An Atlas of Dietary Intakes and Medication Uses on Risk of Bladder Cancer: A Wide-Angle Mendelian Randomization Analysis.

BACKGROUND: Observational studies suggests that diets and medications affect bladder cancer (BC) development, which are subject to confounding and difficult to make causal inference. Here we aimed to investigate whether those observational associations are causal and determining the potential directions and pathways. METHODS: We used 2-sample Mendelian randomization (MR) analysis to assess associations of dietary intakes, medication uses and molecules with BC risk. Genetic summary data were derived from participants of predominantly European ancestry with rigorous instruments selection, where univariable MR, mediation MR and multivariable MR were performed. RESULTS: The results of univariable MR showed 4 dietary intakes and 4 medication uses having a protective effect on BC, while 4 circulating metabolites, 440 circulating proteins and 2 gut microbes were observed to be causally associated with BC risk. Through mediation MR, we found 572 analytes showing consistent mediating effects between dietary intakes or medication uses and BC risk. Furthermore, 9 out of 16 diet-medication pairs showed significant interactions and alterations on BC when consumed jointly. CONCLUSION: In summary, the findings obtained from the current study have important implications for informing prevention strategies that point to potential lifestyle interventions or medication prescriptions to reduce the risk of developing BC.HighlightsThe current study extends observational literature in showing the importance of diets and medications on bladder cancer prevention.The associations of diets and medications on bladder cancer prevention might be through circulating metabolites, circulating proteins and gut microbiotaOur results provide a new understanding of interactions in certain diet-medication pairs which should be taken into account by both physicians and patients during the development of a treatment strategy.

A 1.1 Mb duplication CNV on chromosome 17 contributes to skeletal muscle development in Boer goats.

The Boer goat is one of the top meat breeds in modern animal husbandry and has attracted widespread attention for its unique growth performance. However, the genetic basis of muscle development in the Boer goat remains obscure. In this study, we identified specific structural variants in the Boer goat based on genome-wide selection signals and analyzed the basis of the molecular heredity of related candidate genes in muscle development. A total of 9 959 autosomal copy number variations (CNVs) were identified through selection signal analysis in 127 goat genomes. Specifically, we confirmed that the highest signal CNV (HSV) was a chromosomal arrangement containing an approximately 1.11 Mb (CHIR17: 60062304-61171840 bp) duplicated fragment inserted in reverse orientation and a 5 362 bp deleted region (CHIR17:60145940-60151302 bp) with overlapping genes (e.g., ARHGAP10, NR3C2, EDNRA, PRMT9, and TMEM184C). The homozygous duplicated HSV genotype (+/+) was found in 96% of Boer goats but was not detected in Eurasian goats and was only detected in 4% of indigenous African goats. The expression network of three candidate genes ( ARHGAP10, NR3C2, and EDNRA) regulating dose transcription was constructed by RNA sequencing. Results indicated that these genes were involved in the proliferation and differentiation of skeletal muscle satellite cells (SMSCs) and their overexpression significantly increased the expression of SAA3. The HSV of the Boer goat contributed to superior skeletal muscle growth via the dose effects of overlapping genes.

The effects of the interaction of genetic predisposition with lifestyle factors on bladder cancer risk.

OBJECTIVES: To investigate the association of polygenic risk score (PRS) and bladder cancer (BC) risk and whether this PRS can be offset by a healthy lifestyle. METHODS: Individuals with BC (n = 563) and non-BC controls (n = 483 957) were identified in the UK Biobank, and adjusted Cox regression models were used. A PRS was constructed based on 34 genetic variants associated with BC development, while a healthy lifestyle score (HLS) was constructed based on three lifestyle factors (i.e., smoking, physical activity, and diet). RESULTS: Overall, a negative interaction was observed between the PRS and the HLS (P = 0.02). A 7% higher and 28% lower BC risk per 1-standard deviation (SD) increment in PRS and HLS were observed, respectively. A simultaneous increment of 1 SD in both HLS and PRS was associated with a 6% lower BC risk. In addition, individuals with a high genetic risk and an unfavourable lifestyle showed an increased BC risk compared to individuals with low genetic risk and a favourable lifestyle (hazard ratio 1.55, 95% confidence interval 1.16-1.91; P for trend <0.001). Furthermore, population-attributable fraction (PAF) analysis showed that 12%-15% of the BC cases might have been prevented if individuals had adhered to a healthy lifestyle. CONCLUSION: This large-scale cohort study shows that a genetic predisposition combined with unhealthy behaviours have a joint negative effect on the risk of developing BC. Behavioural lifestyle changes should be encouraged for people through comprehensive, multifactorial approaches, although high-risk individuals may be selected based on genetic risk.

