant influence. This correlation remained consistent throughout pregnancy, and this effect was proportional to the half-lives of PFAS.

Identification of diagnostic model in heart failure with myocardial fibrosis and conduction block by integrated gene co-expression network analysis.

BACKGROUND: Despite the advancements in heart failure(HF) research, the early diagnosis of HF continues to be a challenging issue in clinical practice. This study aims to investigate the genes related to myocardial fibrosis and conduction block, with the goal of developing a diagnostic model for early treatment of HF in patients. METHOD: The gene expression profiles of GSE57345, GSE16499, and GSE9128 were obtained from the Gene Expression Omnibus (GEO) database. After merging the expression profile data and adjusting for batch effects, differentially expressed genes (DEGs) associated with conduction block and myocardial fibrosis were identified. Gene Ontology (GO) resources, Kyoto Encyclopedia of Genes and Genomes (KEGG) resources, and gene set enrichment analysis (GSEA) were utilized for functional enrichment analysis. A protein-protein interaction network (PPI) was constructed using a string database. Potential key genes were selected based on the bioinformatics information mentioned above. SVM and LASSO were employed to identify hub genes and construct the module associated with HF. The mRNA levels of TAC mice and external datasets (GSE141910 and GSE59867) are utilized for validating the diagnostic model. Additionally, the study explores the relationship between the diagnostic model and immune cell infiltration. RESULTS: A total of 395 genes exhibiting differential expression were identified. Functional enrichment analysis revealed that these specific genes primarily participate in biological processes and pathways associated with the constituents of the extracellular matrix (ECM), immune system processes, and inflammatory responses. We identified a diagnostic model consisting of 16 hub genes, and its predictive performance was validated using external data sets and a transverse aortic coarctation (TAC) mouse model. In addition, we observed significant differences in mRNA expression of 7 genes in the TAC mouse model. Interestingly, our study also unveiled a correlation between these model genes and immune cell infiltration. CONCLUSIONS: We identified sixteen key genes associated with myocardial fibrosis and conduction block, as well as diagnostic models for heart failure. Our findings have significant implications for the intensive management of individuals with potential genetic variants associated with heart failure, especially in the context of advancing cell-targeted therapy for myocardial fibrosis.

Perfluoroalkyl substances in umbilical cord blood and blood pressure in offspring: a prospective cohort study.

BACKGROUND: Humans are widely exposed to perfluoroalkyl substances (PFAS), which have been found to be associated with various adverse birth outcomes. As blood pressure (BP) is an important parameter reflecting cardiovascular health in early life, it is necessary to investigate the association of PFAS exposure during early lifetime and BP in childhood. Therefore, we investigated the potential association between PFAS levels in umbilical cord blood and BP of the offspring at 4 years of age in a prospective cohort study. METHODS: PFAS in umbilical cord blood samples after birth were measured with high-performance liquid chromatography/tandem mass spectrometry in the Shanghai Birth Cohort. BP was measured at 4 years of age in the offspring. Multiple linear regression model was used to investigate the association between individual PFAS level and BP of the offspring. Bayesian kernel machine regression (BKMR) was used to analyze the relationship between the PFAS mixture and BP of the offspring, while weighted quantile sum (WQS) regression was utilized for sensitivity analysis. RESULTS: A total of 129 mother-child pairs were included in our analysis. In multiple linear regressions, we observed that long-chain PFAS, mainly including perfluorooctane sulfonate (PFOS), perfluorodecanoic acid (PFDA) and perfluoroundecanoic acid (PFUA), was negatively associated with systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial blood pressure (MAP). BKMR showed that an increase in umbilical cord blood PFAS mixture levels was significantly associated with a decrease in SBP, DBP and MAP [Estimated differences (SD): -0.433 (0.161); -0.437 (0.176); -0.382 (0.179), respectively]. The most important component in the association with SBP, DBP, and MAP was PFUA. PFDoA was found to be positively associated with SBP, DBP and MAP in both models. Sensitivity analysis with WQS regression showed consistent results. CONCLUSION: Our findings suggested that umbilical blood PFAS exposure was negatively associated with BP in offspring at 4 years of age, including SBP, DBP, and MAP.

Recent positive selection signatures reveal phenotypic evolution in the Han Chinese population.

