Genotype Subgroups Research Articles

Association Analysis Between Genotype and Environment: Differentiation Between Cyclocarya paliurus Resources That Accumulate Triterpenoids.

Cyclocarya paliurus is mainly distributed in subtropical areas of China. Its leaves are rich in beneficial triterpenoids that have bioactivities against human diseases, including hyperlipemia, diabetes, and hypertension. In this study, data on the genetic diversity, distributing environment, and triterpenoids of C. paliurus samples were collected from a wide area in China. The data covered 316 C. paliurus germplasms collected from 26 distinct populations. Association analysis between genotype and triterpenoids was carried out to describe triterpenoids accumulation pattern. Based on our analyses, we identified the important trend that genotypes with higher triterpenoid contents belonged to a unique genotype subgroup. The results showed that pterocaryoside B and pterocaryoside A significantly vary among the genotypic subgroups. In addition, the different genotypic subgroups showed distinct geographical distributing areas. These findings provide information about the relationship between genetic and environmental factors and how this affects triterpenoids accumulation. This information will be valuable for targeted breeding and for further germplasm selection of C. paliurus resources.

Altered Balance of Reelin Proteolytic Fragments in the Cerebrospinal Fluid of Alzheimer's Disease Patients.

Reelin binds to the apolipoprotein E receptor apoER2 to activate an intracellular signaling cascade. The proteolytic cleavage of reelin follows receptor binding but can also occur independently of its binding to receptors. This study assesses whether reelin proteolytic fragments are differentially affected in the cerebrospinal fluid (CSF) of Alzheimer’s disease (AD) subjects. CSF reelin species were analyzed by Western blotting, employing antibodies against the N- and C-terminal domains. In AD patients, we found a decrease in the 420 kDa full-length reelin compared with controls. In these patients, we also found an increase in the N-terminal 310 kDa fragment resulting from the cleavage at the so-called C-t site, whereas the 180 kDa fragment originated from the N-t site remained unchanged. Regarding the C-terminal proteolytic fragments, the 100 kDa fragment resulting from the cleavage at the C-t site also displayed increased levels, whilst the one resulting from the N-t site, the 250 kDa fragment, decreased. We also detected the presence of an aberrant reelin species with a molecular mass of around 500 kDa present in AD samples (34 of 43 cases), while it was absent in the 14 control cases analyzed. These 500 kDa species were only immunoreactive to N-terminal antibodies. We validated the occurrence of these aberrant reelin species in an Aβ42-treated reelin-overexpressing cell model. When we compared the AD samples from APOE genotype subgroups, we only found minor differences in the levels of reelin fragments associated to the APOE genotype, but interestingly, the levels of fragments of apoER2 were lower in APOE ε4 carriers with regards to APOE ε3/ε3. The altered proportion of reelin/apoER2 fragments and the occurrence of reelin aberrant species suggest a complex regulation of the reelin signaling pathway, which results impaired in AD subjects.

Contact patterns and HPV-genotype interactions yield heterogeneous HPV-vaccine impacts depending on sexual behaviors: An individual-based model

Human papillomaviruses are common sexually transmitted infections, caused by a large diversity of genotypes. In the context of vaccination against a subgroup of genotypes, better understanding the role of genotype interactions and human sexual behavior on genotype dynamics is essential. Herein, we present an individual-based model that integrates realistic heterosexual partnership behaviors and simulates interactions between vaccine and non-vaccine genotypes. Genotype interactions were considered, assuming a previous vaccine-genotype infection shortened (competition) or extended (synergy) the duration of a secondary non-vaccine-genotype infection. Sexual behavior determined papillomavirus acquisition and transmission: only 19.5% of active individuals at most 1 partner r during the year, but > 80% of those with ≥ 2 partners, were infected before vaccine introduction. The pre-vaccination situation was consistent with all genotype interaction scenarios. These genotype interactions, despite being undetectable during the pre-vaccination era, markedly impacted genotype prevalence after vaccination started, with a significant increase/decrease of non-vaccine genotypes prevalence for respectively competitive/synergistic interactions. These prevalence changes were more pronounced in individuals with ≤ 3 partners per year (up to 30% of prevalence modification assuming 65% vaccine coverage) but barely visible for individuals with > 3 partners per year (at most 0.30%). Results suggest the presence of genotype interaction, which is consistent with the pre-vaccine situation, may impact the dynamics of non-vaccine genotypes, particularly in less active individuals.

