Variant Genotypes Research Articles

Upregulation of Interferon Gamma Gene Expression among Asymptomatic Malaria Adults in Bayelsa State, Nigeria

Despite concerted efforts, malaria remains a global public health problem. Treatment for asymptomatic malaria will reduce the health care burden of malaria. However evidence-based data for the presence of systemic pathology in asymptomatic malaria, which might inform treatment remains limited. The present study investigated the current prevalence of asymptomatic malaria in Bayelsa State, Nigeria and differences in interferon gamma (IFNγ) mRNA expression between asymptomatic malaria individuals (AMIs) and uninfected individuals (UIs), in relation to ABO blood groups and hemoglobin genotype (Hb) variants. A cross-sectional design was employed to randomly select 146 non-febrile participants from Sagbama LGA, Bayelsa State. Plasmodium falciparum infection was determined using high-resolution melting analysis and participants were grouped into UIs and AMIs. Hb, blood groups, and IFNγ mRNA expression were determined using electrophoresis, agglutination, and real-time PCR method respectively. Logistic regression and t-test were used to determine significant differences between groups at P < 0.05. The current prevalence of asymptomatic malaria in Bayelsa State was found to be 89.73%. Age and sex were associated with asymptomatic malaria (P < 0.05). Plasmodium falciparum DNA melt curves for AMIs aligned at 83.89±0.34°C, while the amplification cycle thresholds were below 30 cycles. Compared with UIs, the gene expression of IFNγ mRNA was significantly (P < 0.001) higher among AMIs. Also, among AMIs those with A, B, and AB blood groups expressed significantly higher levels of IFNγ mRNA compared with blood groups O AMIs. Furthermore, AMIs with HbAA expressed significantly higher levels of IFNγ mRNA compared with HbAS AMIs. The novelty of the present study is the demonstration of the existence of systemic pathology in asymptomatic malaria and the demonstration that the intensity of systemic pathology is dependent on blood types and haemoglobin genotype variants. Findings of the present study have implications for policy creation towards asymptomatic malaria treatment.

The association of combined GSTM1, GSTT1, and GSTP1 genetic polymorphisms with lung cancer risk in male Iraqi Waterpipe Tobacco (Nargila) smokers

Mutations in genes encoding proteins necessary for detoxifying oxidative stress products have been predicted to increase susceptibility to lung cancer (LC). Despite this, the association between waterpipe tobacco smoking (WP), genetic polymorphisms, and LC risk remains poorly understood. This is the first study to explore the relationship between WP tobacco smoking and these genetic factors. Previously, we investigated the association of GSTP1 SNPs (rs1695-A/G and rs1138272-C/T) with LC in Iraqi males who smoke WP. Here, we expanded our analysis to include GSTM1 (active/null) and GSTT1 (active/null) genotypes, both individually and in combination with GSTP1 SNPs. Multiplex PCR and RFLP-PCR assays were utilized to determine the genotypes of 123 cases and 129 controls. No significant association was observed between GSTM1-null or GSTT1-null genotypes and LC risk, either separately or in combination with variant genotypes of GSTP1 (rs1695 "AG+GG" and rs1138272 "CT+TT"). However, smoking WP and carrying null genotypes elevated the risk five-fold for GSTM1-null (OR 5.17, 95 % CI 2.02–13.24, P<0.001) and three-fold for GSTT1-null (OR 3.08, 95 % CI 1.55–6.13, P=0.001) compared to non-smokers carrying active genotypes. Conversely, genotype distribution analysis based on LC histological types did not indicate an increased risk of LC. Lung cancer is a complex multifactorial disease. WP smoking and GSTs genetic polymorphisms might be associated with an increased risk of developing LC. However, our data did not confirm an association between GST polymorphisms alone and the risk of LC.

Reconstruction of a matrix of genotypic correlations between variants within a gene for joint analysis of imputed and sequenced data

When combining imputed and sequenced data in a single gene-based association analysis, the problem of reconstructing genetic correlation matrices arises. It is related to the fact that for a gene, we know the correlations between genotypes of all imputed variants and the correlations between genotypes of all sequenced variants, but we do not know the correlations between genotypes of variants, one of which is imputed and the other is sequenced. To recover these correlations, we propose an efficient method based on maximising the determinant of the matrix. This method has a number of useful properties and has an analytical solution for our task. Approbation of the proposed method was performed by comparing reconstructed and real correlation matrices constructed on individual genotypes from the UK biobank. Comparison of the results of gene-based association analysis performed by the SKAT, BT and PCA methods on reconstructed and real matrices, using modelled summary statistics and calculated summary statistics on real phenotypes, showed high quality of reconstruction and robustness of the method to different gene structures.