Characterizing natural selection signatures and relationships with phenotype spectra is important for understanding human evolution and both biological and pathological mechanisms. Here, we identified 24 genetic loci under recent selection by analyzing rare singletons in 3946 high-depth whole-genome sequencing data of Han Chinese. The loci include immune-related gene regions (MHC cluster, IGH cluster, STING1, and PSG), alcohol metabolism-related gene regions (ADH1B, ALDH2, and ALDH3B2), and the olfactory perception gene OR4C16, in which the MHC cluster, ADH1B, and ALDH2 were also identified by TOPMed and WestLake Biobank. Among the signals, the IGH cluster is particularly interesting, in which the favored allele of variant 14_105737776_C_T (rs117518546, IgG1-G396R) promotes immune response, but also increases the risk of an autoimmune disease systemic lupus erythematosus (SLE). It is also surprising that our newly discovered ALDH3B2 evolved in the opposite direction to ALDH2 for alcohol metabolism. Besides monogenic traits, we found that multiple complex traits experienced polygenic adaptation. Particularly, multi-methods consistently revealed that lower blood pressure was favored in natural selection. Finally, we built a database named RePoS (recent positive selection, http://bigdata.ibp.ac.cn/RePoS/) to integrate and display multi-population selection signals. Our study extended our understanding of natural evolution and phenotype adaptation in Han Chinese as well as other populations.

Analysis of pathogenic variants in 605 Chinese children with non-syndromic cardiac conotruncal defects based on targeted sequencing.

OBJECTIVE: Deleterious genetic variants comprise one cause of cardiac conotruncal defects (CTDs). Genes associated with CTDs are gradually being identified. In the present study, we aimed to explore the profile of genetic variants of CTD-associated genes in Chinese patients with non-syndromic CTDs. METHODS: Thirty-nine CTD-related genes were selected after reviewing published articles in NCBI, HGMD, OMIM, and HPO. In total, 605 patients with non-syndromic CTDs and 300 healthy controls, all of Han ethnicity, were recruited. High-throughput targeted sequencing was used to detect genetic variants in the protein-coding regions of genes. We performed rigorous variant-level filtrations to identify potentially damaging variants (Dvars) using prediction programs including CADD, SIFT, PolyPhen-2, and MutationTaster. RESULT: Dvars were detected in 66.7% (26/39) of the targeted CTD-associated genes. In total, 11.07% (67/605) of patients with non-syndromic CTDs were found to carry one or more Dvars in targeted CTD-associated genes. Dvars in FOXH1, TBX2, NFATC1, FOXC2, and FOXC1 were common in the CTD cohort (1.5% [9/605], 1.2% [7/605], 1.2% [7/605], 1% [6/605], and 0.5% [3/605], respectively). CONCLUSION: Targeted exon sequencing is a cost-effective approach for the genetic diagnosis of CTDs. Our findings contribute to an understanding of the genetic architecture of non-syndromic CTDs.

Characterization of genome-wide STR variation in 6487 human genomes.

Short tandem repeats (STRs) are abundant and highly mutagenic in the human genome. Many STR loci have been associated with a range of human genetic disorders. However, most population-scale studies on STR variation in humans have focused on European ancestry cohorts or are limited by sequencing depth. Here, we depicted a comprehensive map of 366,013 polymorphic STRs (pSTRs) constructed from 6487 deeply sequenced genomes, comprising 3983 Chinese samples (~31.5x, NyuWa) and 2504 samples from the 1000 Genomes Project (~33.3x, 1KGP). We found that STR mutations were affected by motif length, chromosome context and epigenetic features. We identified 3273 and 1117 pSTRs whose repeat numbers were associated with gene expression and 3'UTR alternative polyadenylation, respectively. We also implemented population analysis, investigated population differentiated signatures, and genotyped 60 known disease-causing STRs. Overall, this study further extends the scale of STR variation in humans and propels our understanding of the semantics of STRs.

The association of gestational age and birthweight with blood pressure, cardiac structure, and function in 4 years old: a prospective birth cohort study.