Assessment of kernel characteristics to predict popping performance in grain sorghum

AbstractGrowth in the niche market of popped grain sorghum [Sorghum bicolor (L.) Moench] has increased the demand for grain sorghum lines or hybrids with improved popping quality. While there is a clear morphological difference in kernel morphology between popcorn [Zea mays L. everta] and most other types of corn, most grain sorghum genotypes have kernels with generally similar morphological structure. The absence of a specific kernel morphology for sorghum makes it impossible to eliminate types of grain sorghum that will not pop based solely on that morphology. Consequently, screening of any sorghum genotype requires the actual popping of grain from that genotype. As such, the identification of traits or combinations thereof that effectively screen grain sorghum genotypes for popping efficiency (PE), expansion ratio (ER), flake size (FS), and popped density (PD) is necessary. Herein, grain from 78 diverse genotypes grown in two environments were characterized for physical (i.e., diameter, thousand kernel weight, kernel hardness index, test weight, and visual hardness rating), compositional (i.e., starch, fiber, fat, ash, and protein), and popping characteristics (i.e., PE, ER, FS, and PD). No single physical or compositional trait was sufficiently correlated to prediction of popping performance. Multi‐trait models better predicted popping performance than the single trait correlations. Further, multi‐trait models using compositional predictors increased prediction accuracies by 10.1% for PE, 42.9% for ER, 24.4% for FS, and 40.6% for PD compared with physical predictors. Among subgroups of genotypes, prediction accuracies varied considerably based on the criteria used to subdivide the genotypes. In conclusion, indirect selection for popping performance is possible by leveraging specific multi‐trait models.

Effects of elagolix on the pharmacokinetics of omeprazole and its metabolites in healthy premenopausal women.

This study evaluated the effect of repeated doses of elagolix on the pharmacokinetics (PK) of omeprazole and its metabolites in healthy premenopausal female subjects. Adult premenopausal female subjects (N = 20) received a single oral dose of omeprazole (40 mg) on day 1 and day 11 and oral doses of elagolix (300 mg) twice‐daily on days 3–11. Serial blood samples for assay of omeprazole and its metabolites were collected for 24 h after dosing on days 1 and 11. PK parameters were calculated for omeprazole, 5‐hydroxyomeprazole and omeprazole sulfone; and were compared between day 1 and day 11. Pharmacogenetic testing was performed for CYP2C19 variant alleles and the results were used to compare the magnitude of elagolix–omeprazole drug–drug interaction (DDI) between the different genotype subgroups. Administration of elagolix 300 mg twice‐daily for 9 days increased omeprazole exposure by 1.8‐fold and decreased the metabolite‐to‐parent ratio for 5‐hydroxyomeprazole by ~60%. Conversely, there was an increase in the metabolite‐to‐parent ratio for omeprazole sulfone by 25%. Elagolix increased omeprazole exposures by 2‐ to 2.5‐fold in CYP2C19 extensive (EM) and intermediate (IM) metabolizer subjects, but decreased omeprazole exposures by 40% in poor metabolizer subjects. Exposures of 5‐hydroxyomeprazole decreased by 20%–30% in all genotype subgroups, and omeprazole sulfone exposures increased by ~3‐fold in EM and IM subjects. Elagolix is a weak inhibitor of CYP2C19 and exposure of CYP2C19 substrates may be increased upon coadministration with elagolix. Omeprazole may exhibit drug interactions due to multiple mechanisms other than CYP2C19‐mediated metabolism; complicating the interpretation of results from omeprazole DDI studies.

Multivariate analysis of blood and brain transcriptome in Alzheimer's reveals unique APOE ε4-related immune pathways.