A single-nucleus transcriptomic atlas of the dog hippocampus reveals the potential relationship between specific cell types and domestication.

The process of domestication has led to dramatic differences in behavioral traits between domestic dogs and gray wolves. Whole-genome research found that a class of putative positively selected genes were related to various aspects of learning and memory, such as long-term potentiation and long-term depression. In this study, we constructed a single-nucleus transcriptomic atlas of the dog hippocampus to illustrate its cell types, cell lineage and molecular features. Using the transcriptomes of 105 057 nuclei from the hippocampus of a Beagle dog, we identified 26 cell clusters and a putative trajectory of oligodendrocyte development. Comparative analysis revealed a significant convergence between dog differentially expressed genes (DEGs) and putative positively selected genes (PSGs). Forty putative PSGs were DEGs in glutamatergic neurons, especially in Cluster 14, which is related to the regulation of nervous system development. In summary, this study provides a blueprint to understand the cellular mechanism of dog domestication.

High Throughput Isolation and Data Independent Acquisition Mass Spectrometry (DIA-MS) of Urinary Extracellular Vesicles to Improve Prostate Cancer Diagnosis.

Proteomic profiling of extracellular vesicles (EVs) represents a promising approach for early detection and therapeutic monitoring of diseases such as cancer. The focus of this study was to apply robust EV isolation and subsequent data-independent acquisition mass spectrometry (DIA-MS) for urinary EV proteomics of prostate cancer and prostate inflammation patients. Urinary EVs were isolated by functionalized magnetic beads through chemical affinity on an automatic station, and EV proteins were analyzed by integrating three library-base analyses (Direct-DIA, GPF-DIA, and Fractionated DDA-base DIA) to improve the coverage and quantitation. We assessed the levels of urinary EV-associated proteins based on 40 samples consisting of 20 cases and 20 controls, where 18 EV proteins were identified to be differentiated in prostate cancer outcome, of which three (i.e., SERPINA3, LRG1, and SCGB3A1) were shown to be consistently upregulated. We also observed 6 out of the 18 (33%) EV proteins that had been developed as drug targets, while some of them showed protein-protein interactions. Moreover, the potential mechanistic pathways of 18 significantly different EV proteins were enriched in metabolic, immune, and inflammatory activities. These results showed consistency in an independent cohort with 20 participants. Using a random forest algorithm for classification assessment, including the identified EV proteins, we found that SERPINA3, LRG1, or SCGB3A1 add predictable value in addition to age, prostate size, body mass index (BMI), and prostate-specific antigen (PSA). In summary, the current study demonstrates a translational workflow to identify EV proteins as molecular markers to improve the clinical diagnosis of prostate cancer.

Integrative Multi-Omics Analysis for the Determination of Non-Muscle Invasive vs. Muscle Invasive Bladder Cancer: A Pilot Study.