UGT1A1 and BLVRA allele and genotype variants in neonatal patients with hyperbilirubinemia in southern China

We explore the allele and genotype distribution of UGT1A1 and BLVRA variants in individuals affected by neonatal hyperbilirubinemia in southern China. Blood specimens were collected from 240 neonates: 126 cases of hyperbilirubinemia and 114 healthy controls. Serum levels of total protein, albumin, bilirubin (total and direct), urea nitrogen, creatinine, and other biochemical parameters were quantified using a biochemical analyzer. Nine UGT1A1 and five BLVRA genetic variants were genotyped using flight time mass spectrometry. The allele and genotype frequencies of these variants and their associations with neonatal hyperbilirubinemia were analyzed. The genotype frequencies of CC and CG for the UGT1A1 variant rs11888492 in the hyperbilirubinemia group were 90.48% and 9.52%, respectively (P = 0.001), in comparison with the control group. The C and G allele frequencies of rs11888492 in the hyperbilirubinemia group were 95.24% and 4.76%, respectively (P = 0.023). Similarly, in the hyperbilirubinemia group, the genotype frequencies for the UGT1A1 variant rs4148325 were 90.48% CC, 8.73% CT, and 0.79% TT (P = 0.001), with corresponding allele frequencies of 94.84% for C and 5.16% for T (P = 0.002). No notable distinctions were detected for other variants. Newborns carrying the CC genotype of rs11888492 exhibited higher total bilirubin (TBIL) levels than those carrying the GG genotype (P = 0.034), whereas newborns carrying the CC genotype of rs4148325 displayed higher TBIL levels than those carrying the CT genotype (P = 0.003). The presence of the G allele at rs11888492 was found to be significantly correlated with a decreased likelihood of developing neonatal hyperbilirubinemia (odds ratio [OR]: 0.363; 95% confidence interval [CI] 0.169–0.777). Furthermore, a substantial reduction in the risk of neonatal hyperbilirubinemia associated with the CT genotype of rs4148325 were revealed (OR = 0.242; 95% CI 0.102–0.574). Additionally, an inverse relationship was identified between TBIL concentration and the quantity of genetic variants. The UGT1A1 variants rs11888492 and rs4148325 are strongly associated with neonatal hyperbilirubinemia in southern China.

Long-term all-cause and cardiovascular-related mortality in patients with ATTR-CM treated with continuous tafamidis vs placebo to tafamidis by NAC stage at baseline

Abstract Background The National Amyloidosis Centre (NAC) staging system is used to stratify patients with transthyretin amyloid cardiomyopathy (ATTR-CM) into prognostic categories.[1] Purpose This post hoc analysis evaluated all-cause and cardiovascular (CV)-related mortality in patients receiving tafamidis 80 mg or placebo by NAC stage at baseline in the phase 3 Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) and its long-term extension (LTE) study.[2,3] Methods Patients in ATTR-ACT were randomised to tafamidis meglumine 80 mg, 20 mg, or placebo for 30 months, stratified by transthyretin (TTR) genotype (wild-type or variant) and NYHA class (I or II/III). Patients with an NT-proBNP &amp;lt;600 ng/l or eGFR &amp;lt;25 ml/min/1.73m² were excluded. After completing ATTR-ACT, patients could receive tafamidis 61 mg up to 60 months in the open-label LTE study. Heart transplant and cardiac mechanical assist device implantation were treated as death in the mortality assessments. Secondary analyses were change from baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical and overall summary (CS, OS) scores and frequency of all-cause and CV-related hospitalisations. Results Of 350 patients, 42%, 38% and 20% had NAC stage I, II and III at baseline, respectively. Patients at stage III tended to be older, more likely female, and with a variant TTR genotype vs those at a lower stage (Table). At the end of follow-up, all-cause mortality was consistently lower in patients continuously treated with tafamidis vs those who initially received placebo across NAC stages (I: 36% vs 61%; : 55% vs 74%; III: 69% vs 88%). The hazard ratio (HR [95% CI]) for all-cause mortality with continuous tafamidis treatment vs placebo to tafamidis was 0.43 (0.26-0.70; P&amp;lt;0.001), 0.51 (0.33-0.80; P=0.003) and 0.75 (0.44-1.29; P=0.298), for patients at stage I, II and III, respectively. Similar trends were observed in CV-related mortality at the end of follow-up, where HR (95% CI) for continuous tafamidis-treated patients at stage I, II and III was 0.39 (0.22-0.70; P=0.001), 0.51 (0.31-0.85; P=0.009) and 0.75 (0.42-1.33; P=0.320). The separation of survival curves was seen in the first few months of tafamidis treatment in patients at NAC stage I (Figure A). Such early separation was not seen in those at stage II or III. Starting from Month 18, statistically smaller declines in KCCQ-OS and CS scores were frequently observed in the continuous tafamidis vs placebo to tafamidis groups at stages I and II. Across NAC stages, all-cause and CV-related hospitalisations were lower in the continuous tafamidis vs placebo to tafamidis group (Figure B). Conclusions Continuous tafamidis treatment reduced mortality and hospitalisations (both all-cause and CV-related) across all NAC stages. These reductions were larger and occurred earlier in patients with NAC stage I, emphasising the importance of early disease-modifying treatment in patients with ATTR-CM.[3] NCT01994889, NCT02791230.