BACKGROUND: Current evidence relating birthweight and gestational age to cardiovascular risk is conflicting. Whether these factors have independent or interactive impacts on cardiovascular parameters during early childhood remains unclear. The goal of this study was to explore whether there were any independent and interactive effects of gestational age and birthweight on blood pressure, left ventricle (LV) structure, and function in 4 years old. METHODS: This study included 1194 children in the Shanghai Birth Cohort from 2013 to 2016. Information about the mothers and children was recorded at time of birth using a questionnaire. Follow-up measurements, including anthropometric, blood pressure, and echocardiography, were taken between 2018 and 2021, when the children were 4 years old. Multiple linear or logistic regressions and restricted cubic spline were used to explore the association of birthweight and gestational age with cardiovascular measurements. RESULTS: Gestational age had a significant negative correlation with both systolic blood pressure [ß = - 0.41, 95% CI: (- 0.76, - 0.07)] and mean arterial pressure [ß = - 0.36, 95%CI: (- 0.66, - 0.07)]. The risk of prehypertension decreased with increased gestational age [OR = 0.54, 95% CI: (0.32, 0.93)]. The relationship between birthweight with blood pressure was U-shape (P for non-linear < 0.001). The wall thickness, volume, mass, and cardiac output of LV increased with birthweight, though the ejection fraction [ß = - 1.02, 95% CI: (- 1.76, - 0.27)] and shorten fraction [ß = 0.72, 95% CI: (- 1.31, - 0.14)] decreased with birthweight. The risk of LV hypertrophy was not associated with birthweight [OR = 1.59, 95% CI: (0.68, 3.73)]. CONCLUSIONS: In this study, we found different associations of birthweight and gestational age with cardiovascular measurements in the offspring at 4 years old. Gestational age influenced blood pressure independent of birthweight. Heart size and function at 4 years old was influenced mostly by birthweight and not by gestational age.

Association of Maternal Glucose Concentrations During Pregnancy With Cardiovascular Alterations in Early Childhood: A Prospective Birth Cohort Study.

BACKGROUND: Maternal hyperglycemia has been associated with cardiovascular disease risks in offspring. Previous studies were mostly conducted to test this association in pregnancies with (pre)gestational diabetes mellitus. However, the association may not be limited to populations with diabetes only. OBJECTIVES: The aim of this study was to assess the association between gestational glucose concentrations in women without (pre)gestational diabetes mellitus and childhood cardiovascular alterations at the age of 4 y. METHODS: Our study was based on the Shanghai Birth Cohort. Briefly, among 1016 nondiabetic mothers (age: 30.8 ± 3.42 y; BMI: 21.3 ± 2.94) and their offsprings (age: 4.41 ± 0.22 y; BMI: 15.0 ± 1.56; 53.0% males), results of maternal 1-h oral OGTT between 24 and 28 gestational weeks were obtained. Childhood blood pressure (BP) measurement, echocardiography, and vascular ultrasound were performed at 4 y old. Linear regression and binary logistic regression were conducted to test the association between maternal glucose and childhood cardiovascular outcomes. RESULTS: Compared with children from mothers with glucose concentrations in the lowest quartile, children from mothers in the highest quartile had higher BP (systolic: 97.0 ± 7.41 compared with 98.9 ± 7.82 mmHg, P = 0.006; diastolic: 56.8 ± 5.83 compared with 57.9 ± 6.03 mmHg, P = 0.051) and lower left ventricular ejection fraction (92.5 ± 9.15 compared with 90.8 ± 9.16 %, P = 0.046). Also, higher maternal OGTT 1-h glucose concentrations across the full range were associated with higher childhood BP (systolic: ß: 0.56; 95% CI: 0.19, 0.93; diastolic: ß: 0.36; 95% CI: 0.05, 0.66). Logistic regression showed, compared with children from mothers in the lowest quartile, children from mothers in the highest quartile had a 58% (OR=1.58; 95% CI: 1.01, 2.47) higher odds of elevated systolic BP (≥90th percentile). CONCLUSIONS: In a population without (pre)gestational diabetes mellitus, higher maternal OGTT 1-h glucose were associated with childhood cardiovascular structure and function alterations. Further studies are needed to assess whether interventions to reduce gestational glucose will mitigate subsequent cardiometabolic risks in offspring.

Maternal plasma perfluoroalkyl substances concentrations in early pregnancy and cardiovascular development in offspring: A prospective cohort study.