OBJECTIVES: The molecular landscape of non-muscle-invasive (NMIBC) and muscle-invasive (MIBC) bladder cancer based on molecular characteristics is essential but poorly understood. In this pilot study we aimed to identify a multi-omics signature that can distinguish MIBC from NMIBC. Such a signature can assist in finding potential mechanistic biomarkers and druggable targets. METHODS: Patients diagnosed with NMIBC (n = 15) and MIBC (n = 11) were recruited at a tertiary-care hospital in Nanjing from 1 April 2021, and 31 July 2021. Blood, urine and stool samples per participant were collected, in which the serum metabolome, urine metabolome, gut microbiome, and serum extracellular vesicles (EV) proteome were quantified. The differences of the global profiles and individual omics measure between NMIBC vs. MIBC were assessed by permutational multivariate analysis and the Mann-Whitney test, respectively. Logistic regression analysis was used to assess the association of each identified analyte with NMIBC vs. MIBC, and the Spearman correlation was used to investigate the correlations between identified analytes, where both were adjusted for age, sex and smoking status. RESULTS: Among 3168 multi-omics measures that passed the quality control, 159 were identified to be differentiated in NMIBC vs. MIBC. Of these, 46 analytes were associated with bladder cancer progression. In addition, the global profiles showed significantly different urine metabolome (p = 0.029), gut microbiome (p = 0.036), and serum EV (extracellular vesicles) proteome (p = 0.039) but not serum metabolome (p = 0.059). We also observed 17 (35%) analytes that had been developed as drug targets. Multiple interactions were obtained between the identified analytes, whereas for the majority (61%), the number of interactions was at 11-20. Moreover, unconjugated bilirubin (p = 0.009) and white blood cell count (p = 0.006) were also shown to be different in NMIBC and MIBC, and associated with 11 identified omics analytes. CONCLUSIONS: The pilot study has shown promising to monitor the progression of bladder cancer by integrating multi-omics data and deserves further investigations.

Genome-wide selective detection of Mile red-bone goat using next-generation sequencing technology.

The ecotype population of goats (Capra hircus) was created by long-term artificial selection and natural adaptation. Mile red-bone goat is an indigenous breed with visible red bones, and its special bone structure has received extensive attention. This study aimed to identify genetic variants and candidate genes associated with specific bone phenotypes using next-generation sequencing technology (NGS). The results revealed that 31,828,206 single nucleotide polymorphisms (SNPs) were obtained from 72 goats (20 Mile red-bone goats and 52 common goats) by NGS. A total of 100 candidate genes were identified on the basis top 1% window interaction from nucleotide diversity (π), π ratio (π A/π B), and pairwise fixation index (F ST). Exactly 77 known signaling pathways were enriched. Specifically, three coding genes (NMNAT2, LOC102172983, and PNLIP) were annotated in the vitamin metabolism signaling pathways, and NCF2 was annotated to the osteoclast (OC) differentiation pathway. Furthermore, 5862 reliable copy number variations (CNVs) were obtained, and 14 and 24 genes were annotated with the top 1‰ CNV based on F ST (>0.490) and V ST (>0.527), respectively. Several pathways related to bone development and metabolism of exogenous substances in vivo, including calcium signaling pathway, OC differentiation, and glycerophospholipid metabolism, were annotated. Specifically, six genes from 19 candidate CNVs, which were obtained by interaction of the top 1‰ CNVs with F ST and V ST, were annotated to mucin-type O-glycan biosynthesis and metabolic pathways. Briefly, the results implied that pseudopurpurin and specific genetic variants work together to contribute to the red-bone color and specific bone structure of Mile red-bone goat. This study is helpful to understanding the genetic basis of the unique bone phenotype of Mile red-bone goats.

Three SNPs within exons of INHA and ACVR2B genes are significantly associated with litter size in Dazu black goats.