Association of FTO variants rs9939609 and rs1421085 with elevated sugar and fat consumption in adult obesity

This cross-sectional study explores the impact of FTO gene single nucleotide polymorphisms (SNPs) rs9939609 and rs1421085 on dietary habits contributing to obesity risk in Thai adults. The study enrolled 384 participants from Bangkok, categorized as non-obese (BMI < 25 kg/m2) or obese (BMI ≥ 25 kg/m2) based on WHO Asia Pacific Guidelines. Genotyping for FTO variants was performed using DNA from blood samples. While both SNPs adhered to Hardy–Weinberg equilibrium, the association between risk alleles and anthropometric measurements was not statistically significant. However, risk allele carriers showed significantly higher intakes of sugar and saturated fat compared to homozygous dominant individuals. In the obese group, the odds ratio for high-sugar intake was 2.22 (95% CI 1.13–4.37, p = 0.021) for rs9939609 risk allele carriers. For high-saturated fat intake, the odds ratio was 1.86 (95% CI 1.02–3.40, p = 0.041). Similar associations were observed for rs1421085. Risk allele carriers also exhibited significantly higher leptin levels (p < 0.043) and a positive correlation with myeloperoxidase levels (p < 0.038). These findings highlight the complex relationship between FTO risk alleles, increased consumption of sugar and saturated fat, and obesity-related parameters. The insights emphasize the importance of considering both genetic and dietary factors in obesity prevention strategies.

Association of selected gene variants with nonsyndromic orofacial clefts in Kuwait

Introduction and objectivesNon-syndromic orofacial clefts (NSOFCs) are complex congenital abnormalities involving both environmental and genetic factors involved in orofacial development. This study aimed to investigate the genetic association of specific genetic variants at different CYRIA gene loci with the development of NSOFCs in Kuwait. MethodsFour genetic variants (rs7552, rs3758249, rs3821949, and rs3917201) at four selected gene loci (CYRIA, FOXE1, MSX1, and TGFB3) were genotyped in a total of 240 DNA samples (patients (n = 114) and random controls (n = 126)) employing TaqMan® allele discrimination assay. For each variant and its genotype, the frequencies were determined and tested for Hardy-Weinberg Equilibrium. Genotype frequencies was compared between patients and controls using Pearson’s test. Logistic regression analyses were employed to test for the associations of the four selected variants with the occurrence of NSOFCSs. ResultsSignificant differences in the distribution of genotypes between cases and controls, rs7552, rs3821949, and rs3917201 were found to have a positive association with NSOFCs. After adjusting for gender, the GG genotype of the rs7552 variant, the AG genotype of the rs3821949 variant, and the CC genotype of the rs3917201 variant showed nearly a two-fold increased risk of NSOFC (p < 0.05). ConclusionThis study reports significant findings on the contribution and modest effect of CYRIA rs7552, MSX1 rs3821949, and TGFB3 rs3917201 in the development of NSOFCs. Our findings provide further evidence on the molecular mechanism and the role of the selected genes in NSOFCs.