BACKGROUND: High maternal plasma perfluoroalkyl substances (PFAS) concentrations has been associated with adverse birth outcomes, but data on early childhood cardiovascular health is limited. This study aimed to assess the potential association between maternal plasma PFAS concentrations during early pregnancy and cardiovascular development in offspring. MATERIAL AND METHODS: Cardiovascular development was assessed through blood pressure measurement, echocardiography and carotid ultrasound examinations among 957 children from the Shanghai Birth Cohort aged at 4 years old. Maternal plasma concentrations of PFAS were measured at mean gestational age of 14.4 (SD:1.8) weeks. The joint associations between PFAS mixture concentrations and cardiovascular parameters were analyzed using a Bayesian kernel machine regression (BKMR). The potential association of individual PFAS chemicals concentrations was explored using multiple linear regression. RESULTS: In BKMR analyses, carotid intima media thickness (cIMT), interventricular septum thickness in diastole and systole, posterior wall thicknesses in diastole and systole, and relative wall thickness were significantly lower when all log10-transformed PFAS were fixed at 75th percentile in comparison to at their 50th percentile[Estimated overall Risk:-0.31 (95%CI: -0.42, -0.20), -0.09 (95%CI: -0.11, -0.07), -0.21 (95%CI: -0.26, -0.16), -0.09 (95%CI: -0.11, -0.07), -0.07 (95%CI: -0.10, -0.04) and -0.005 (95%CI: -0.006, -0.004)].Furthermore, maternal plasma concentrations of individual short-chain PFAS was associated with a decrease in left ventricular wall thickness, intraventricular septum thickness and enlarged chamber volume, and long-chain with a decrease in cIMT. CONCLUSIONS: Our findings suggest that maternal plasma PFAS concentrations during early pregnancy was adversely associated with cardiovascular development in offspring, including thinner cardiac wall thickness and cIMT.

De novo disruptive heterozygous MMP21 variants are potential predisposing genetic risk factors in Chinese Han heterotaxy children.

BACKGROUND: Heterotaxy syndrome (HTX) is caused by aberrant left-right patterning early in embryonic development, which results in abnormal positioning and morphology of the thoracic and abdominal organs. Currently, genetic testing discerns the underlying genetic cause in less than 20% of sporadic HTX cases, indicating that genetic pathogenesis remains poorly understood. In this study, we aim to garner a deeper understanding of the genetic factors of this disease by documenting the effect of different matrix metalloproteinase 21 (MMP21) variants on disease occurrence and pathogenesis. METHODS: Eighty-one HTX patients with complex congenital heart defects and 89 healthy children were enrolled, and we investigated the pathogenetic variants related to patients with HTX by exome sequencing. Zebrafish splice-blocking Morpholino oligo-mediated transient suppression assays were performed to confirm the potential pathogenicity of missense variants found in these patients with HTX. RESULTS: Three MMP21 heterozygous non-synonymous variants (c.731G > A (p.G244E), c.829C > T (p.L277F), and c.1459A > G (p.K487E)) were identified in three unrelated Chinese Han patients with HTX and complex congenital heart defects. Sanger sequencing confirmed that all variants were de novo. Cell transfection assay showed that none of the variants affect mRNA and protein expression levels of MMP21. Knockdown expression of mmp21 by splice-blocking Morpholino oligo in zebrafish embryos revealed a heart looping disorder, and mutant human MMP21 mRNA (c.731G > A, c.1459A > G, heterozygous mRNA (wild-type&c.731G > A), as well as heterozygous mRNA (wild-type& c.1459A > G) could not effectively rescue the heart looping defects. A patient with the MMP21 p.G244E variant was identified with other potential HTX-causing missense mutations, whereas the patient with the MMP21 p.K487E variant had no genetic mutations in other causative genes related to HTX. CONCLUSION: Our study highlights the role of the disruptive heterozygous MMP21 variant (p.K487E) in the etiology of HTX with complex cardiac malformations and expands the current mutation spectrum of MMP21 in HTX.

Different Associations of Systolic Blood Pressure and Body Mass Index With Cardiac Structure and Function in Young Children.

BACKGROUND: Both elevated systolic blood pressure (SBP) and excess weight can lead to early cardiovascular organ damage in children. In this study, we investigated whether there is a difference in the associations of SBP and body mass index (BMI) with cardiovascular structure and function in 4-year-old children. METHODS: In 1474 children (52.3% males) from the Shanghai Birth Cohort, physical examination and echocardiography were performed. Standardized linear regression models were used to evaluate the associations of BMI Z score and SBP Z score with cardiovascular parameters and to compare the strengths of these associations. RESULTS: The incidence of SBP elevation significantly increased in overweight children. SBP was positively related to heart rate, left ventricular (LV) ejection fraction and fraction shortening (ß=1.824 [95% CI, 1.014-2.634], 0.579 [0.294-0.864], and 0.480 [0.257-0.704], respectively). BMI Z score was positively associated with LV mass index (ß=1.225 [0.863-1.587]) and the risk of LV hypertrophy (odds ratio=1.428 [1.157-1.761]) but negatively related to measures of systolic function, including LV ejection fraction, LV fraction short, and global longitudinal strain (ß=-0.417 [-0.735 to -0.099], -0.302 [-0.551 to -0.053], and -0.392 [-0.621 to -0.163], respectively). No noteworthy additive or multiplicative interactions between BMI and SBP were detected. CONCLUSIONS: Elevations in both BMI and SBP were related to cardiac structure and function in children as young as 4 years old. Elevated SBP was associated with increased heart rate and LV ejection at the early stage of BP elevation. BMI showed a closer relationship with left heart diameters and geometry than SBP.