While Alzheimer's disease (AD) is generally considered a brain disease, plasma levels of AD-related proteins including amyloid-β, phosphorylated tau, and neurofilament light chain are associated with neurodegeneration and neuroinflammation. The APOE ε4 allele has shown cerebrovascular effects including acceleration of blood brain barrier (BBB) breakdown. We evaluated differential expression (DE) of previously established AD genes in brains obtained from 344 pathologically confirmed AD cases and 232 controls and in blood obtained from 112 clinically diagnosed AD cases and 67 controls from the Religious Orders Study and Memory and Aging Project. We analyzed DE between AD and controls in the blood and brain jointly using O'Brien's multivariate approach in the total sample and APOE genotype groups (ε2/ε3, ε3/ε3, ε3/ε4). To identify biologically important pathways, gene set enrichment analysis was performed within APOE genotype groups using DE results for all genes ranked by Z-score from the combined blood and brain analyses. Pathway results were corrected by the false-discovery rate (FDR). Nominally significant (P<0.05) DE was observed in both brain and blood for INDPP5D (upregulated) and HLA-DQA1 (downregulated). Gene-set enrichment analysis revealed 21 significant pathways (FDR-adjusted P<0.05) in at least one APOE genotype subgroup. Ten pathways were significantly enriched in the ε3/ε4 group and six of these were unique to these subjects (apoptosis, estrogen response late, hypoxia, il6/jak/stat3 signaling, inflammatory response, and p53 pathway). The other four pathways (allograft rejection, interferon gamma response, peroxisome, and TNFA signaling via NFKB) were enriched for AD upregulated genes from the ε3/ε4 group and different from AD downregulated genes identified in APOE ε4- subjects. Expression profiles from two AD genes involved in immune function, INPP5D and HLA-DQA1, were consistent in both blood and brain. The same immune related pathways are enriched in AD upregulated genes in APOE ε4+ subjects and in AD downregulated genes in ε4- subjects. These results suggest that the ε4 allele contributes to a unique expression profile in both blood and brain, potentially related to ε4's effect on the cerebrovasculature.

Effect of the Interrelation between CYP3A5 Genotype, Concentration/Dose Ratio and Intrapatient Variability of Tacrolimus on Kidney Graft Function: Monte Carlo Simulation Approach

Background: Tacrolimus (Tac) is characterized by large between- and within-patient (IPV) variability in pharmacokinetics and exposure. Aim: This study aimed to assess and validate the effect of Tac IPV and trough concentration-to-dose ratio (C0/D) over 6–12 months on reduced estimated glomerular filtration rate (eGFR) values in the late period after kidney transplantation (Tx), applying Monte Carlo (MC) simulation. Methods: The previously published linear regression was the basis for MC simulation, performed to determine how variations in significant predictors affect the distribution of eGFR from 13 to 36 months post-transplantation. The input C0/D values were derived from CYP3A5 genotype subgroups. Results: Patients characterized by high Tac IPV and low mean C0/D over 6–12 months could have been at greater risk of lower eGFR values in a three-year period following Tx compared to the other patient groups. This effect was more pronounced in patients with a lower eGFR at the 6th month and a history of acute rejection. The proven contribution of CYP3A5 expresser genotype to low C0/D values may suggest its indirect effect on long-term graft function. Conclusion: The findings indicate that simultaneous assessment of Tac IPV, C0/D, and CYP3A5 genotype may identify patients at risk of deterioration of graft function in the long-term post-transplantation period.

Abstract 13342: Transcriptional Profiling of Surgical Myectomy Tissue in Patients With Hypertrophic Cardiomyopathy Reveals Genotype Independent Counterregulatory Alterations in Hypertrophy Pathways

Introduction: Hypertrophic cardiomyopathy (HCM) is one of the most common genetic heart diseases characterized by asymmetric left ventricular hypertrophy (LVH) and vast clinical and genetic heterogeneity. Several transcriptional studies in HCM heart tissues have shown severe alterations in gene expression. However, these earlier studies relied on microarray technology or were limited by small sample size or lack of genotype-specific analyses. Methods: We obtained flash-frozen cardiac tissue from patients with HCM undergoing surgical myectomy/septal reduction therapy for relief of left ventricular outflow tract obstruction. RNA-sequencing (RNAseq) was performed using paired-end index reading on 97 myectomy tissues (44 female [45%]; mean age at surgery of 47 ± 18 years) and 23 control tissues (10 female [43%]; mean age at death of 43 ± 12 years) to identify differentially expressed genes (DEGs) using edgeR and pathways in HCM using Ingenuity Pathway Analysis. Additionally, genome sequencing (GS) was performed and HCM patients were divided into genotype-based subgroups to compare the transcriptional profile across different genotypes. Results: Overall, 43% had a pathogenic, HCM-associated variant including 23% with MYBPC3-HCM and 15% with MYH7-HCM. Among the 15,634 genes expressed in the cardiac tissue,1,246 genes (8%) were upregulated and 738 genes (3%) were downregulated significantly in HCM vs. controls. Pathway analysis showed alterations in 126 pathways with downregulation of 44 pathways and upregulation of 1 pathway. There were notable transcriptional alterations of most canonical, pro-hypertrophic pathways, including statistically and biologically significant downregulation of five pathways [-log (BH p-value)≥ 1.3; Z-score≤ -2]: ERK/MAPK, p38 MAPK, ERK5, IL6, and NF-κB signaling. Far less DEGs were observed between genotypic subgroups, with only 37 DEGSs identified between sarcomere positive- and genotype negative-HCM. Conclusions: At the time of surgical myectomy, the ventricular myocardium’s transcriptome, independent of genotype, reveals widespread downregulation of pro-hypertrophic pathways. Whether these counter regulatory measures can be targeted therapeutically warrants further investigation.