Association of IL-6 G-174C (rs1800795) variant with the susceptibility to hepatocellular carcinoma in patients with chronic hepatitis

AimAn ineffective immune response resulting from dysregulation of cytokine production might encourage viral persistence and cause chronic viral hepatitis to worsen. This study examined the relationship between alterations in interleukin-6 (IL-6) levels and the IL-6 − 174 G > C (rs1800795) polymorphism, as well as how this polymorphism affects the development and progression of chronic hepatitis brought on by hepatitis B (HBV) and hepatitis C (HCV) into hepatocellular carcinoma (HCC).Patients and methodsWhole blood samples from 126 Egyptian patients with HCC (111 with HCV and 15 with HBV), as well as 126 age- and sex-matched healthy individuals, were used to extract DNA. Using PCR-based allele-specific amplification (ASA), the existence of the IL-6 G-174C polymorphism was investigated. Additionally, each participant's serum IL-6 levels were determined using an enzyme-linked immunosorbent assay (ELISA).ResultsThe primary observations revealed that HCC patients had greater serum levels of IL-6 compared to the control groups (p < 0.001). Patients with the variant (CG and GG) genotype in the HCC group were found to have more disease severity indicated by higher levels of alpha-fetoprotein (AFP) and a higher ascites grade, as well as increased inflammatory activity as defined by higher levels of IL-6 and C-reactive protein (CRP) (p < 0.001 for both) in comparison to patients with the wild-type (CC) genotype (p < 0.001 and p = 0.002, respectively).ConclusionThe rs1800795 SNP in the IL-6 gene was associated with increased inflammatory activity and high levels of IL-6, indicating that this SNP may play a role in the development of HCC in Egyptian patients with chronic viral hepatitis.

Association of polymorphism of NLRP3, ICAM-1, PTPN22, INS genes in childhood onset type 1 diabetes in a Pakistani population.

Type 1 diabetes (T1D) is an organ-specific autoimmune disorder characterized by the destruction of pancreatic β cells, leading to absolute insulin deficiency. The genes NLRP3, ICAM-1, PTPN22, and INS are reportedly associated with T1D in other populations. However, the genetic pattern of T1D in the Pakistani population is not clear. This study aimed to find the association of polymorphisms in the PTPN22, INS, NLRP3, and ICAM-1 genes with T1D susceptibility in the Pakistani population. This case-control study includes 100 T1D patients (3-14 years), recruited randomly from the pediatric endocrinology department of Fatima Memorial Hospital, Lahore, Pakistan and 100 age-matched healthy controls were selected from different localities of the same population. The polymorphisms in PTPN22 (rs601, rs33996649, rs2488457), INS (rs80356664), NLRP3 (rs10754558, rs35829419), and ICAM-1 (rs1799969, rs5498) genes were genotyped by Sanger sequencing. The genotypic and allelic frequencies, haplotypes, and linkage disequilibrium were computed using the genetic toolset PLINK to investigate their relationship to T1D. The results indicate that the occurrence of the GT genotype of the rs33996649 variant is significantly higher in children with T1D compared to a control group of healthy individuals (P = 0.001, OR: 2.0, 95% CI = 0.15-0.45). Furthermore, the CT genotype of rs2488457 was notably associated with T1D patients (P = 0.007, OR: 2.8, 95% CI = 0.56-0.67). The CG genotype of rs80356664 showed a slight association with T1D (P = 0.03, OR: 1.9, 95% CI = 0.35-0.59). The prevalence of the AT genotype of rs10754558 showed a strong association with T1D (P = 0.005, OR: 3.4, 95% CI = 0.45-0.69). The TG genotype of rs5498 was also strongly associated with T1D (P = 0.009, OR: 2.8, 95% CI = 0.75-0.89). The present study provides evidence that SNPs in the PTPN22, INS, NLRP3, and ICAM-1 genes are associated with the development of T1D. Further research is needed to explore their potential use in genetic screening and personalized medication.

Allelic, Genotypic, and Haplotypic Analysis of Cytokine IL17A, IL17F, and Toll-like Receptor TLR4 Gene Polymorphisms in Metabolic-Dysfunction-Associated Steatotic Liver Disease: Insights from an Exploratory Study.