Associations of maternal gestational diabetes mellitus with alterations in cardiovascular system in early childhood.

AIMS: The association of maternal gestational diabetes mellitus (GDM) with childhood cardiovascular alterations is not well established. This study aims to test the hypothesis that prenatal exposure to GDM is associated with vascular and cardiac alterations in early childhood. METHODS: In a population-based prospective cohort among 1094 mothers and their offspring, GDM was diagnosed according to the International Association of Diabetes and Pregnancy Study Groups criteria. Childhood blood pressure (BP) measurement, echocardiography and vascular ultrasound were performed using standardised methods at 4 years old. The associations between maternal GDM and childhood cardiovascular outcomes were modelled using linear regression and binary logistic regression. Mediation analysis was conducted to test the potential mediators. RESULTS: Maternal GDM was associated with higher systolic BP (SBP; ß, 1.20; [0.11, 2.28]), lower left ventricular end-diastolic diameter (LVEDD; ß, -0.36; [-0.71, -0.01]), lower end-diastolic volume (EDV; ß, -1.42; [-2.71, -0.13]) and increased risk of high blood pressure (HBP, OR = 1.522; 95% CI, 1.023 to 2.264) in offspring at the age of 4 years. After stratification by sex, the association remained strong only in male offspring (SBP: ß, 1.94; [0.37, 3.51]; LVEDD: ß, -0.60; [-1.09, -0.12]; EDV: ß, -2.09; [-3.86, -0.31]; HBP: OR = 1.797; 95% CI, 1.063 to 3.037) and was independent of maternal and child characteristics. However, carotid intima-media thickness (cIMT) was not associated with maternal GDM. Mediation analysis showed that the effects on childhood cardiovascular alterations were attributable mostly to the direct effects of maternal GDM. CONCLUSIONS: Our results provide evidence that maternal GDM is associated with offspring cardiovascular adaptations at preschool age. Further studies are needed to replicate our results and the long-term effect of these adaptations on later cardiovascular risks needs further investigation.

Characterizing mobile element insertions in 5675 genomes.

Mobile element insertions (MEIs) are a major class of structural variants (SVs) and have been linked to many human genetic disorders, including hemophilia, neurofibromatosis, and various cancers. However, human MEI resources from large-scale genome sequencing are still lacking compared to those for SNPs and SVs. Here, we report a comprehensive map of 36 699 non-reference MEIs constructed from 5675 genomes, comprising 2998 Chinese samples (∼26.2×, NyuWa) and 2677 samples from the 1000 Genomes Project (∼7.4×, 1KGP). We discovered that LINE-1 insertions were highly enriched in centromere regions, implying the role of chromosome context in retroelement insertion. After functional annotation, we estimated that MEIs are responsible for about 9.3% of all protein-truncating events per genome. Finally, we built a companion database named HMEID for public use. This resource represents the latest and largest genomewide study on MEIs and will have broad utility for exploration of human MEI findings.

Sex-Disparity in the Association Between Birthweight and Cardiovascular Parameters in 4-Year-Old Children: A Chinese Cohort Study.