Abstract 10251: Intracranial Aneurysms in Sickle Cell Adults Screened by Mra

Introduction: Sickle cell disease(SCD) is the most common genetic disease globally. It is an autosomal recessive disease that affects the β-globin chain which most often presents with anemia and vaso-occlusive symptoms. This condition includes multiples genotypes/phenotypes, the most common of which is HbSS (homozygosity for Hemoglobin S); others are compound heterozygosity with HbC variant (HbSC) and HbS-β-thalassemia (HbSβ+/HbSβ0). Stroke occurs in up to 25% of SCD patients and MRI screening is already recommended by the American Society of Hematology. Small case series have shown a higher prevalence of intracranial aneurysms (ICAN) in SCD, and MR angiography (MRA) may therefore be of benefit for the detection of arterial pathology. Hypothesis: There is an increased prevalence of ICAN in adults with SCD; Frequency of anevrysms is associated with SCD genotype and age. Methods: Adult patients from the SCD clinic of our institution were screened with 3T brain MR complemented with MRA in order to accurately determine the prevalence of ICAN. Results: Our study included 245 asymptomatic SCD adults (369 MRIs). Median age was 32; 52% were women. The overall prevalence of ICAN was 0.11 (0.95 CI 0.07-0.15). All aneurysms were saccular ≤ 10 mm. Forty-four aneurysms were detected in 27 patients with a third presenting with multiple aneurysms. Genotype subgroup analysis revealed a higher prevalence of ICAN in SS/Sb0 (0.17; 0.95 CI 0.11-0.25) compared to the SC/Sb+ (0.06; 0.95 CI 0.02-0.11) (p = 0.007). An association between age and ICAN was also statistically significant (p = 0.03) with stratification revealing a higher prevalence of ICAN for &gt;30 years old, 0.15 (0.95 CI 0.09-0.21). In addition, in patients aged 18-30, the prevalence was 0.06 (0.95 CI 0.26-0.12). Conclusions: This is the largest cohort of SCD adults screened specifically with MRA. We confirm with higher confidence the increased prevalence of ICAN in this population which is in the range of other established indications for aneurysm screening such as Familial Intracranial Aneurysm and Autosomal Dominant Polycystic Kidney Disease. This knowledge could therefore impact the existing screening guidelines for SCD patients via systematic inclusion of an MRA sequence in the recommended imaging protocol.

Formation of Potential Heterotic Groups of Oat Using Variation at Microsatellite Loci.

An evaluation of polymorphism at the microsatellite loci was applied in distinguishing 85 oat (Avena sativa L.) genotypes selected from the collection of genetic resources. The set of genotypes included oats with white, yellow, and brown seeds as well as a subgroup of naked oat (Avena sativa var. nuda Koern). Variation at these loci was used to form potential heterotic groups potentially used in the oat breeding program. Seven from 20 analyzed microsatellite loci revealed polymorphism. Altogether, 35 microsatellite alleles were detected (2–10 per locus). Polymorphic patterns completely differentiated all genotypes within the subgroups of white, brown, and naked oats, respectively. Only within the greatest subgroup of yellow genotypes, four pairs of genotypes remained unseparated. Genetic differentiation between the oat subgroups allowed the formation of seven potential heterotic groups using the STRUCTURE analysis. The overall value of the fixation index (Fst) suggested a high genetic differentiation between the subgroups and validated a heterotic grouping. This approach can be implemented as a simple predictor of heterosis in parental crosses prior to extensive field testing or development and implementation of more accurate genomic selection.

