Genetic characterization and molecular epidemiological analysis of enterovirus C99 in China.

Enterovirus C99 (EV-C99) is a newly identified EV serotype within the species Enterovirus C. Few studies on EV-C99 have been conducted globally. More information and research on EV-C99 are needed to assess its genetic characteristics, phylogenetic relationships, and associations with enteroviral diseases. Here, the phylogenetic characteristics of 11 Chinese EV-C99 strains have been reported. The full-length genomic sequences of these 11 strains show 79.4-80.5% nucleotide identity and 91.7-94.3% amino acid (aa) identity with the prototype EV-C99. A maximum likelihood phylogenetic tree constructed based on the entire VP1 coding region identified 13 genotypes (A-M), revealing a high degree of variation among the EV-C99 strains. Phylogeographic analysis showed that the Xinjiang Uygur Autonomous Region is an important source of EV-C99 epidemics in various regions of China. Recombination analysis revealed inter-serotype recombination events of 16 Chinese EV-C99 strains in 5' untranslated regions and 3D regions, resulting in the formation of a single recombination form. Additionally, the Chinese strain of genotype J showed rich aa diversity in the P1 region, indicating that the genotype J of EV-C99 is still going through variable dynamic changes. This study contributes to the global understanding of the EV-C99 genome sequence and holds substantial implications for the surveillance of EV-C99.

Characterizing enterovirus C96 genome and phylodynamics analysis.

Enterovirus C96 (EV-C96) is a recently discovered serotype belonging to enterovirus C species. It had been isolated from patients with acute flaccid paralysis, hand, foot, and mouth disease, diarrhea, healthy people, or environmental specimens. Despite increasing reports of the virus, the small number of full-length genomes available for EV-C96 has limited molecular epidemiological studies. In this study, newly collected rare EV-C96 strains in China from 1997 to 2020 were combined with sequences available in GenBank for comprehensive analyses. Sequence analysis revealed that the nucleotide sequence similarity of EV-C96 and the prototype strain (BAN00-10488) was 75%-81.8% and the amino acid sequence similarity was 85%-94.9%. EV-C96 had a high degree of genetic variation and could be divided into 15 genogroups. The mean evolutionary rate was 5.16 × 10-3 substitution/site/year, and the most recent common ancestor was dated to 1925. A recombination analysis revealed that EV-C96 may be a recombinant derived from other serotypes in the EV-C group in the nonstructural protein coding region. This comprehensive and integrated analysis of the whole genome sequence of EV-C96 provides valuable data for further studies on the molecular epidemiology of EV-C96 worldwide.

Effects of polyunsaturated fatty acids serum levels on vascular dementia: A two-sample Mendelian randomization study.

INTRODUCTION: Several observational studies have indicated that polyunsaturated fatty acids serum levels (PUFAs) are associated with vascular dementia (VaD), but their causal relationships remain elusive. Therefore, we attempted to evaluate the causal effect of PUFAs on VaD in a two-sample Mendelian randomization (MR) analysis by using summary statistics from aggregated genome-wide association studies. METHODS: The inverse-variance weighted (IVW) method was performed as the primary analysis. Sensitivity analyses (MR-Egger regression, weighted median, penalized weighted median and MR pleiotropy residual sum and outlier methods) were also implemented to estimate the effects of potential violations of MR hypotheses. RESULTS: No causality was found for PUFAs (OR, 1.14; 95% CI, .91-1.42; p = .25) on VaD in the IVW model. The results were consistent in sensitivity analyses. There was no notable horizontal pleiotropy or heterogeneity. CONCLUSION: In this two-sample MR analysis, our findings did not support the assumption that PUFAs play causal role in the occurrence or development of VaD.

Genotype F of Echovirus 25 with multiple recombination pattern have been persistently and extensively circulating in Chinese mainland.

Echovirus 25 (E25), a member of the Enterovirus B (EV-B) species, can cause aseptic meningitis (AM), viral meningitis (VM), and acute flaccid paralysis (AFP). However, systematic studies on the molecular epidemiology of E25, especially those concerning its evolution and recombination, are lacking. In this study, 18 strains of E25, isolated from seven provinces of China between 2009 and 2018, were collected based on the Chinese hand, foot, and mouth disease (HFMD) surveillance network, and 95 sequences downloaded from GenBank were also screened. Based on the phylogenetic analysis of 113 full-length VP1 sequences worldwide, globally occurring E25 strains were classified into 9 genotypes (A-I), and genotype F was the dominant genotype in the Chinese mainland. The average nucleotide substitution rate of E25 was 6.08 × 10-3 substitutions/site/year, and six important transmission routes were identified worldwide. Seventeen recombination patterns were determined, of which genotype F can be divided into 9 recombination patterns. A positive selector site was found in the capsid protein region of genotype F. Recombination analysis and pressure selection analysis for genotype F showed multiple recombination patterns and evolution characteristics, which may be responsible for it being the dominant genotype in the Chinese mainland. This study provides a theoretical basis for the subsequent prevention and control of E25.