Background: Sex-related differences in cardiovascular parameters have been well documented in adults, and the impact of birthweight on cardiovascular health in later life has been acknowledged. However, data was limited regarding the association between birthweight and cardiovascular outcomes at an early age, and the sex-disparity in the association remained unclear. Objective: To investigate the association between birthweight and cardiovascular parameters in 4-year-old children. Furthermore, to explore whether sex-disparity exist in this association or in cardiovascular risk. Methods: Follow-up data from the Shanghai Birth Cohort (SBC) was analyzed. Detailed perinatal information including both maternal and offspring datum were recorded. Blood pressure, echocardiography, and anthropometry assessment were conducted during the follow-up of 4-year-old children. Linear regression models were used to analyze the association between birthweight and left ventricle (LV) structure and function changes in each sex and birthweight category. Multivariable logistic regression models were used to compare risk of left ventricular hypertrophy (LVH) in different birthweight subgroups. Results: Overall, macrosomia was significantly associated with thickened LV posterior wall thickness in systole [LVPWs, (ß = 0.26, 95% CI: 0.06, 0.45)] and diastole [LVPWd, (ß = 0.18, 95% CI: 0.06, 0.30)], and thickened interventricular septal thickness in diastole [IVSd, (ß = 0.16, 95% CI: 0.05, 0.28)]. Boys with macrosomia showed a higher left ventricle mass index [LVMI, (ß = 1.29, 95% CI: 0.14, 2.43)], thickened LVPWs (ß = 0.30, 95% CI: 0.05, 0.56) and LVPWd (ß = 0.21, 95% CI: 0.06, 0.36), and thickened IVSd (ß = 0.23, 95% CI: 0.09, 0.36). However, no significant association of structural changes was found in girls. Furthermore, an increased risk of LVH was found solely in macrosomic boys (OR = 2.79, 95% CI: 1.17, 6.63). Conclusion: Children with macrosomia developed cardiovascular changes as early as 4 years of age. Macrosomia was associated with LV structural changes and higher LVH risk in pre-school-aged boys, while no association was found in girls.

NyuWa Genome resource: A deep whole-genome sequencing-based variation profile and reference panel for the Chinese population.

The lack of haplotype reference panels and whole-genome sequencing resources specific to the Chinese population has greatly hindered genetic studies in the world's largest population. Here, we present the NyuWa genome resource, based on deep (26.2×) sequencing of 2,999 Chinese individuals, and construct a NyuWa reference panel of 5,804 haplotypes and 19.3 million variants, which is a high-quality publicly available Chinese population-specific reference panel with thousands of samples. Compared with other panels, the NyuWa reference panel reduces the Han Chinese imputation error rate by a margin ranging from 30% to 51%. Population structure and imputation simulation tests support the applicability of one integrated reference panel for northern and southern Chinese. In addition, a total of 22,504 loss-of-function variants in coding and noncoding genes are identified, including 11,493 novel variants. These results highlight the value of the NyuWa genome resource in facilitating genetic research in Chinese and Asian populations.

Growth patterns in early childhood and cardiovascular structure and function at 4 years old: A prospective cohort study.

BACKGROUND AND AIMS: Childhood overweight and obesity are lifetime risk factors for cardiovascular disease but the relationship between dynamic body mass index (BMI) change and cardiovascular structure and function in early childhood remains unclear. METHODS AND RESULTS: This cohort study consisted 525 participants with 6 distinct representative growth patterns to examine the associations between BMI growth patterns and subsequent cardiovascular structure and function at age 4. BMIs were obtained at birth, 2 and 4 years old. Cardiovascular assessments were performed, including blood pressure (BP), cardiac geometric parameters, left ventricular (LV) function, speckle-tracking, integrated backscatter analysis and carotid intima-media thickness. Compared to the stable normal BMI pattern, children with the stable overweight (OW) pattern had significantly greater LV anatomic parameters in fully adjusted models. Children with the catch-up (CU) pattern revealed a uniform trend and had poorer strain. LV diameters and integrated backscatter signals were larger for those with BMI gain and lose pattern. Children with BMI lose pattern showed improved tendency involving LV mass index and BP. Both OW and CU patterns were associated with high systolic BP [odds ratio (95% CI): OW: 3.67 (1.08, 12.47); CU: 4.24 (1.75, 10.28)]. Compared to static BMI measurements at birth, 2 and 4 years old, dynamic BMI growth patterns were more predictive of cardiovascular structure and function at 4. CONCLUSIONS: Children with overweight-related BMI growth patterns in early childhood experienced undesirable cardiovascular functional or structural changes as early as 4 years old, indicating that early intervention is needed and potentially beneficial.

The draft genome of the specialist flea beetle Altica viridicyanea (Coleoptera: Chrysomelidae).