Patients with transthyretin amyloid cardiomyopathy may have preserved, mildly reduced, or reduced ejection fraction

Abstract Background Transthyretin amyloid cardiomyopathy (ATTR-CM) is an often-overlooked form of heart failure with preserved ejection fraction (HFpEF). Previous studies have demonstrated that relatively high proportions of older patients with HFpEF have underlying ATTR-CM. However, while ATTR-CM should not be overlooked as a cause of HFpEF, it also should not be assumed that all patients with ATTR-CM present with HFpEF. Purpose To categorise patients with ATTR-CM from a large clinical trial by left ventricular ejection fraction (LVEF) at enrolment in order to describe the prevalence of HFpEF, HF with mildly reduced EF (HFmrEF), and HF with reduced EF (HFrEF). Methods The Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) enrolled 441 patients with ATTR-CM, including both hereditary (ATTRv) and wild-type (ATTRwt) patients. In ATTR-ACT, all patients underwent echocardiography at enrolment using a standardised protocol, and all images were reviewed and analysed at an independent central laboratory. In this analysis of patient data at enrolment, all patients in ATTR-ACT were categorised by LVEF as: HFpEF (LVEF ≥50%), HFmrEF (LVEF 41–49%), or HFrEF (LVEF ≤40%). The proportions of patients in these LVEF categories in the sub-groups of race, sex, genotype, and disease severity (by NYHA class) were assessed, together with myocardial contraction fraction (MCF) in each category. Results In ATTR-ACT, there were 220 (50.5%) patients with HFpEF, 119 (27.3%) with HFmrEF, and 97 (22.3%) with HFrEF (Table). Five subjects with missing LVEF at enrolment were not categorized. Asian patients had the highest proportion with HFpEF, followed by White, then Black patients. The ATTRwt group had a higher proportion of patients with HFpEF than the ATTRv group. There were significant differences (as assessed by Chi-square test; P=0.0001) in the proportion of patients in each EF category between NYHA class I or II and NYHA class III patients. Median MCF was higher in NYHA class I/II (16.6%) than NYHA class III (14.8%) patients, and higher in patients with HFpEF compared with HFmrEF and HFrEF. Conclusions Not all patients with ATTR-CM have HFpEF. In this analysis of patients at enrolment in ATTR-ACT half had mildly reduced or reduced LVEF, with even higher proportions of reduced EF observed in Black patients, ATTRv patients, and patients with worse functional class (NYHA class III). These data demonstrate that ATTR-CM should be considered as a possible diagnosis in all patients with HF regardless of EF. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Pfizer Table 1

Association between serum amyloid A1 genotype and age of onset restricts to M694 homozygote familial Mediterranean fever patients in Armenia.

Familial Mediterranean fever (FMF) is an autosomal-recessive, inflammatory disorder characterised by short, recurrent attacks of fever, accompanied by pain in the abdomen, chest, or joints and complications of amyloidosis. Recently, we observed a significant association between the serum amyloid A1 (SAA1) β/β genotype and a delayed disease onset in 386 M694V homozygous FMF patients. This follow-up study was conducted to additionally analyse MEFV genotypes other than M694V/M694V for a possible influence of the SAA1 genotype on the age of disease onset. A total of 700 Armenian patients diagnosed with FMF based on the Tel-Hashomer criteria and carrying two MEFV mutant alleles were included in this study. Patients were divided into three MEFV genotypic subgroups: M694V homozygotes (M694V/M694V), M694V compound heterozygotes (M694V/Other), and patients with genotypes excluding M694V (Other/Other). MEFV and SAA1 analyses were performed by a commercial reverse-hybridisation assay, and resulting genotypes were matched against the demographic and clinical characteristics of the patients. Within the subgroup of M694/M694 homozygotes, SAA1 genotype β/β could be identified in 115 (34.43%) and 32 (61.54%) patients with an age of onset <20 and ≥20 years, respectively(p<0.001). However, no such relationship could be observed for MEFV genotypic subgroups M694V/Other (p=0.465) and Other/Other (p=0.697). Our data suggest, that the influence of SAA1 genotypic variation on the age of disease onset restricts to FMF patients homozygous for MEFV mutation M694V.

