Risk Genotypes Research Articles

SNP-SNP positive interaction between MMP2 and MMP12 increases the risk of COPD.

Determining SNP-SNP interaction of the disease has become important for further investigation of pathogenesis and experimental research. Although many studies have been published on the effect of MMPs gene polymorphisms on chronic obstructive pulmonary disease (COPD), there is a lack of information on SNP-SNP and SNP-environment interactions. This study aimed to investigate the interaction between the polymorphisms of MMP1, MMP2, MMP9 and MMP12 genes and its combined effect with smoking on the risk of developing COPD. Totally 181 COPD patients and 292 healthy individuals were involved. Blood samples from the participants were tested for genotyping and data were collected through questionnaires. Genotyping was performed with nested allele-specific polymerase chain reaction (AS-PCR) and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). SNP-SNP and SNP-environment interactions were investigated using multifactor dimensionality reduction and logistic regression analysis. The result showed that participants with high nicotine dependence and heavy smokers had a higher risk of COPD than non-smokers. Also, G/G genotype (cOR = 5.83; 95% CI, 1.19-28.4, p = 0.029) of MMP2 rs243864 and T/T genotype (cOR = 1.79; 95% CI, 1.16-2.76, p = 0.008) of MMP12 rs652438 independently contributes to the susceptibility of COPD. For SNP-SNP interaction, the positive interaction between rs243864 G/G genotype of MMP2 and rs652438 T/T genotype of MMP12 was found, and the combination of risk genotypes has a high risk of COPD (OR = 12.92; 95% CI, 1.46-114.4, p = 0.021). Moreover, the combination of T/T genotype of MMP12 rs652438 and smoking-related factors increases the risk of COPD approximately 4.5 to 6-fold. The results suggests that there is a combination of MMP2, MMP12, and smoking-related factors may increase the risk of developing COPD.

Development of a Risk Model and Genotyping Patterns Based on Disulfidptosis-Related lncRNAs to Predict Prognosis and Immune Landscape in Osteosarcoma.

Osteosarcoma (OS) is the most prevalent orthopedic malignancy with a dismal prognosis. Disulfidptosis-related lncRNAs (DRLncs) may be related to the progression of OS, but their potential molecular regulatory role is still unclear. Based on the data collected from The Cancer Genome Atlas (TCGA), we conducted correlation analysis and the univariate Cox analysis to screen prognosis-related DRLncs, followed by developing genotyping patterns and corresponding classifier. Subsequently, the survival analysis, enrichment analysis, drug sensitivity analysis and immune infiltration analysis were performed. Afterward, multivariate Cox regression was used to construct a risk model, which was further validated by the receiver operating characteristic (ROC) curve. The aberrant expression of hub DRLncs in OS was validated using the Reverse Transcription Polymerase Chain Reaction (RT-qPCR) assay. We identified 262 DRLncs and eleven prognosis-related DRLncs through filtering. We then constructed two distinct expression patterns of prognosis-related DRLncs and developed a classifier. We obtained 393 differentially expressed genes (DEGs) between different subtypes, which were significantly enriched in biological processes related to the extracellular matrix, integrin binding, focal adhesion, and Wnt signaling pathways. Through immune infiltration analysis, the activated CD4 memory T cells, resting natural killer (NK) cells, M1 macrophages, and resting dendritic cells (DC) were observed to exhibit different abundance in distinct subtypes. In the drug sensitivity analysis, tamoxifen showed a promising effect for drug-resistant OS. Furthermore, we identified five hub DRLncs and constructed a risk model. The RT-qPCR confirmed the aberrant expression of five hub DRLncs in OS. The present study identified DRLncs in OS, and conducted a comprehensive investigation of DRLncs-related expression patterns, survival status, immune landscape and drug sensitivity to reveal the difference in prognostic, pharmacological and immunological phenotype characteristics between distinct subtypes. Additionally, we developed a risk model to predict the prognosis, and constructed a genotyping classifier to predict the above phenotype characteristics in OS.

TLR9 gene polymorphism confers risk to Helicobacter pylori infection in Jiangsu, China and its inspiration for precision nursing car.

The number of studies which investigate the association between TLR9 gene polymorphism and Helicobacter pylori (H.pylori) infection is low and their results are not consistent. To get a better understanding of the association between TLR9 gene polymorphism and H.pylori infection, providing basis and risk assessment for precision nursing for hospital nurses. A total of 630 normal physical examination subjects were collected including 240 H.pylori (+) and 390 H.pylori (-) subjects. PCR-RFLP was applied to investigate the present polymorphism. At the same time, the meta-analysis was performed between TLR9 gene polymorphism and H.pylori infection risk. Three genotypes (TT, TC, and CC) were observed for TLR9 gene rs187084 polymorphism. CC genotype and C allele were responsible for the significant associations (all P< 0.05). Meta-analysis found no significant associations were found by any genetic models (all P> 0.05). TLR9 polymorphism has a crucial role in H.pylori infection risk and CC genotype confers increased risk to H.pylori infection in the Southern Chinese population. After understanding the influence of TLR9 gene polymorphism on H.pylori infection, nurses can improve the risk assessment of Helicobacter pylori infection and provide health education more personally.

