Novel genetic variants linked to prelabor rupture of membranes among Chinese pregnant women.

INTRODUCTION: The etiology of prelabor rupture of membranes (PROM), either preterm or term PROM (PPROM or TPROM), remains largely unknown. This study aimed to investigate the association between maternal genetic variants (GVs) and PROM and further establish a GV-based prediction model for PROM. METHODS: In this case-cohort study (n = 1166), Chinese pregnant women with PPROM (n = 51), TPROM (n = 283) and controls (n = 832) were enrolled. A weighted Cox model was applied to identify the GVs (single nucleotide polymorphisms [SNPs], insertions/deletions, and copy number variants) associated with either PPROM or TPROM. Gene set enrichment analysis (GSEA) was to explore the mechanisms. The suggestively significant GVs were applied to establish a random forest (RF) model. RESULTS: PTPRT variants (rs117950601, P = 4.37 × 10-9; rs147178603, P = 8.98 × 10-9) and SNRNP40 variant (rs117573344, P = 2.13 × 10-8) were associated with PPROM. STXBP5L variant (rs10511405, P = 4.66 × 10-8) was associated with TPROM. GSEA results showed that genes associated with PPROM were enriched in cell adhesion, and TPROM in ascorbate and glucuronidation metabolism. The area under the receiver operating characteristic curve of SNP-based RF model for PPROM was 0.961, with a sensitivity of 100.0% and specificity of 83.3%. DISCUSSION: Maternal GVs in PTPRT and SNRNP40 were associated with PPROM, and GV in STXBP5L was associated with TPROM. Cell adhesion participated in PPROM, while ascorbate and glucuronidation metabolism contributed in TPROM. The PPROM might be well predicted using the SNP-based RF model.

Preterm Prelabor Rupture of Membranes Linked to Vaginal Bacteriome of Pregnant Females in the Early Second Trimester: a Case-Cohort Design.

Preterm prelabor rupture of membranes (PPROM) is a major cause of spontaneous preterm birth (sPTB), one of the greatest challenges facing obstetrics with complicated pathogenesis. This case-cohort study investigated the association between vaginal bacteriome of singleton pregnant females in the early second trimester and PPROM. The study included 35,255 and 180 pregnant females with PPROM as cases and term-birth without prelabor rupture of membranes (TWPROM) and term prelabor rupture of membranes (TPROM) pregnant females as controls, respectively. Using 16S rRNA sequencing, the vaginal microbiome traits were analyzed. Females with PPROM had higher alpha and beta diversity (P < 0.05) than TWPROM and TPROM. The presence of L. mulieris was associated with a decreased risk of PPROM (adjusted odds ratio [aOR] = 0.35; 95% confidence interval [CI]: 0.17-0.72) compared with TWPROM. Meanwhile, the presence of Megasphaera genus (aOR = 2.27; 95% CI: 1.09-4.70), Faecalibacterium genus (aOR = 3.29; 95% CI: 1.52-7.13), Bifidobacterium genus (aOR = 3.26; 95% CI: 1.47-7.24), Xanthomonadales genus (aOR = 2.76; 95% CI: 1.27-6.01), Gammaproteobacteria class (aOR = 2.36; 95% CI: 1.09-5.14), and Alphaproteobacteria class (aOR = 2.45; 95% CI: 1.14-5.26) was associated with an increased risk of PPROM compared with TWPROM. Our results indicated that the risk of PPROM can decrease with vaginal L. mulieris but increase with high alpha or beta diversity, and several vaginal bacteria in pregnant females may be involved in the occurrence of PPROM.

Differential Effect of Vaginal Microbiota on Spontaneous Preterm Birth among Chinese Pregnant Women.