(1) Background: Interleukin 17 (IL17) and toll-like receptor 4 (TLR4) elevate the risk of metabolic and liver diseases. (2) Methods: This study's objective was to explore the association of IL17 and TLR4 gene polymorphisms with MASLD susceptibility and test their effect on serum IL17 and TLR4 levels. A total of 43 patients with MASLD (MASH/MAFL) and 38 healthy individuals were genotyped for IL17F-A7488G, IL17A-G197A, TLR4-Asp299Gly, and TLR4-Thr399Ile polymorphisms using PCR-RFLP. ELISA methods determined IL17F, IL17A, and TLR4 serum levels. (3) Conclusions: Patients carrying the variant genotypes (A/G + G/G) of IL17-A7448G (OR = 5.25), (G/A + A/A) of IL17-G197A (OR = 10.57), (Asp/Gly + Gly/Gly) of TLR4-Asp299Gly (OR = 3.52), or (Thr/Ile + Ile/Ile) of TLR4-Thr399Ile (OR = 9.87) had significantly increased odds of MASH. Genotype (G/A + A/A) of IL17-G197A was significantly associated with the odds of MAFL (p = 0.0166). Allele A of the IL17-G197A polymorphism was significantly related to increased odds of MAFL (OR = 4.13, p = 0.0133). In contrast, allele A of IL17-G197A (OR = 5.41, p = 0.008), allele Gly of TLR4-Asp299Gly (OR = 3.19, p = 0.046), and allele Ile of TLR4-Thr399Ile (OR = 6.94, p = 0.008) polymorphisms were significantly related to an increased risk of MASH. Allele A of IL17A-G197A, allele Gly of TLR4-Asp299Gly, and allele Ile of TLR4-Thr399Ile gene polymorphisms were significantly associated with the increased odds of MASLD. In patients with MASLD, we found significant influence from the IL17A-G197A gene polymorphism on IL17F levels (p = 0.0343).

Erratum: JFH1-based Core-NS2 genotype variants of HCV with genetic stability in vivo and in vitro: Important tools in the evaluation of virus neutralization.

Erratum: JFH1-based Core-NS2 genotype variants of HCV with genetic stability in vivo and in vitro: Important tools in the evaluation of virus neutralization.

MUC5B rs35705950 Promoter Variant Is Associated with Usual Interstitial Pneumonia in Patients with Antisynthetase Syndrome

Background: The presence of the rs35705950 variant in the MUC5B gene promoter is a critical genetic risk factor in idiopathic pulmonary fibrosis (IPF). It has been associated with usual interstitial pneumonia (UIP) in several interstitial lung diseases (ILDs). In antisynthetase syndrome (ASSD), most high-resolution computed tomography (HRCT) patterns are inflammatory, but up to 13% have UIP, leading to a worse prognosis. Methods: This single-center study included 60 patients with ASSD-ILD. We investigated whether carrying the MUC5B rs35705950 promoter variant was associated with UIP. To estimate the strength of the association between the genotype of the MUC5B rs35705950 promoter variant and the fibrotic pattern we used the odds ratio (cOR), and to assess the effect of confounding variables (age, evolution time, and sex), we performed a logistic regression to obtained the adjusted odds ratio (aOR). Results: The GT genotype of the MUC5B rs35705950 promoter variant is associated with up to a 4-fold increased risk of UIP (cOR 5.0, 95% CI 1.13–22.10), and the effect was even maintained after adjusting for potentially confounding variables such as sex, age, and time to progression (aOR 5.2, 95% CI 1.04–25.89). Conclusions: our study supports the role of MUC5B rs35705950 in ASSD-ILD with UIP. It reinforces that this polymorphism in our population could have a similar genetic basis to that already described in other ILDs that present predominantly fibrotic patterns.

Predictors of COVID-19 severity among a cohort of Egyptian patients

BackgroundAs the outbreak of COVID-19 progresses, prognostic markers for the identification of high-risk individuals are urgently needed. The angiotensin system is implicated in the pathogenesis of COVID-19 as ACE2 is the cellular receptor for SARS-COV-2 virus, and expression of the ACE2 gene could regulate an individual’s susceptibility to infection. In addition, the balance between ACE and ACE2 activity may play a role in the severity of COVID-19.Aim of workThe aim of the work is to explore the role of ACE1 I/D and ACE2 G8790A gene variants and serum ACE l/ACE2 ratio as risk factors for severity of COVID-19 infection.MethodsOne hundred and eighty COVID-19 patients were divided into three groups: mild (60 patients), moderate (60 patients), and severe (60 patients). The enzyme levels of ACE and ACE2 were measured by ELISA. ACE I/D (rs4646994) was assayed using PCR and ACE2 (rs2285666) gene variant was determined using real-time PCR.ResultsACE/ACE2 ratio was significantly lower in the mild group than in the moderate-to-severe group (P < 0.001). GG (reference) genotype and G allele of ACE2 were more frequent in mild group, AA (variant) genotype, and A allele were more frequent in severe group (P value < 0.001). In the multiple logistic regression, COVID-19 severity was associated with older age (> 50y) (OR 10.4, 95% CI 3.8–28.4, P < 0.001), comorbidities (OR 8.2, 95% CI 1.6–42.1, P 0.012), and higher ACE/ACE2 ratio (OR 8.3, 95% CI 3.7–18.6 P < 0.001) were independent significant predictors of severity. Haplotype analysis revealed that patients with D allele of the ACE gene combined with the A allele of the ACE2 gene had nearly double the risk of having severe COVID infection (OR = 1.9, 95% CI 1.1–3.5, P = 0.024).ConclusionOld age (> 50 years), presence of comorbidities, and a high ACE/ACE2 ratio are recognized as pivotal predictors of COVID-19 severity.