African ancestry-derived APOL1 risk genotypes show proximal epigenetic associations

Apolipoprotein L1 (APOL1) coding variants, termed G1 and G2, are established genetic risk factors for a growing spectrum of diseases, including kidney disease, in individuals of African ancestry. Evidence suggests that the risk variants, which show a recessive mode of inheritance, lead to toxic gain-of-function changes of the APOL1 protein. Disease occurrence and presentation vary, likely due to modifiers or second hits. To understand the role of the epigenetic landscape in relation to APOL1 risk variants, we performed methylation quantitative trait locus (meQTL) analysis to identify differentially methylated CpGs influenced by APOL1 risk variants in 611 African American individuals. We identified five CpGs that were significantly associated with APOL1 risk alleles in discovery and replication studies, and one CpG-APOL1 association was independent of other genomic variants. Our study highlights proximal DNA methylation alterations that may help explain the variable disease risk and clinical manifestation of APOL1 variants.

Assessment of glial fibrillary acidic protein and anti-glial fibrillary acidic protein autoantibody concentrations and necrotising meningoencephalitis risk genotype in dogs with pug dog myelopathy.

Pugs commonly present with thoracolumbar myelopathy, also known as pug dog myelopathy (PDM), which is clinically characterised by progressive signs involving the pelvic limbs, no apparent signs of pain and, often, incontinence. In addition to meningeal fibrosis and focal spinal cord destruction, histopathology has confirmed lymphohistiocytic infiltrates in the central nervous system (CNS) in a considerable number of pugs with PDM. Lymphohistiocytic CNS inflammation also characterises necrotising meningoencephalitis (NME) in pugs. This study aimed to investigate the potential contribution of an immunological aetiology to the development of PDM. The concentrations of glial fibrillary acidic protein (GFAP) in serum and CSF and of anti-GFAP autoantibodies in CSF were measured with an ELISA. In addition, a commercial test was used for genetic characterisation of the dog leukocyte antigen class II haplotype, which is associated with NME susceptibility. This study included 87 dogs: 52 PDM pugs, 14 control pugs, four NME pugs and 17 dogs of breeds other than pugs that were investigated for neurological disease (neuro controls). Anti-GFAP autoantibodies were present in 15 of 19 (79%) of the PDM pugs tested versus six of 16 (38%) of the neuro controls tested (p = 0.018). All 18 PDM pugs evaluated had detectable CSF GFAP. Serum GFAP was detected in two of three (67%) of the NME pugs and in two of 11 (18%) of the control pugs but not in any of the 40 tested PDM pugs. Male pugs heterozygous for the NME risk haplotype had an earlier onset of clinical signs (70 months) compared to male pugs without the risk haplotype (78 months) (p = 0.036). The study was limited bythe lack of healthy dogs of breeds other than pugs and the small numbers of control pugs and pugs with NME. The high proportion of PDM pugs with anti-GFAP autoantibodies and high CSF GFAP concentrations provide support for a potential immunological contribution to the development of PDM.

Polymorphism of Genes Encoding Inflammatory Interleukins and the Risk of Anterior Cruciate Ligament Injury: A Systematic Review and Meta-Analysis.