Objective: The effect of vaginal microbiota on spontaneous preterm birth (sPTB) has not been fully addressed, and few studies have explored the associations between vaginal taxa and sPTB in the gestational diabetes mellitus (GDM) and non-GDM groups, respectively. Study Design. To minimize external interference, a total of 41 pregnant women with sPTB and 308 controls (pregnant women without sPTB) from same regain were enrolled in this case-cohort study. Controls were randomly selected at baseline. With the exception of GDM, other characteristics were not significantly different between the two groups. Vaginal swabs were collected at early second trimester. Using 16S amplicon sequencing, the main bioinformatics analysis was performed on the platform of QIIME 2. Vaginal microbiota traits of the sPTB group were compared with controls. Finally, the effects of binary taxa on sPTB in the GDM group and the non-GDM group were analyzed, respectively. Results: The proportion of GDM in the sPTB (19.51%) was higher than the controls (7.47%, P = 0.018). The vaginal microbiota of pregnant women with sPTB exhibited higher alpha diversity metrics (observed features, P = 0.001; Faith's phylogenetic diversity, P = 0.013) and different beta diversity metrics (unweighted UniFrac, P = 0.006; Jaccard's distance, P = 0.004), compared with controls. The presence of Lactobacillus paragasseri/gasseri (aOR: 3.12, 95% CI: 1.24-7.84), Streptococcus (aOR: 3.58, 95% CI: 1.68-7.65), or Proteobacteria (aOR: 3.39, 95% CI: 1.55-7.39) was associated with an increased risk of sPTB in the non-GDM group (P < 0.05). However, the relative abundance of novel L. mulieris (a new species of the L. delbrueckii group) was associated with a decreased risk of sPTB (false discovery rate, 0.10) in all pregnant women. Conclusion: GDM may modify the association of vaginal taxa with sPTB, suggesting that maternal GDM should be considered when using vaginal taxa to identify pregnant women at high risk of sPTB.

Association between Human Genetic Variants and the Vaginal Bacteriome of Pregnant Women.

The influence of human genetic variants on the vaginal bacterial traits (VBTs) of pregnant women is still unknown. Using a genome-wide association approach based on the 16S rRNA bacteriome analysis, a total of 72 host genetic variant (single nucleotide polymorphisms [SNPs], indels, or copy number variations [CNVs])-VBT associations were found that reached the genome-wide significance level (P < 5 × 10-8) with an acceptable genomic inflation factor λ of <1.1. The majority of these SNPs that reached the genome-wide significance level had a relatively low minor allele frequency (MAF), and only seven of them had MAFs greater than 0.05. rs303212, located at the IFIT1 gene on chromosome 10, was the most eye-catching variant, which had a genome-wide association with the relative abundance (RAB) of Actinobacteria and Bifidobacteriaceae and also had a suggestive association with the RAB of a few common vaginal bacteria including Actinobacteriota, Firmicutes, Lactobacillus, and Gardnerella vaginalis and the beta diversity weighted UniFrac (P < 1 × 10-5). The findings of the study suggest that the vaginal bacteriome may be influenced by a number of genetic variants across the human genome and that interferon signaling may have an important influence on vaginal bacterial communities during pregnancy. IMPORTANCE Knowledge about the influence of host genetics on the vaginal bacteriome in pregnancy is still limited. Although a number of environmental and behavioral factors may exert influences on the structure of vaginal bacterial communities, the vaginal bacteriome often undergoes a relatively fixed transition to a more stable and less diverse state as the menstrual cycle stops, which raises questions on the effects of human genetics. We utilized a genome-wide approach to identify the associations between genetic variants and multiple VBTs and performed enrichment analyses. The human genetics during pregnancy may be involved in multiple pathways. The results may disclose innate functional factors involved in shaping the vaginal bacteriome during pregnancy and provide insight into the establishment of specific strategies for prevention and clinical treatment of pregnancy complications.

Histone Deacetylases and Cardiometabolic Diseases.

Cardiometabolic disease, emerging as a worldwide epidemic, is a combination of metabolic derangements leading to type 2 diabetes mellitus and cardiovascular disease. Genetic and environmental factors are linked through epigenetic mechanisms to the pathogenesis of cardiometabolic disease. Post-translational modifications of histone tails, including acetylation and deacetylation, epigenetically alter chromatin structure and dictate cell-specific gene expression patterns. The histone deacetylase family comprises 18 members that regulate gene expression by altering the acetylation status of nucleosomal histones and by functioning as nuclear transcriptional corepressors. Histone deacetylases regulate key aspects of metabolism, inflammation, and vascular function pertinent to cardiometabolic disease in a cell- and tissue-specific manner. Histone deacetylases also likely play a role in the metabolic memory of diabetes mellitus, an important clinical aspect of the disease. Understanding the molecular, cellular, and physiological functions of histone deacetylases in cardiometabolic disease is expected to provide insight into disease pathogenesis, risk factor control, and therapeutic development.

Role of histone deacetylase 9 in regulating adipogenic differentiation and high fat diet-induced metabolic disease.