Molecular testing in a patient with multiple alloantibodies and warm autoimmune hemolytic anemia: A case study

Abstract Introduction/Objective We present a case of RBC alloimmunization and warm autoimmune hemolytic anemia (WAIHA) in a patient with a recent RBC transfusion. Serological testing followed by molecular testing revealed a rare D+ C- E- partial c+ partial e+ VS+ V+ hrS+ hrB+vw/- predicted phenotype. Methods/Case Report A 75-year-old black male with secondary myelofibrosis presented with a sudden onset of chest pain, dyspnea and weakness during an RBC transfusion. The patient was subsequently admitted for further workup. Labs showed low hemoglobin, low haptoglobin, elevated LDH and a positive direct antiglobulin (DAT) test. The patient was started on intravenous immunoglobulin and steroids for suspected WAIHA. On immunohematology serologic testing, blood typed as B-positive and polyspecific DAT positive with anti-IgG positive and anti-C3 negative. Serum plasma studies showed probable warm autoimmune hemolytic anemia and allo anti-S, -E, and -C by previous history. Eluate studies showed panagglutinin and antibody with D-like specificity. Immucor PreciseTypeTM Human Erythrocyte Antigen (HEA) Molecular BeadChip test predicted a partial e antigen and potential hrB-. Genotyping for RHD variants was performed and revealed RHD*01 (homozygous or hemizygous). Targeted genomic testing did not detect variants associated with common partial or weak RhD antigens. Based on this testing, the patient was not predicted to be at risk of allo-anti-D. An RHCE genotype for C, c, E and e variants including hrB and hrS showed RHCE*ce48C,733G/RHCE*ce733G with predicated phenotype of D+ C- E- partial c+ partial e+ VS+ V+ hrS+ hrB+vw/-. Based on the RHCE testing, the patient was predicted to be at risk for allo-anti-c, -e, -f (ce) and possibly anti-hrB. Results (if a Case Study enter NA) NA Conclusion In this case, serologic testing alone did not reveal a precise diagnosis. Molecular testing aided in the diagnosis of WAIHA and will help guide future transfusions. Pathologists must consider molecular testing when faced with a challenging serologic diagnosis.

Investigations of associations between TNF-α promoter polymorphisms and genetic susceptibility to type 2 diabetes mellitus: A cross-sectional study in Chinese Han population.

Type 2 diabetes (T2DM) is characterised by insulin resistance and a relative shortage of insulin secretion. Tumour necrosis factor-α (TNF-α) plays an important role in insulin resistance by impairing insulin signal transduction. The variants of the TNF-α promoter region are considered to influence its transcription and are associated with the TNF-α level. Therefore, it is worth detecting the association of the variants in the TNF-α gene with the development of T2DM. The aim of this study was to investigate the association of five variants (rs1799964, rs1800630, rs1799724, rs1800629 and rs361525) in the TNF-α gene promoter region with T2DM in a Chinese Han population. A total of 713 subjects with T2DM and 751 nondiabetic subjects were genotyped using the TaqMan method. The associations of the five variants with the development of T2DM were evaluated. The associations of the five variant genotypes with metabolic traits in nondiabetic subjects were analysed. Our data showed that the A allele of rs1800629 could increase the risk of developing T2DM (p=.002, OR=1.563; 95% CI: 1.18-2.08). According to inheritance mode analysis, compared with the G/G genotype, the G/A+2A/A genotype of rs1800629 showed a risk effect on T2DM in the log-additive mode (p=.002, OR=1.56; 95% CI: 1.17-2.07). The haplotypes analysis identified that the rs1799724-rs1800629CA was associated with high risk of the development of T2DM (p=.002, OR=1.559, 95% CI: 1.173-2.072). Conversely, the rs1799724-rs1800629CG was a protective haplotype of T2DM (p=.001, OR=0.732, 95% CI: 0.607-0.884). Moreover, compared with the rs1799964 (T/T+C/T) genotype, the rs1799964 C/C genotype was associated with higher glycosylated haemoglobin (HbA1c) levels in nondiabetic subjects (p=.017). Our results revealed that the rs1800629 in the TNF-α gene promoter region was associated with T2DM in a Chinese Han population.