Sport injuries, including the anterior crucial ligament rupture (ACLR) seem to be related to complex genetic backgrounds, including the genes responsible for inflammatory response. This review and meta-analysis investigated the contribution of the polymorphisms of genes encoding inflammatory cytokines and their receptors to the risk of ACLR. The scientific databases Science Direct, EBSCO host, Scopus, PubMed, and Google Scholar were screened (completed on 14 June 2023) according to the established inclusion/exclusion criteria (only fully accessible, original, human case-control studies written in English concerning the effect of interleukin genes' polymorphisms on the occurrence of ACL injury were included) and statistical meta-analysis using R version 4.0.3 was performed. The PRISMA methodology was used to review articles. The review protocol was registered under the number CRD42024514316 in the Prospero database. Eighty-nine studies were identified and narrowed down to three original case-control studies used for the meta-analysis. The studies analyzed Polish, South African, and Swedish cohorts, altogether 1282 participants. The candidate polymorphisms indicated in the studies involved IL6 rs1800795, IL6R rs2228145 and IL1B rs16944. The systematic review showed the relationships between IL6 rs1800795 polymorphism and ACLR in the Polish subpopulation, and IL6R rs2228145 and IL1B rs16944 in the South African subpopulations. The meta-analysis revealed that the IL6 rs1800795 CG genotype was over-represented (OR = 1.30, 95% CI 1.02-1.66), while the CC genotype was under-represented (OR = 0.75, 95% CI 0.54-1.03) in ACLR subjects, but no significant impact of IL6R rs2228145 was shown. Additionally, a tendency of the IL1B rs16944 CT genotype to be protective (OR 0.89, 95% CI 0.70-1.14), while the TT to be a risk genotype (OR 1.19, 95% CI 0.84-1.68) was observed. Thus, the relationship between the interleukin receptor IL6R rs2228145 and ACLR risk was not confirmed. However, the impact of genes coding pleiotropic IL6 rs1800795 on the incidences of ACLR was clear and the effect of pro-inflammatory IL1B rs16944 was possible.

APOLIPOPROTEIN-L1 RISK GENOTYPES ARE ASSOCIATED WITH CHRONIC KIDNEY DISEASE REGARDLESS OF HYPERTENSION STATUS IN A TRYPANOSOMA BRUCEI GAMBIENSE ENDEMIC AREA

Objective: this study assessed the frequency of Apolipoprotein-L1 high-risk genotypes in an African rural endemic area to Trypanosoma Brucei Gambiense, and evaluated their association with arterial hypertension according to human African trypanosomiasis infection status. Design and method: The study enrolled 94 human African trypanosomiasis-infected and 144 non–infected participants in Masimanimba, the Democratic Republic of the Congo. Apolipoprotein-L1 high-risk genotype was the presence of two variants (G1G1, G2G2, or G1G2), and low-risk genotype the presence of 0 or 1 variant. Albuminuria was an albumin/creatinine ratio greater than or equal to 30 mg/g on freshly voided urine. We evaluated the association between Apolipoprotein-L1 risk genotypes and hypertension in human African trypanosomiasis-infected and non-infected participants. Results: The study population was aged 39.7 ± 17.1 years (females 62.2%). The frequency of high-risk genotypes among hypertensive participants was 14.3% in both human African trypanosomiasis - infected and uninfected individuals. Albuminuria (100% vs. 38.9%; p=0.09) was higher and estimated Glomerular Filtration Rate lower (88.5 vs. 106 ml/min/1.73 m2, p =0.066) in high-risk genotypes than low-risk carrying hypertensive participants. The respective values in non-hypertensive individuals were 100% vs. 37.5% (p=0.002) and 83 vs. 109.5 ml/min/1.73 m2 (p &lt;0.001) for albuminuria and estimated Glomerular Filtration Rate. Conclusions: Apolipoprotein-L1 high-risk genotypes are associated with Chronic Kidney Disease regardless of the hypertension status in Human African Trypanosomiasis endemic area

Association of obesity and menarche SNPs and interaction with environmental factors on precocious puberty.

Obesity is an important cause for the precocious or early puberty. However, the association between obesity-related loci and the risk of precocious puberty as well as the effect of gene-environment interaction are unclear, especially in the Chinese children population. This was a case-control study using baseline data from two cohorts and hospital cases in China. 15 SNPs loci and several environmental factors were included in the analysis of 1201 participants. Chi-square test and logistic regression were used to analyze the association between SNPs and precocious puberty. Additionally, exploratory factor analysis was conducted on 13 environmental variables, and then to explore their interaction with genes on precocious puberty. The effect allele C of rs571312, and G of rs12970134MC4R were associated with precocious puberty in girls with obesity. Regarding the gene-environment interaction, we found that when girls were in the high socioeconomic status, the rs571312 (OR: 3.996; 95% CI: 1.694-9.423) and rs12970134 (OR: 3.529; 95% CI: 1.452-8.573) risk genotypes had a greater effect on precocious puberty. The obesity risk gene polymorphisms MC4R rs571312 and rs12970134 were associated with precocious puberty in Chinese girls with obesity, and girls with risk genotypes and high socioeconomic status should be given extra attention. This is the first study that identified the association between rs571312 and rs12970134 of MC4R gene and precocious puberty in Chinese children. We found that when girls were in the high socioeconomic status, the risk genotypes of rs571312 and rs12970134 had a greater effect on precocious puberty. The results of this study have great public health implications. It is recommended that girls who are in high socioeconomic status and have a high genetic risk for early sexual maturity should closely monitor their pubertal development and consider early intervention strategies.