The aim of this study was to analyse the association between single-nucleotide polymorphisms within INHA and ACVR2B and litter size in Dazu black goats. In total, twenty-two SNPs were genotyped in 190 individuals by SNaPshot and resequencing. The results showed that three SNPs (SNP_1, SNP_12 and SNP_13 in this study) were detected to have significant additive genetic effect on the recorded goat litter size (p < .05). The SNP_1 (NC_030809.1), a non-synonymous substitution of G for T at chr2-g. 28314990 in the exon 2 of INHA gene (NM_001285606.1), resulted in homozygote 2 (HOM2) contributed 0.25 and heterozygote (HET) contributed 0.12 larger litter than homozygote 1 (HOM1). Meanwhile, SNP_12 (Chr22-g. 11721225 A > T) and SNP_13 (Chr22-g. 11721227 A > C) (NC_030829.1) simultaneously mutated at the first and third position of a triplet AAA (lysine, K) in the exon 4 of ACVR2B gene (XM_018066623.1) had estimated genetic effects of HOM1 (0.00) and HOM2 (0.03) larger than HET (-0.12). In conclusion, one SNPs (chr2-g. 28314990 T > G) within the exon 2 of INHA and two SNPs (Chr22-g. 11721225 A > T and Chr22-g. 11721227 A > C) in the exon 4 of ACVR2B gene were highly recommended as candidate markers of litter size in Dazu black goats. A large-scale association study to assess the impact of these variants on litter size is still necessary.

Polymorphisms of mismatch repair gene hMLH1 and hMSH2 and risk of gastric cancer in a Chinese population.

The purpose of this study was to determine the genotype and allele frequencies of hMLH1 (-93G>A and I219V) and hMSH2 (-118T>C and IVS12-6T>C) polymorphisms in patients with gastric carcinoma and normal controls, and to evaluate the association between these polymorphisms and the risk of gastric cancer in a hospital-based Chinese population. Genomic DNA was extracted from peripheral blood lymphocytes. A TaqMan assay was used to determine the genotype and allele frequencies of hMLH1 and hMSH2 polymorphisms in data obtained from 554 gastric cancer cases and 592 controls. Unconditional logistic regression was used to assess the association between the four single nucleotide polymorphisms (SNPs) and gastric carcinoma risk. No evidence of an association among any of the four polymorphisms and the risk of gastric cancer was observed. However, when gastric cancer patients were further stratified by age, gender, smoking status, alcohol use and clinicopathological characteristics, and compared with the control populations, the combined variant genotype hMSH2 -118T>C (TC+CC) was not only associated with an increased risk of gastric cancer in subgroups of younger subjects [ages ≤63years; adjusted odds ratio (OR)=1.51, 95% confidence interval (CI), 1.05-2.16], but also with diffuse tumors (adjusted OR=1.41, 95% CI, 1.01-1.96). These data indicate that the polymorphisms of -93G>A, I219V and IVS12-6T>C are not associated with the risk of gastric cancer. However, hMSH2-118T>C combined with variant genotypes (TC+CC) may confer a potential risk of gastric cancer in the Chinese population.

Genetic variations in the SMAD4 gene and gastric cancer susceptibility.

AIM: To explore the association between mothers against decapentaplegic homolog 4 (SMAD4) gene polymorphisms and gastric cancer risk. METHODS: Five tagging single nucleotide polymorphisms (tSNPs) in the SMAD4 gene were selected and genotyped in 322 gastric cancer cases and 351 cancer-free controls in a Chinese population by using the polymerase chain reaction restriction fragment length polymorphism method. Immunohistochemistry was used to examine SMAD4 protein expression in 10 normal gastric tissues adjacent to tumors. RESULTS: In the single-locus analysis, two significantly decreased risk polymorphisms for gastric cancer were observed: the SNP3 rs17663887 TC genotype (adjusted odds ratio = 0.38, 95% confidence interval: 0.21-0.71), compared with the wild-type TT genotype and the SNP5 rs12456284 GG genotype (0.31, 0.16-0.60), and with the wild-type AA genotype. In the combined analyses of these two tSNPs, the combined genotypes with 2-3 protective alleles (SNP3 C and SNP5 G allele) had a significantly decreased risk of gastric cancer (0.28, 0.16-0.49) than those with 0-1 protective allele. Furthermore, individuals with 0-1 protective allele had significantly decreased SMAD4 protein expression levels in the normal tissues adjacent to tumors than those with 2-3 protective alleles (P = 0.025). CONCLUSION: These results suggest that genetic variants in the SMAD4 gene play a protective role in gastric cancer in a Chinese population.