Study of the driving factors of the abnormal influenza A (H3N2) epidemic in 2022 and early predictions in Xiamen, China

BackgroundInfluenza outbreaks have occurred frequently these years, especially in the summer of 2022 when the number of influenza cases in southern provinces of China increased abnormally. However, the exact evidence of the driving factors involved in the prodrome period is unclear, posing great difficulties for early and accurate prediction in practical work.MethodsIn order to avoid the serious interference of strict prevention and control measures on the analysis of influenza influencing factors during the COVID-19 epidemic period, only the impact of meteorological and air quality factors on influenza A (H3N2) in Xiamen during the non coronavirus disease 2019 (COVID-19) period (2013/01/01-202/01/24) was analyzed using the distribution lag non-linear model. Phylogenetic analysis of influenza A (H3N2) during 2013–2022 was also performed. Influenza A (H3N2) was predicted through a random forest and long short-term memory (RF-LSTM) model via actual and forecasted meteorological and influenza A (H3N2) values.ResultsTwenty nine thousand four hundred thirty five influenza cases were reported in 2022, accounting for 58.54% of the total cases during 2013–2022. A (H3N2) dominated the 2022 summer epidemic season, accounting for 95.60%. The influenza cases in the summer of 2022 accounted for 83.72% of the year and 49.02% of all influenza reported from 2013 to 2022. Among them, the A (H3N2) cases in the summer of 2022 accounted for 83.90% of all A (H3N2) reported from 2013 to 2022. Daily precipitation(20–50 mm), relative humidity (70–78%), low (≤ 3 h) and high (≥ 7 h) sunshine duration, air temperature (≤ 21 °C) and O3 concentration (≤ 30 µg/m3, > 85 µg/m3) had significant cumulative effects on influenza A (H3N2) during the non-COVID-19 period. The daily values of PRE, RHU, SSD, and TEM in the prodrome period of the abnormal influenza A (H3N2) epidemic (19–22 weeks) in the summer of 2022 were significantly different from the average values of the same period from 2013 to 2019 (P < 0.05). The minimum RHU value was 70.5%, the lowest TEM value was 16.0 °C, and there was no sunlight exposure for 9 consecutive days. The highest O3 concentration reached 164 µg/m3. The range of these factors were consistent with the risk factor range of A (H3N2). The common influenza A (H3N2) variant genotype in 2022 was 3 C.2a1b.2a.1a. It was more accurate to predict influenza A (H3N2) with meteorological forecast values than with actual values only.ConclusionThe extreme weather conditions of sustained low temperature and wet rain may have been important driving factors for the abnormal influenza A (H3N2) epidemic. A low vaccination rate, new mutated strains, and insufficient immune barriers formed by natural infections may have exacerbated this epidemic. Meteorological forecast values can aid in the early prediction of influenza outbreaks. This study can help relevant departments prepare for influenza outbreaks during extreme weather, provide a scientific basis for prevention strategies and risk warnings, better adapt to climate change, and improve public health.

Generation and epitope mapping of novel neutralizing monoclonal antibodies against glycoprotein E2 of CSFV