Helicobacter pylori cagA, vacA, iceA and babA Genotypes from Peruvian Patients with Gastric Intestinal Metaplasia.

We explored the clinical-stage association of gastric intestinal metaplasia (IM) compared to cases of chronic non-atrophic gastritis (CNAG) and its relationship with virulence genotypes of Helicobacter pylori (H. pylori) clinical isolates from patients with dyspepsia in Peru. This study was cross-sectional and included 158 H. pylori clinical isolates; each isolate corresponded to a different Peruvian patient, genotyped by polymerase chain reaction to detect cagA gene and EPIYA motifs, the vacA gene (alleles s1, s2, i1, i2, d1, d2, m1, m2 and subtypes s1a, s1b and s1c), the iceA gene (alleles 1 and 2), and the babA gene (allele 2). We observed that 38.6% presented with IM and that all clinical isolates were CagA positive. The EPIYA-ABC motif was predominant (68.4%), and we observed a high frequency for the vacA gene alleles s1 (94.9%), m1 (81.7%), i1 (63.9%), and d1 (70.9%). Strains with both iceA alleles were also detected (69.6%) and 52.2% were babA2 positive. In addition, it was observed that the cagA+/vacAs1m1 (PR: 2.42, 1.14 to 5.13, p < 0.05) and cagA+/vacAs1am1 (PR: 1.67, 1.13 to 2.45, p < 0.01) genotypes were associated with IM. Our findings revealed the cagA and vacA risk genotypes predominance, and we provided clinically relevant associations between Peruvian patients with H. pylori infection and IM clinical stage.

FTO rs9939609: T>A Variant and Physical Inactivity as Important Risk Factors for Class III Obesity: A Cross-Sectional Study.

The prevalence of obesity has been increasing worldwide. It has been reported that physiological and environmental factors such as diet, culture, physical activity, and genetics are the principal factors related to obesity. The fat mass and obesity-associated (FTO) gen variant (rs9939609: T>A) has been associated with class III obesity. The A variant has been correlated with anthropometric and metabolic alterations. Therefore, the purpose of this study was to analyze the association of the FTO rs9939609: T>A variant and environmental factors with clinical, anthropometric, and biochemical variables in subjects with class III obesity. The A variant frequency was higher in the class III obesity group compared with the normal weight group (44% vs. 25%, p < 0.001). Subjects with the AA genotype had a higher body mass index (BMI) than those with the AT genotype (35.46 kg/m2 (31-39.8) vs. 26.91 kg/m2 (23.7-30), p = 0.005). Women with the AA genotype showed higher waist circumferences than the AT group (101.07 cm (90.9-111.1) vs. 85.45 cm (77-93.8) p = 0.047). The FTO A variant increases the risk by 3.54 times and physical inactivity increases the risk by 6.37 times for class III obesity. Our results suggest that among the studied variables, those most related to class III obesity were the FTO risk genotype (A allele) and physical inactivity.

Association Between RORA Polymorphisms and Obesity.

RORα is a transcription factor encoded by RORA gene. This protein is involved in several metabolic conditions, including obesity. We assessed association between two polymorphisms within this gene (namely rs11639084 and rs4774388) and severe obesity in Iranian population. Both SNPs were associated with obesity in all models (P < 0.0001) except for over-dominant model. T allele of rs11639084 was associated with this trait with OR (95% CI) of 16.85 (13.11-21.67) and was considered as the risk allele. Allelic model best fit the data, since the AIC value for this model was the highest (AIC = 28.82). In the co-dominant model, TT genotype was associated with obesity with OR (95% CI) of 301.6 (137.4-662.1). This genotype was shown to be the risk genotype in the recessive model when compared with TC+CC (OR (95% CI) = 60.54 (30.35-120.7)). The C allele of rs4774388 was shown to be the risk allele with OR (95% CI) of 4.61 (3.72-5.71). In the recessive model, the CC genotype was associated with the mentioned trait with OR (95% CI) of 9.92 (6.62-14.8). This model best fit the data (AIC = 37.08). Cumulatively, the current study suggests contribution of RORα to the pathogenesis of obesity.