A randomized, double-blind, placebo-controlled trial of ondansetron for the treatment of cocaine use disorder with post hoc pharmacogenetic analysis

BackgroundCocaine use disorder (CUD) has significant consequences and there remain no FDA-approved pharmacotherapies. Ondansetron is an indirect dopaminergic modulator that has shown efficacy in alcohol use disorder, particularly in phenotypic and genotypic subgroups, and was found to be efficacious in a pilot dose-finding trial for CUD. MethodsOne-hundred eight (108) adults with CUD were randomized to ondansetron 4 mg twice daily or placebo for 9 weeks and assessed up to thrice weekly to evaluate self-reported cocaine use and urine benzoylecgonine. Participants received cognitive-behavioral therapy and brief behavioral compliance enhancement therapy. Consenting participants (N = 79) provided blood samples for exploratory pharmacogenetic analyses. ResultsParticipants in both arms reduced cocaine use over time, but there was no statistically significant difference on percentage of cocaine-free days (PCFD; p = 0.972) or percentage of cocaine-free urine samples (PCFU; p = 0.909). Participants with early-onset CUD had greater improvement regardless of study arm (p = 0.002). Post hoc pharmacogenetic analyses demonstrated an interaction effect between treatment and rs1176713 SNP on PCFU in the total sample (p = 0.040) and African ancestry subset (p = 0.03). Constipation, fatigue, and somnolence were more common among ondansetron-treated participants (Fisher exact p < 0.05). Those who developed constipation were mostly rs1176713:GG carriers (Fisher exact p = 0.029). ConclusionsOndansetron did not demonstrate efficacy in the treatment of CUD. However, these preliminary results suggest a genotype-based variance in response to ondansetron in African ancestry individuals with CUD. Further studies are needed to validate findings for developing a personalized genomic approach for CUD treatment in racially and ethnically diverse populations.

Clinical Study of the Impact of ACE I/D Gene Variation on the Clinical Parameters of Patients with Polycystic Ovary Syndrome

To investigate the relationship between angiotensin Ⅰ-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism and the genetic risks for polycystic ovary syndrome (PCOS) and to evaluate the impact of ACE I/D genotypes on clinical, hormonal, metabolic and oxidative stress parameters in patients with PCOS. This was a retrospective case-control study involving a total of 1 020 PCOS patients and 825 female controls who visited the outpatient clinic of the Department of Reproductive Endocrinology, West China Second Hospital of Sichuan University between 2006 and 2019. The ages of the subjects ranged between 17 and 44. The ACE I/D genotypes were determined by polymerase chain reaction (PCR) and gel electrophoresis. 667 PCOS patients and 527 controls were selected for an analysis of their genotypes and the hormonal, metabolic and oxidative stress parameters. The genotype distributions of the ACE I/D single nucleotide polymorphism was in Hardy-Weinberg equilibrium in both the PCOS group and the control group (all P>0.05), which was representative of the population. There were no statistically significant differences in genotype and allele frequencies between the PCOS and the control groups ( P>0.05). After adjusting for both age and body mass index (BMI), there was no statistically significant difference in clinical characteristics among all genotypes in either the PCOS group or the control group. In the PCOS group, compared with the II genotype subgroup, the ID genotype subgroup had lower luteinizing hormone (LH)/follicle-stimulating hormone (FSH) ratio, while the DD genotype subgroup had higher homeostatic model assessment of insulin resistance (HOMA-IR) and malondialdehyde (MDA) levels. Compared with the ID genotype subgroup, the DD genotype subgroup had lower serum sex hormone binding globulin (SHBG) level, but higher total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels ( P<0.05). In the control group, II genotype subgroup had a higher level of total oxidant status (TOS) than that of the DD genotype subgroup. ACE I/D genetic polymorphism is not associated with risks for PCOS. The I/D variation of ACE gene may be related to insulin resistance, dyslipidaemia, hyperandrogenemia and oxidative stress in PCOS patients.

Association between cognitive impairment and apolipoprotein A1 or apolipoprotein B levels is regulated by apolipoprotein E variant rs429358 in patients with chronic schizophrenia.

ApoE gene polymorphism may be involved in the change in blood lipid profile and cognitive impairment of the general population. However, few studies explored the effects of ApoE gene polymorphism on blood lipid levels and cognition in schizophrenia. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was employed to evaluate the cognition and the SNPStats was used to investigate the association of ApoE rs429358 with schizophrenia. The models of analysis of covariance and multivariate analysis were conducted to investigate the effect of ApoE rs429358 on cognition in schizophrenia. Altogether, 637 patients with schizophrenia and 467 healthy controls were recruited in this study. The findings in the case group found that both the ApoA1 and ApoB levels were predictors for RBANS total score (p < 0.001 vs. p = 0.011), immediate memory (p < 0.001 vs. p = 0.019), language (p < 0.001 vs. p = 0.013), attention (p < 0.001 vs. p < 0.001), except ApoA1 level only was a predictor for visuospatial/constructional (p = 0.014) and delayed memory (p < 0.001). When the association was examined in different ApoE rs429358 genotype subgroups, the association between ApoA1 level and RBANS scores (except for the language score) or between ApoB level and RBANS scores (except for the attention score) was regulated by ApoE rs429358. Our results suggest that patients with schizophrenia have broad cognitive impairment compared with healthy controls. For patients with schizophrenia, both ApoA1 and ApoB levels were positively associated with cognition. There was a significant association between ApoA1 or ApoB levels and cognition in schizophrenia, which was regulated by the ApoE rs429358.