Classical swine fever virus (CSFV) is a highly contagious and economically important pathogen threatening pig industry worldwide, the envelope glycoprotein E2 of CSFV is the dominant antigen inducing strong antiviral neutralizing immunity. In this study, 7 monoclonal antibodies (mAbs) with neutralizing potency were generated using E2 protein of CSFV Shimen strain (SM) expressed by eukaryotic cells. Their reactivity with 116 CSFV strains in cell cultures and E2 proteins of 10 subgenotypes in western blots showed different CSFV spectrums they recognized. Of them, three (HCL-001, HCL-005 and HCL-010) reacted with all CSFV subgenotypes, while HCL-014 and HCL-002 reacted with most CSFV strains, except for some variants in genotype 2.3. In contrast, mAb HCL-009 reacted only with a few subgenotype 1.1 strains including SM, field strains and some vaccine strains. Interestingly, mAb HCL-018 reacted only with SM and field subgenotype 1.1 strains, not with any vaccine strains. Further epitope mapping using chimeric and site-directed mutated E2 proteins showed that HCL-001, HCL-005 and HCL-010 recognized a conservative epitope motif 143SPT145,L147, and HCL-002 recognized a conformational epitope with key aa motifs of 95GDD97,157RX(D/E)K(R)XFXXR164. HCL-014 recognized a new conservative epitope with key aa motifs of 41D,58XNVVXRR64. HCL-009 and HCL-018 recognized the epitope with key aa motifs of 36D,40ND41,45KXI47 and 69LHXGXLLT76, respectively. Taken together, present study has provided not only new insights into the antigenic structure of E2 protein, but also key reagents for antigenic characterization of CSFV strains and development of antibody assay for evaluation of the vaccination efficacy.

Hot topic: Influenza A H5N1 virus exhibits a broad host range, including dairy cows

The widespread circulation of highly pathogenic avian influenza (HPAI) H5N1 clade 2.3.4.4b in wild birds in North America since late 2021 has resulted in multiple outbreaks in commercial and backyard poultry leading to major economic losses. Since the emergence of the virus in North America, multiple reassortment events have led to the emergence of many new variant genotypes that have been isolated from wild birds, with several viruses spilling over into poultry and other terrestrial and aquatic mammalian hosts. Notably, the most recent emerging HPAI H5N1 reassortant genotype B3.13 spilled over into dairy cattle (Bos taurus), resulting in unprecedented efficient transmission of the virus in this species, the first case of sustained transmission in a mammalian species. The transmission pathways involved in the spread of the virus from its first detection in Texas to several other states are complex. However, movement of subclinically infected cattle likely played a major role in virus spread. Infection in dairy cattle is characterized by the virus's tropism for milk-secreting cells in the mammary gland, leading to high viral load and shedding in milk. Replication of the virus in milk-secreting cells results in destruction of infected cells leading to severe viral mastitis, which is characterized by marked changes in milk quality (altered consistency and color) and pronounced decline in milk production by clinically affected animals. Here, we provide an overview of the HPAI H5N1 panzootic virus and discuss its host range and the current knowledge of its pathogenesis in the new bovine host.

High plasma concentration of tenofovir alafenamide in people living with HIV with ABCB1 genetic variants

ObjectivesWe aimed to analyze the relationships between single nucleotide polymorphisms in the ATP-binding cassette transporter B1 (ABCB1) and G2 (ABCG2) genes and plasma concentrations of tenofovir alafenamide (TAF), tenofovir (TFV), and emtricitabine (FTC). MethodsWe recruited 10 people living with HIV receiving once-daily treatment with a single tablet containing TAF (25 mg), FTC (200 mg), and bictegravir (50 mg). Peripheral blood samples were collected at 0, 1, 2, 3, 4, 6, 8, 12, and 24 h after administration. Plasma concentrations of TAF, TFV, and FTC were quantified using liquid chromatography-tandem mass spectrometry. Genotyping for allelic variants of ABCB1, including 1236 C>T (rs1128503), 2677 G>T/A (rs2032582), 3435 C>T (rs1045642), 4036 A>G (rs3842) and ABCG2 421 C>A (rs2231142), was performed using TaqMan Drug Metabolism Assays. ResultsNone of the genotypes for ABCB1 1236 C>T, 2677 G>T/A, 3435 C>T, and ABCG2 421 C>A exhibited correlations with plasma concentrations of TAF, TFV, and FTC. In contrast, individuals with the ABCB1 4036 AG genotype (188.7 ng/mL, n = 3) exhibited a significantly higher mean peak plasma concentration of TAF than those with the ABCB1 4036 AA genotype (67.7 ng/mL, n = 7) (p = 0.0167). However, these genotypes did not affect the elimination of terminal half-lives of TAF. ConclusionsThe allelic variant ABCB1 4036 A>G is associated with reduced protein expression and function of ABCB1. Individuals with this genetic variant exhibited significantly high peak plasma concentrations of TAF, potentially due to the reduced expression of efflux transporters in the intestines linked to this variant.

Atypical ADPKD Due to Complex Genotypes of Both PKD1 and HNF1B Pathogenic Variants: An Educational Case Report

Atypical ADPKD Due to Complex Genotypes of Both PKD1 and HNF1B Pathogenic Variants: An Educational Case Report