The polymorphism ZNF804A rs1344706 is differentially associated with negative symptoms domains in schizophrenia

IntroductionNegative symptoms (NS) are an important clinical characteristic of schizophrenia. In recent years, clinical research on NS has focused on their clinical heterogeneity. Based on two-factor analysis, it has been proposed to divide NS into abulia-apathy (AA) and expressive deficit (ED) domains. A number of studies have shown that these domains have different effects on the clinical features of schizophrenia, which suggests different pathophysiological mechanisms of their development. Neurobiological differences between AA and DE have been identified in neuroimaging and immunological studies but there is less research on the genetic background of NS.ObjectivesTo search for an association between the rs1344706 polymorphism of the zinc finger protein gene (ZNF804A) and the AA and ED subdomains. The rs1344706 polymorphism is one of the best-supported risk variants for schizophrenia. The risk genotype AA has been shown to be associated with clinical presentations of the disease.MethodsThe study included 1116 (741 (66.3% women) patients with schizophrenia. The diagnosis was made according to ICD-10 criteria (item F20). The average age of the patients was 38.4 (13.6) years, age at disease onset was 26.1 (10.6) years. NS were assessed with the PANSS. The PANSS-derived AA domain consisted of Emotional withdrawal (PANSS item N2), Apathetic social withdrawal (N4), Active social avoidance (G16). The DE domain included Blunted affect (N1), Poor rapport (N3), Lack of spontaneity (N6), Mannerism and posturing (G5), Motor retardation (G7), Disturbance of volition (G13). Genotyping of the ZNF804A rs1344706 polymorphism was carried out using HRM-PCR. ANOVA with genotype and sex as independent variables, and age at the time of disease manifestation and its duration as covariates was used. Post hoc tests were performed using Bonferroni correction.ResultsA significant effect of the rs1344706 polymorphism on the severity of symptoms in the AA domain was revealed (F=5.88, df=2, p=0.002). In carriers of the CC genotype, the severity of symptoms was significantly lower than in carriers of the AA genotype and the AC genotype (8.4(3.5), 9.4(7.4) and 8.8(3.5) points, respectively). This effect was independent of sex and was not mediated by age at onset or duration of disease. There was no effect of the rs1344706 polymorphism on the severity of symptoms in the ED domain.ConclusionsThe association of the ZNF804A rs1344706 (A/C) polymorphism with NS of schizophrenia has not been reported so far though some studies have found the effect of this polymorphism on PANSS positive symptoms and PANSS total score. The finding of the association with NS can be explained by the fact that the NS heterogeneity was taken into account in the present study.Disclosure of InterestNone Declared

Interaction Effects of FTO and MC4R Polymorphisms on Total Body Weight Loss, Post-Surgery Weight, and Post-Body Mass Index after Bariatric Surgery.

Bariatric surgery (BS) is considered the most effective intervention for patients with severe obesity and is used to maintain long-term weight loss and glycemic control. The aim of this study was to analyze the effects of genotypes and haplotypes of the fat mass and obesity-associated (FTO) and melanocortin 4 receptor (MC4R) genes on total body weight loss (TBWL), post-surgery weight, and post-BMI after bariatric surgery. We retrospectively selected 101 patients from Bajio High Specialty Regional Hospital, León Guanajuato, México, who underwent Roux-en-Y gastric bypass (RYGB) to determine their body mass index (BMI), blood pressure, biochemical characteristics, and comorbidities. Post-surgery, patients were referred for registered anthropometry and blood pressure. Glucose, lipid and hepatic profiles, and insulin, leptin, and ghrelin levels were measured, and rs9939609, rs9930506, and rs1421085 FTO and rs17782313 MC4R polymorphisms were genotyped. Six (4-8) years after BS, post-surgery weight was greater in carriers of the rs9939609 and rs1421085 risk genotypes. TBWL was lower for the rs9930506 and rs1421085 risk genotypes. Insulin and HOMA-IR were greater in patients with the three FTO polymorphisms. There were significant interaction effects of the rs9930506 and rs1421085 FTO risk genotypes on weight and BMI in response to BS. No association was found with the MC4R polymorphism. The genotypes and haplotypes of the FTO gene influence post-surgery weight, TBWL, insulin levels, and HOMA-IR.

APOL 1 Risk Genotype is associated with Albuminuria in Sub-Saharan African without Hypertension: A Case Study of Trypanosoma Brucei Gambiense Endemic Area