Adipose tissue serves as both a storage site for excess calories and as an endocrine organ, secreting hormones such as adiponectin that promote metabolic homeostasis. In obesity, adipose tissue expands primarily by hypertrophy (enlargement of existing adipocytes) rather than hyperplasia (generation of new adipocytes via adipogenic differentiation of preadipocytes). Progressive adipocyte hypertrophy leads to inflammation, insulin resistance, dyslipidemia, and ectopic lipid deposition, the hallmark characteristics of metabolic disease. We demonstrate that during chronic high fat feeding in mice, adipogenic differentiation is impaired due to the actions of histone deacetylase 9 (HDAC9), a member of the class II family of HDACs. Mechanistically, upregulated HDAC9 expression blocks the adipogenic differentiation program during chronic high fat feeding, leading to accumulation of improperly differentiated adipocytes with diminished expression of adiponectin. These adipocytes are inefficient at storing lipid, resulting in ectopic lipid deposition in the liver. HDAC9 gene deletion prevents the detrimental effects of chronic high fat feeding on adipogenic differentiation, increases adiponectin expression, and enhances energy expenditure by promoting beige adipogenesis, thus leading to reduced body mass and improved metabolic homeostasis. HDAC9 is therefore emerging as a critical regulator of adipose tissue health and a novel therapeutic target for obesity-related disease.

Conjugation of synthetic cannabinoids JWH-018 and JWH-073, metabolites by human UDP-glucuronosyltransferases.

K2, a synthetic cannabinoid (SC), is an emerging drug of abuse touted as "legal marijuana" and marketed to young teens and first-time drug users. Symptoms associated with K2 use include extreme agitation, syncope, tachycardia, and visual and auditory hallucinations. One major challenge to clinicians is the lack of clinical, pharmacological, and metabolic information for the detection and characterization of K2 and its metabolites in human samples. Information on the metabolic pathway of SCs is very limited. However, previous reports have shown the metabolites of these compounds are excreted primarily as glucuronic acid conjugates. Based on this information, this study evaluates nine human recombinant uridine diphosphate-glucuronosyltransferase (UGT) isoforms and human liver and intestinal microsomes for their ability to glucuronidate hydroxylated metabolites of 1-naphthalenyl-1(1-pentyl-1H-indol-3-yl)-methanone (JWH-018) and (1-butyl-1H-indol-3-yl)-1-naphthalenyl-methanone (JWH-073), the two most common SCs found in K2 products. Conjugates were identified and characterized using liquid chromatography/tandem mass spectrometry, whereas kinetic parameters were quantified using high-performance liquid chromatography-UV-visible methods. UGT1A1, UGT1A3, UGT1A9, UGT1A10, and UGT2B7 were shown to be the major enzymes involved, showing relatively high affinity with K(m) ranging from 12 to 18 µM for some hydroxylated K2s. These UGTs also exhibited a high metabolic capacity for these compounds, which indicates that K2 metabolites may be rapidly glucuronidated and eliminated from the body. Studies of K2 metabolites will help future development and validation of a specific assay for K2 and its metabolites and will allow researchers to fully explore their pharmacological actions.

[Clinical detection of 22q11 microdeletion in the patients with congenital heart disease by multiplex ligation dependent probe amplification].

OBJECTIVE: To detect 22q11 microdeletion in the children and fetuses affected by congenital heart defects. METHOD: MLPA P250 kit was used to detect 22q11 microdeletion in 100 cases of sporadic congenital heart defects including 40 fetuses and 60 patients diagnosed by ultrasound. RESULT: Two cases from the fetuses and 1 case from the patients were found to have 22q11 microdeletion. CONCLUSION: Three cases had 22q11 microdeletion in the congenital heart defects.

[22q11 microdeletion test in patients with congenital heart defects by quantitative fluorescent PCR].

OBJECTIVE: To establish an assay for screening chromosome 22q11 microdeletion efficiently, and apply it for detecting del22q11 in patients with non-syndromic congenital heart defects (CHD). METHODS: Seventy nine patients with non-syndromic CHD and 84 normal controls were genotyped for 8 short tandem repeat (STR) markers located in 22q11 region, by using quantitative fluorescence polymerase chain reaction (QF-PCR). RESULTS: The average heterozygosity of the STR markers in patients and controls was 0.76 and 0.79, respectively. One patient with Tetralogy of Fallot (TOF) from the 79 CHD cases (1.3%) was found to have a deletion within chromosome 22q11.2, which was confirmed by multiplex ligation-dependent probe amplification (MLPA). CONCLUSION: The QF-PCR assay developed in this study was a reliable and an efficient alterative approach to screen for 22q11 microdeletion in clinical diagnosis and genetic counseling.