Evolution, recombination and geographic spreading of global Coxsackievirus A6.

BACKGROUND: The increasing incidence of hand, foot, and mouth disease (HFMD) associated with Coxsackievirus A6 (CVA6) has become a very significant public health problem. The aim of this study is to investigate the recombination, geographic transmission, and evolutionary characteristics of the global CVA6. METHODS: From 2019 to 2022, 73 full-length CVA6 sequences were obtained from HFMD patients in China and analyzed in combination with 1032 published whole genome sequences. Based on this dataset, the phylogenetic features, recombinant diversity, Bayesian phylodynamic characteristics, and key amino acid variations in CVA6 were analyzed. RESULTS: The four genotypes of CVA6, A, D, E, and F, are divided into 24 recombinant forms (RFs, RF-A - RF-X) based on differences in the P3 coding region. The eastern China region plays a key role in the dissemination of CVA6 in China. VP1-137 and VP1-138 are located in the DE loop on the surface of the CVA6 VP1 protein, with the former being a highly variable site and the latter having more non-synonymous substitutions. CONCLUSIONS: Based on whole genome sequences, this study contributes to the CVA6 monitoring, early warning, and the pathogenic mechanism by studying recombination diversity, geographical transmission characteristics, and the variation of important amino acid sites.

Assessing the Causal Effects of Adipokines on Uric Acid and Gout: A Two-Sample Mendelian Randomization Study.

Previous observational studies have highlighted associations between adipokines and hyperuricemia, as well as gout, but the causality and direction of these associations are not clear. Therefore, we attempted to assess whether there are causal effects of specific adipokines (such as adiponectin (ADP) and soluble leptin receptors (sOB-R)) on uric acid (UA) or gout in a two-sample Mendelian randomization (MR) analysis, based on summary statistics from large genome-wide association studies. The inverse-variance weighted (IVW) method was performed as the primary analysis. Sensitivity analyses (including MR-Egger regression, weighted median, penalized weighted median, and MR pleiotropy residual sum and outlier methods) were also performed, to ensure reliable results. In the IVW models, no causal effect was found for sOB-R (odds ratios (OR), 1.002; 95% confidence intervals (CI), 0.999-1.004; p = 0.274) on UA, or ADP (OR, 1.198; 95% CI, 0.865-1.659; p = 0.277) or sOB-R (OR, 0.988; 95% CI, 0.940-1.037; p = 0.616) on gout. The results were confirmed in sensitivity analyses. There was no notable directional pleiotropy or heterogeneity. This study suggests that these specific adipokines may not play causal roles in UA or gout development.

Assessment of the Causal Effect of IgG N-Glycosylation Level on Risk of Dementia: A 2-Sample Mendelian Randomization Study.

BACKGROUND: Previous prospective studies highlighted aberrant immunoglobulin G (IgG) N-glycosylation as a risk factor for dementia [such as Alzheimer's disease (AD) and vascular dementia (VaD)]. It is unclear whether this association is causal or explained by confounding or reverse causation. OBJECTIVE: The aim is to examine the association of genetically predicted IgG N-glycosylation with dementia using 2-sample Mendelian randomization (MR). METHODS: Independent genetic variants for IgG N-glycosylation traits were selected as instrument variables from published genome-wide association studies (GWAS) among individuals of European ancestry. We extracted their corresponding summary statistics from large-scale clinically diagnosed AD GWAS dataset and FinnGen biobank VaD GWAS dataset. The inverse variance weighted (IVW) was performed to calculate the effect estimates. Meanwhile, multiple sensitivity analyses were used to assess horizontal pleiotropy and outliers. RESULTS: There were no associations of genetically predicted IgG N-glycosylation traits with the risk of AD and VaD using the IVW method (all Bonferroni corrected p > 0.0013). These estimates of four additional sensitivity analyses methods were consistent with the IVW estimates in terms of direction and magnitude. Additionally, the MR-PRESSO global test and the intercept of MR-Egger regression indicated no evidence of horizontal pleiotropy. Meanwhile, the heterogeneity test showed no significant heterogeneity using the Cochran Q statistic. The leave-one-out sensitivity analyses also did not detect any significant change. CONCLUSION: Our MR study did not support evidence for the hypothesis that IgG N-glycosylation level may be causally associated with the risk of dementia.