Purpose. An association between APOL1 risk genotypes (HRG) and hypertension has been reported in African Americans with chronic kidney diseases (CKD). However, such data from African populations living in a Human African Trypanosomiasis (HAT) endemic area remain limited.This study assessed the association between APOL1 high-risk genotypes (HRG) and hypertension among sub-Saharan African in T.b. gambiense endemic area.&#x0D; Methodology. This cross-sectional study enrolled 94 HAT-infected and 144 non–infected participants in Masimanimba, the Democratic Republic of the Congo, from April 2019 to April 2021. We evaluated the association between APOL1 HRG and hypertension in HAT-infected and non–infected participants. APOL1 HRG was defined as the presence of two risk variants (G1/G1, G2/G2, or G1/G2), and a low-risk genotype (LRG) with the presence of 0 or 1 single variant. The elevated albuminuria was defined as urinary albumin/creatinine ratio ≥ 30 mg/g. Student’s and Pearson's Chi2 tests or Fisher’s exact test were used to compare means and proportions. The Wilcoxon/Mann–Whitney test was used to compare medians. A multivariate logistic regression model was used to identify independent determinants of hypertension. Odds ratios were provided with their 95% confidence intervals (Cis). Statistical significance was set at p &lt; 0.05, based on 2-tailed test.&#x0D; Findings. APOL1 sequence analysis revealed that 3 of 21 (14.3%) hypertensive participants carried HRG (G1G1) and 7 of 103 (6.8%) non-hypertensive carried HRG (G1G1, G2G2, and G1G2) (p=0.371). The frequency of APOL1 HRG among hypertensive participants was 14.3% in both HAT- infected and uninfected individuals. Ten of 21 (47.6%) hypertensive individuals with elevated albuminuria had a higher incidence of CKD (100% vs. 0%; p &lt; 0.001) and HRG (30% vs. 0%; p = 0.09) than 11 (52.3%) without albuminuria who carried LRG. Of 103 non-hypertensive subjects, 43 (41.7%) with elevated albuminuria had a higher frequency of HRG (16.3% vs. 0%; p = 0.002) and CKD (100% vs. 1.7%; p&lt;0.001) compared with 60 of 103 (58.3%) without albuminuria who carried LRG.&#x0D; Unique contributor to theory, policy and practice: APOL1 HRG was associated with albuminuria and CKD, regardless of the hypertension status in T.b. gambiense HAT endemic area. However, further prospective cohort studies are required to confirm these results. The High-risk subjects will benefit from early preventive measures in low-income countries.

Genetic variants in m5C modification genes are associated with survival of patients with HBV-related hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with a high mortality rate. The 5-methylcytosine (m5C), a type of RNA modification, plays crucial regulatory roles in HCC carcinogenesis, metastasis, and prognosis. However, a few studies have investigated the effect of genetic variants in m5C modification genes on survival of patients with hepatitis B virus (HBV)-related HCC. In the present study, we evaluated associations between 144 SNPs in 15 m5C modification genes and overall survival (OS) in 866 patients with the HBV-related HCC. Expression quantitative trait loci (eQTL) analysis and differential expression analysis were conducted to investigate biological mechanisms. As a result, we identified that two SNPs (NSUN7 rs2437325 A > G and TRDMT1 rs34434809 G > C) were significantly associated with HBV-related HCC OS with adjusted allelic hazards ratios of 1.25 (95% confidence interval = 1.05-1.48 and P = 0.011) and 1.19 (1.02-1.38 and P = 0.027), respectively, with a trend of combined risk genotypes (Ptrend < 0.001). Moreover, the results of eQTL analyses showed that both NSUN7 rs2437325 G and TRDMT1 rs34434809 C alleles were associated with a reduced mRNA expression level in 208 normal liver tissues (P = 0.007 and P < 0.001, respectively). Taken together, genetic variants in the m5C modification genes may be potential prognostic biomarkers of HBV-related HCC after hepatectomy, likely through mediating the mRNA expression of corresponding genes.

Association of ARRDC3 and NFIA variants with bovine congestive heart failure in feedlot cattle.

Bovine congestive heart failure (BCHF) has become increasingly prevalent among feedlot cattle in the Western Great Plains of North America with up to 7% mortality in affected herds. BCHF is an untreatable complex condition involving pulmonary hypertension that culminates in right ventricular failure and death. Genes associated with BCHF in feedlot cattle have not been previously identified. Our aim was to search for genomic regions associated with this disease. A retrospective, matched case-control design with 102 clinical BCHF cases and their unaffected pen mates was used in a genome-wide association study. Paired nominal data from approximately 560,000 filtered single nucleotide polymorphisms (SNPs) were analyzed with McNemar's test. Two independent genomic regions were identified as having the most significant association with BCHF: the arrestin domain-containing protein 3 gene ( ARRDC3), and the nuclear factor IA gene ( NFIA, mid- p-values, 1x10 -8 and 2x10 -7, respectively). Animals with two copies of risk alleles at either gene were approximately eight-fold more likely to have BCHF than their matched pen mates with either one or zero risk alleles at both genes (CI 95 = 3-17). Further, animals with two copies of risk alleles at both genes were 28-fold more likely to have BCHF than all others ( p-value = 1×10 -7, CI 95 = 4-206). A missense variant in ARRDC3 (C182Y) represents a potential functional variant since the C182 codon is conserved among all other jawed vertebrate species observed. A two-SNP test with markers in both genes showed 29% of 273 BCHF cases had homozygous risk genotypes in both genes, compared to 2.5% in 198 similar unaffected feedlot cattle. This and other DNA tests may be useful for identifying feedlot animals with the highest risk for BCHF in the environments described here. Although pathogenic roles for variants in the ARRDC3 and NFIA genes are unknown, their discovery facilitates classifying animals by genetic risk and allows cattle producers to make informed decisions for selective breeding and animal health management.