Genetic and Antigenic Characterization of Avian Avulavirus Type 6 (AAvV-6) Circulating in Canadian Wild Birds (2005–2017)

We describe for the first time the genetic and antigenic characterization of 18 avian avulavirus type-6 viruses (AAvV-6) that were isolated from wild waterfowl in the Americas over the span of 12 years. Only one of the AAvV-6 viruses isolated failed to hemagglutinate chicken red blood cells. We were able to obtain full genome sequences of 16 and 2 fusion gene sequences from the remaining 2 isolates. This is more than double the number of full genome sequences available at the NCBI database. These AAvV-6 viruses phylogenetically grouped into the 2 existing AAvV-6 genotype subgroups indicating the existence of an intercontinental epidemiological link with other AAvV-6 viruses isolated from migratory waterfowl from different Eurasian countries. Antigenic maps made using HI assay data for these isolates showed that the two genetic groups were also antigenically distinct. An isolate representing each genotype was inoculated in specific pathogen free (SPF) chickens, however, no clinical symptoms were observed. A duplex fusion gene based real-time assay for the detection and genotyping of AAvV-6 to genotype 1 and 2 was developed. Using the developed assay, the viral shedding pattern in the infected chickens was examined. The chickens infected with both genotypes were able to shed the virus orally for about a week, however, no significant cloacal shedding was detected in chickens of both groups. Chickens in both groups developed detectable levels of anti-hemagglutinin antibodies 7 days after infection.

The miR-200c/141-ZEB2-TGFβ axis is aberrant in human T-cell prolymphocytic leukemia.

T-cell prolymphocytic leukemia (T-PLL) is mostly characterized by aberrant expansion of small- to medium-sized prolymphocytes with a mature post-thymic phenotype, high aggressiveness of the disease and poor prognosis. However, T-PLL is more heterogeneous with a wide range of clinical, morphological, and molecular features, which occasionally impedes the diagnosis. We hypothesized that T-PLL consists of phenotypic and/or genotypic subgroups that may explain the heterogeneity of the disease. Multi-dimensional immuno-phenotyping and gene expression profiling did not reveal clear T-PLL subgroups, and no clear T-cell receptor a or b CDR3 skewing was observed between different T-PLL cases. We revealed that the expression of microRNA (miRNA) is aberrant and often heterogeneous in T-PLL. We identified 35 miRNA that were aberrantly expressed in T-PLL with miR-200c/141 as the most differentially expressed cluster. High miR- 200c/141 and miR-181a/181b expression was significantly correlated with increased white blood cell counts and poor survival. Furthermore, we found that overexpression of miR-200c/141 correlated with downregulation of their targets ZEB2 and TGFbR3 and aberrant TGFb1- induced phosphorylated SMAD2 (p-SMAD2) and p-SMAD3, indicating that the TGFb pathway is affected in T-PLL. Our results thus highlight the potential role for aberrantly expressed oncogenic miRNA in T-PLL and pave the way for new therapeutic targets in this disease.

Use of Artificial Intelligence and Deep Neural Networks in Evaluation of Patients With Electrocardiographically Concealed Long QT Syndrome From the Surface 12-Lead Electrocardiogram