BACKGROUND: Altica (Coleoptera: Chrysomelidae) is a highly diverse and taxonomically challenging flea beetle genus that has been used to address questions related to host plant specialization, reproductive isolation, and ecological speciation. To further evolutionary studies in this interesting group, here we present a draft genome of a representative specialist, Altica viridicyanea, the first Alticinae genome reported thus far. RESULTS: The genome is 864.8 Mb and consists of 4490 scaffolds with a N50 size of 557 kb, which covered 98.6% complete and 0.4% partial insect Benchmarking Universal Single-Copy Orthologs. Repetitive sequences accounted for 62.9% of the assembly, and a total of 17,730 protein-coding gene models and 2462 non-coding RNA models were predicted. To provide insight into host plant specialization of this monophagous species, we examined the key gene families involved in chemosensation, detoxification of plant secondary chemistry, and plant cell wall-degradation. CONCLUSIONS: The genome assembled in this work provides an important resource for further studies on host plant adaptation and functionally affiliated genes. Moreover, this work also opens the way for comparative genomics studies among closely related Altica species, which may provide insight into the molecular evolutionary processes that occur during ecological speciation.

LncRNA HRCEG, regulated by HDAC1, inhibits cells proliferation and epithelial-mesenchymal-transition in gastric cancer.

Recently, a number of long noncoding RNAs (lncRNAs) have been reported to play significant roles in human tumorigenesis. However, only few gastric cancer related lncRNAs have been well characterized. Here, we identified one lncRNA HRCEG, whose expression was decreased in the gastric cancer tissues compared with adjacent normal tissues. Overexpression of HRCEG significantly promoted cell apoptosis and inhibited cell proliferation. Importantly, we demonstrated that HRCEG levels inversely correlated with EMT process and HRCEG was regulated by the histone deacetylase 1 (HDAC1) in gastric cancer. These findings suggest that HRCEG might be regulated by HDAC1 to inhibit gastric cancer progress and metastatic capability via EMT pathway.

Dynamic-BM: multispecies Dynamic BodyMap database from temporal RNA-seq data.

Biological processes, especially developmental processes, are often dynamic. Previous BodyMap projects for human and mouse have provided researchers with portals to tissue-specific gene expression, but these efforts have not included dynamic gene expression patterns. Over the past few years, substantial progress in our understanding of the molecular mechanisms of protein-coding and long noncoding RNA (lncRNA) genes in development processes has been achieved through numerous time series RNA sequencing (RNA-seq) studies. However, none of the existing databases focuses on these time series data, thus rendering the exploration of dynamic gene expression patterns inconvenient. Here, we present Dynamic BodyMap (Dynamic-BM), a database for temporal gene expression profiles, obtained from 2203 time series of RNA-seq samples, covering >25 tissues from five species. Dynamic-BM has a user-friendly Web interface designed for browsing and searching the dynamic expression pattern of genes from different sources. It is an open resource for efficient data exploration, providing dynamic expression profiles of both protein-coding genes and lncRNAs to facilitate the generation of new hypotheses in developmental biology research. Additionally, Dynamic-BM includes a literature-based knowledgebase for lncRNAs associated with tissue development and a list of manually selected lncRNA candidates that may be involved in tissue development. Dynamic-BM is available at http://bioinfo.ibp.ac.cn/Dynamic-BM.

NONCODEV5: a comprehensive annotation database for long non-coding RNAs.

NONCODE (http://www.bioinfo.org/noncode/) is a systematic database that is dedicated to presenting the most complete collection and annotation of non-coding RNAs (ncRNAs), especially long non-coding RNAs (lncRNAs). Since NONCODE 2016 was released two years ago, the amount of novel identified ncRNAs has been enlarged by the reduced cost of next-generation sequencing, which has produced an explosion of newly identified data. The third-generation sequencing revolution has also offered longer and more accurate annotations. Moreover, accumulating evidence confirmed by biological experiments has provided more comprehensive knowledge of lncRNA functions. The ncRNA data set was expanded by collecting newly identified ncRNAs from literature published over the past two years and integration of the latest versions of RefSeq and Ensembl. Additionally, pig was included in the database for the first time, bringing the total number of species to 17. The number of lncRNAs in NONCODEv5 increased from 527 336 to 548 640. NONCODEv5 also introduced three important new features: (i) human lncRNA-disease relationships and single nucleotide polymorphism-lncRNA-disease relationships were constructed; (ii) human exosome lncRNA expression profiles were displayed; (iii) the RNA secondary structures of NONCODE human transcripts were predicted. NONCODEv5 is also accessible through http://www.noncode.org/.