(148) The Prevalence and Genotype Distribution of Human Papillomaviruses in Korean

Abstract Introduction Human papillomavirus (HPV) prevalence and genotype distribution are different between various nations and regions. Additionally, previous studies have mainly focused on HPV infection in western female and epidemiological studies of HPV infection in regional populations have been rarely reported. The lack of information on the HPV genotype distribution of the regional population in each individual country or region raises questions about the effectiveness of the current 9-valent vaccination. Objective To assess the prevalence and genotype of HPV(+) Korean and to know whether currently available 9-valent vaccine can cover the most prevalent and high risk genotype as HPV vaccine in Korean. Methods Between January 2014 to June 2022, samples of 44,065 men (Study I, M) and 564,499 females (Study II, F), who were volunteered for testing or recommended by a clinician, were tested for HPV detection and genotyping. Samples were collected swabs from the pap smear test. HPV detection and typing were conducted using the Anyplex™ II HPV 28 Detection system, which detects 19 high-risk (HR) HPVs and 9 low-risk (LR) HPVs. Results In Study I &amp; Study II, overall prevalence were 59.7% (M), 44.3%(F), prevalence of HR were 30.6%(M), 37.5%(F) and LR HPVs were 50.1%(M), 18.3%(F), respectively. Overall HPV prevalence was higher in teens (34.1% in M and 58.3% in F) and 20s (33.8% in M and 51.9% in F) with age [Table 1]. The most prevalent genotypes of HR were 16 (5.2%), 53 (4.6%), 51 (4.2%), 52 (3.8%), 58 (3.7%), 39(3.6%) and 66(3.4%) in Study I. In Study II of Female, the most prevalent genotypes of HR were 52 (7.1%), 53 (6.2%), 58 (5.0%), 68 (4.8%), and 16 (4.3%). In Study I of 26,299 men with HPV infection, 9,259 (35.2%) had a genotype with HR; 53 (4.6%), 51 (4.2%), 39(3.6%) and 66(3.4%), which could not prevented by the 9-valent vaccine. In Study II of 211,883 females with HPV infection, 72,252 (34.1%) had a genotype with HR, 68 (4.8%), 51 (4.1%), 39 (3.8%), and 56 (3.7%) which could not be prevented by the 9-valent vaccine. Conclusions In this study, Korea male and female aged under 30 years showed a high prevalence of HR HPVs. In both Male and Female groups, a significant number of HR HPVs infections were not prevented by 9-valent vaccine. Based on this result, it is necessary to develop nation-specific HPV vaccination for Korean. Further, this approach can be applied in other countries. Disclosure No.

TET3 gene rs828867 G>A polymorphism reduces neuroblastoma risk in Chinese children

ObjectiveNeuroblastoma (NB) is a prevalent pediatric tumor originating from primordial neural crest cells. As one of the latest epigenetics investigations focuses, RNA 5-methylcytosine (m5C) is closely related to cancer risk. TET methylcytosine dioxygenase 3 (TET3) is a demethylase for m5C modification. Whether there is an association between TET3 gene polymorphisms and neuroblastoma risk remains unclear. MethodsWe conducted an epidemiological study in 402 patients and 473 controls to evaluate the relationship between TET3 gene SNPs (rs7560668 T > C, rs828867 G > A, and rs6546891 A > G) and NB susceptibility. ResultsOur results showed that rs828867 G > A significantly reduced NB risk in Chinese children [GA vs. GG, adjusted odds ratio (OR) = 0.72, 95% confidence interval (CI) = 0.52–0.98, P=0.040; GA/AA vs. GG, adjusted OR = 0.74, 95% CI = 0.55–0.998, P=0.048]. Individuals with 2–3 risk genotypes had a significantly higher NB risk than those with 0–1 risk genotypes (adjusted OR = 1.40, 95% CI = 1.04–1.88, P=0.027). The stratified analysis showed that the rs828867 G > A associated with decreased NB risk is remarkable among children aged >18 months (adjusted OR = 0.67, 95% CI = 0.46–0.96, P=0.029) and patients at clinical III + IV stages (adjusted OR = 0.67, 95% CI = 0.45–0.98, P=0.040). Compared with the 0–1 risk genotype, the concurrence of 2–3 risk genotypes significantly increased NB risk in the following subgroups: children aged >18 months and patients at clinical III + IV stages. GTEx analysis suggested that rs828867 G > A was significantly associated with RP11-287D1.4 and POLE4 mRNA expression. ConclusionsOverall, our results revealed that rs828867 G > A in the TET3 gene is significantly associated with predisposition to NB.