Long QT syndrome (LQTS) is characterized by prolongation of the QT interval and is associated with an increased risk of sudden cardiac death. However, although QT interval prolongation is the hallmark feature of LQTS, approximately 40% of patients with genetically confirmed LQTS have a normal corrected QT (QTc) at rest. Distinguishing patients with LQTS from those with a normal QTc is important to correctly diagnose disease, implement simple LQTS preventive measures, and initiate prophylactic therapy if necessary. To determine whether artificial intelligence (AI) using deep neural networks is better than the QTc alone in distinguishing patients with concealed LQTS from those with a normal QTc using a 12-lead electrocardiogram (ECG). A diagnostic case-control study was performed using all available 12-lead ECGs from 2059 patients presenting to a specialized genetic heart rhythm clinic. Patients were included if they had a definitive clinical and/or genetic diagnosis of type 1, 2, or 3 LQTS (LQT1, 2, or 3) or were seen because of an initial suspicion for LQTS but were discharged without this diagnosis. A multilayer convolutional neural network was used to classify patients based on a 10-second, 12-lead ECG, AI-enhanced ECG (AI-ECG). The convolutional neural network was trained using 60% of the patients, validated in 10% of the patients, and tested on the remaining patients (30%). The study was conducted from January 1, 1999, to December 31, 2018. The goal of the study was to test the ability of the convolutional neural network to distinguish patients with LQTS from those who were evaluated for LQTS but discharged without this diagnosis, especially among patients with genetically confirmed LQTS but a normal QTc value at rest (referred to as genotype positive/phenotype negative LQTS, normal QT interval LQTS, or concealed LQTS). Of the 2059 patients included, 1180 were men (57%); mean (SD) age at first ECG was 21.6 (15.6) years. All 12-lead ECGs from 967 patients with LQTS and 1092 who were evaluated for LQTS but discharged without this diagnosis were included for AI-ECG analysis. Based on the ECG-derived QTc alone, patients were classified with an area under the curve (AUC) value of 0.824 (95% CI, 0.79-0.858); using AI-ECG, the AUC was 0.900 (95% CI, 0.876-0.925). Furthermore, in the subset of patients who had a normal resting QTc (<450 milliseconds), the QTc alone distinguished those with LQTS from those without LQTS with an AUC of 0.741 (95% CI, 0.689-0.794), whereas the AI-ECG increased this discrimination to an AUC of 0.863 (95% CI, 0.824-0.903). In addition, the AI-ECG was able to distinguish the 3 main genotypic subgroups (LQT1, LQT2, and LQT3) with an AUC of 0.921 (95% CI, 0.890-0.951) for LQT1 compared with LQT2 and 3, 0.944 (95% CI, 0.918-0.970) for LQT2 compared with LQT1 and 3, and 0.863 (95% CI, 0.792-0.934) for LQT3 compared with LQT1 and 2. In this study, the AI-ECG was found to distinguish patients with electrocardiographically concealed LQTS from those discharged without a diagnosis of LQTS and provide a nearly 80% accurate pregenetic test anticipation of LQTS genotype status. This model may aid in the detection of LQTS in patients presenting to an arrhythmia clinic and, with validation, may be the stepping stone to similar tools to be developed for use in the general population.

The genomic distribution map of human papillomavirus in Western China.

Human papillomavirus (HPV) has been confirmed as the causative agent for cervical cancer. In this study, a total of 301 880 women were recruited from four different regions of Western China, with 301 880 exfoliated cervical cell samples collected from women for DNA isolation and purification. The HPV genotype was tested by polymerase chain reaction. The overall HPV prevalence rate, high-risk (HR) HPV infection rate, low-risk (LR) HPV infection rate and mixed HPV infection rate was 18.24%, 79.14%, 12.56% and 8.30%, respectively. The four most common HR HPV subtypes were HPV-52, 16, 58 and 53, which accounted for 20.49%, 19.93%, 14.54% and 10.01%, respectively. In LR HPV genotype, HPV-6 ranked the highest (28.17%), followed by HPV-81 (9.09%) and HPV-11 (3.78%). HPV genotype subgroup analysis also showed that single-type infection was the most common (77.26%) among HPV-positive individuals. Among multi-infection genotypes, double infection was the most common with frequencies of 76.04%. The overall prevalence of HPV is high in Western China, whose distribution demonstrates different patterns across different ages and regions. Viral genotypes HPV 53, 6 were frequently detected in this population, which is worth of significant clinical attention.

Detection of coinfection of a divergent subgroup of genotype I Japanese encephalitis virus in multiple classical swine fever virus outbreaks in pigs of Assam, India.

A retrospective investigation of pig tissue samples from different classical swine fever virus (CSFV) outbreaks was undertaken employing RT-PCR for possible coinfection with other swine viruses. Four samples from three different outbreaks were found to be coinfected with Japanese encephalitis virus (JEV). Phylogenetic analysis was done based on complete E gene sequenced from all four coinfected samples. This revealed a new introduction of a divergent subgroup of JEV genotype I in India. This is the first report of detection of coinfection of JEV and CSFV in pigs and the first incidence of JEV genotype I in pigs in India.