Association of polymorphisms in SEC16B, DNAJC27, FTO and MC4R genes with overweight and obesity in Han preschool children

To investigate the association of polymorphisms in SEC16B rs633715, DNAJC27 rs713586, FTO rs11642015 and MC4R rs6567160 with overweight and obesity in Han Chinese preschool children. A total of 749 Han Chinese preschool children from Henan and Guizhou Province of Long-term Health Effects Assessment Project of Infants and Toddlers Nutritional Pack were selected for the study and divided into an overweight and obese group and a normal control group in 2022. rs633715, rs713586, rs11642015 and rs6567160 were genotyped using Kompetitive allele-specific PCR(KASP) technology. The distribution of genotypic polymorphisms was compared using the χ~2 test. The association between the four loci and overweight and obesity in preschool children was analyzed using a multifactorial logistic regression model. The statistical analysis revealed a significant disparity(P&lt;0.05) in the distribution of genotypic polymorphisms of rs633715 and rs6567160 among preschoolers in Henan and Guizhou Province. CC heterozygous mutant and recessive models at rs633715 locus were associated with susceptibility to overweight and obesity in preschool children [OR and 95% CI 2.915(1.163-7.305), and 2.997(1.226-7.323), respectively, both P&lt;0.05]. TC heterozygous mutant and dominant models at rs713586 locus were also associated susceptibility to overweight and obesity in preschool children(OR and 95% CI were 2.362(1.054-5.289)and 2.362(1.054-5.289), respectively, both P&lt;0.05). rs11642015 and rs6567160 loci were not associated with susceptibility to overweight and obesity in preschool children(P&gt;0.05). The result of the analysis of the cumulative effect of rs633715 and rs713586 showed that the number of genotypes carrying the risk genotype was positively associated with the risk of overweight and obesity in preschool children(P_(trend)&lt;0.01). Among Han Chinese preschool children, SEC16B rs633715 and DNAJC27 rs713586 were associated with susceptibility to overweight and obesity in preschool children. Moreover, rs633715 and rs713586 had a cumulative effect on susceptibility to overweight and obesity in preschool children, the number of risk genotypes carried was positively associated with childhood overweight and obesity risk.

Synergistic toxicity with copper contributes to NAT2-associated isoniazid toxicity

Anti-tuberculosis (AT) medications, including isoniazid (INH), can cause drug-induced liver injury (DILI), but the underlying mechanism remains unclear. In this study, we aimed to identify genetic factors that may increase the susceptibility of individuals to AT-DILI and to examine genetic interactions that may lead to isoniazid (INH)-induced hepatotoxicity. We performed a targeted sequencing analysis of 380 pharmacogenes in a discovery cohort of 112 patients (35 AT-DILI patients and 77 controls) receiving AT treatment for active tuberculosis. Pharmacogenome-wide association analysis was also conducted using 1048 population controls (Korea1K). NAT2 and ATP7B genotypes were analyzed in a replication cohort of 165 patients (37 AT-DILI patients and 128 controls) to validate the effects of both risk genotypes. NAT2 ultraslow acetylators (UAs) were found to have a greater risk of AT-DILI than other genotypes (odds ratio [OR] 5.6 [95% confidence interval; 2.5–13.2], P = 7.2 × 10−6). The presence of ATP7B gene 832R/R homozygosity (rs1061472) was found to co-occur with NAT2 UA in AT-DILI patients (P = 0.017) and to amplify the risk in NAT2 UA (OR 32.5 [4.5–1423], P = 7.5 × 10−6). In vitro experiments using human liver-derived cell lines (HepG2 and SNU387 cells) revealed toxic synergism between INH and Cu, which were strongly augmented in cells with defective NAT2 and ATP7B activity, leading to increased mitochondrial reactive oxygen species generation, mitochondrial dysfunction, DNA damage, and apoptosis. These findings link the co-occurrence of ATP7B and NAT2 genotypes to the risk of INH-induced hepatotoxicity, providing novel mechanistic insight into individual AT-DILI susceptibility.Yoon et al. showed that individuals who carry NAT2 UAs and ATP7B 832R/R genotypes are at increased risk of developing isoniazid hepatotoxicity, primarily due to the increased synergistic toxicity between isoniazid and copper, which exacerbates mitochondrial dysfunction-related apoptosis.