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Advancing understanding of human variability through toxicokinetic modeling, in vitro-in vivo extrapolation, and new approach methodologies. 通过毒物动力学建模、体外-体内外推法和新的方法,促进对人体变异性的了解。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-11-21 DOI: 10.1186/s40246-024-00691-9
Anna Kreutz, Xiaoqing Chang, Helena T Hogberg, Barbara A Wetmore

The merging of physiology and toxicokinetics, or pharmacokinetics, with computational modeling to characterize dosimetry has led to major advances for both the chemical and pharmaceutical research arenas. Driven by the mutual need to estimate internal exposures where in vivo data generation was simply not possible, the application of toxicokinetic modeling has grown exponentially in the past 30 years. In toxicology the need has been the derivation of quantitative estimates of toxicokinetic and toxicodynamic variability to evaluate the suitability of the tenfold uncertainty factor employed in risk assessment decision-making. Consideration of a host of physiologic, ontogenetic, genetic, and exposure factors are all required for comprehensive characterization. Fortunately, the underlying framework of physiologically based toxicokinetic models can accommodate these inputs, in addition to being amenable to capturing time-varying dynamics. Meanwhile, international interest in advancing new approach methodologies has fueled the generation of in vitro toxicity and toxicokinetic data that can be applied in in vitro-in vivo extrapolation approaches to provide human-specific risk-based information for historically data-poor chemicals. This review will provide a brief introduction to the structure and evolution of toxicokinetic and physiologically based toxicokinetic models as they advanced to incorporate variability and a wide range of complex exposure scenarios. This will be followed by a state of the science update describing current and emerging experimental and modeling strategies for population and life-stage variability, including the increasing application of in vitro-in vivo extrapolation with physiologically based toxicokinetic models in pharmaceutical and chemical safety research. The review will conclude with case study examples demonstrating novel applications of physiologically based toxicokinetic modeling and an update on its applications for regulatory decision-making. Physiologically based toxicokinetic modeling provides a sound framework for variability evaluation in chemical risk assessment.

生理学和毒物代谢动力学(或称药代动力学)与计算建模相结合来描述剂量学特征,为化学和制药研究领域带来了重大进展。在过去的 30 年里,毒代动力学建模的应用呈指数级增长。在毒理学中,需要对毒代动力学和毒效学的变异性进行定量估算,以评估风险评估决策中使用的十倍不确定系数是否合适。为了全面描述特征,需要考虑一系列生理、本体、遗传和暴露因素。幸运的是,以生理为基础的毒物动力学模型的基本框架可以容纳这些输入,此外还能捕捉时变动态。与此同时,国际社会对推进新方法的兴趣也促进了体外毒性和毒物动力学数据的产生,这些数据可用于体外-体内外推法,为历来缺乏数据的化学品提供特定于人类的基于风险的信息。本综述将简要介绍毒物动力学模型和基于生理学的毒物动力学模型的结构和演变,这些模型在发展过程中纳入了变异性和各种复杂的暴露情景。随后将介绍最新的科学状况,描述针对群体和生命阶段变异性的当前和新兴实验和建模策略,包括在制药和化学品安全研究中越来越多地应用体外-体内外推法和基于生理的毒物动力学模型。综述最后将以案例研究的形式展示基于生理学的毒物动力学模型的新应用,并介绍其在监管决策中的最新应用。基于生理学的毒物动力学模型为化学品风险评估中的变异性评价提供了一个合理的框架。
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引用次数: 0
Genetic heterogeneity in familial forms of genetic generalized epilepsy: from mono- to oligogenism. 遗传性全身性癫痫家族形式的遗传异质性:从单基因到寡基因。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-11-21 DOI: 10.1186/s40246-024-00659-9
Maha Dahawi, Jean-Madeleine de Sainte Agathe, Mohamed S Elmagzoub, Elhami A Ahmed, Julien Buratti, Thomas Courtin, Eric Noé, Julie Bogoin, Bruno Copin, Fatima A Elmugadam, Wasma A Abdelgadir, Ahmed K M A Ahmed, Mohamed A Daldoum, Rayan Mamoon Ibrahim Altayeb, Mohamed Bashir, Leena Mohamed Khalid, Sahar Gamil, Sara Baldassari, Liena Elsayed, Boris Keren, Gregory Nuel, Ammar E Ahmed, Eric Leguern

Genetic generalized epilepsy (GGE) including childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy (JME), and GGE with tonic-clonic seizures (TCS) (GGE-TCS), is genetically influenced with a two- to four- fold increased risk in the first-degree relatives of patients. Since large families with GGE are very rare, international studies have focused on sporadic GGE patients using whole exome sequencing, suggesting that GGE are highly genetically heterogeneous and rather involve rare or ultra-rare variants. Moreover, a polygenic mode of inheritance is suspected in most cases. We performed SNP microarrays and whole exome sequencing in 20 families from Sudan, focusing on those with at least four affected members. Standard genetic filters and Endeavour algorithm for functional prioritization of genes selected likely susceptibility variants in FAT1, DCHS1 or ASTN2 genes. FAT1 and DCHS1 are adhesion transmembrane proteins interacting during brain development, while ASTN2 is involved in dendrite development. Our approach on familial forms of GGE is complementary to large-scale collaborative consortia studies of sporadic cases. Our study reinforces the hypothesis that GGE is genetically heterogeneous, even in a relatively limited geographic area, and mainly oligogenic, as supported by the low familial penetrance of GGE and by the Bayesian algorithm that we developed in a large pedigree with JME. Since populations with founder effect and endogamy are appropriate to study autosomal recessive pathologies, they would be also adapted to decipher genetic components of complex diseases, using the reported bayesian model.

遗传性全身性癫痫(GGE),包括儿童失神癫痫、青少年失神癫痫、青少年肌阵挛性癫痫(JME)和伴强直阵挛发作(TCS)的全身性癫痫(GGE-TCS),受遗传因素影响,患者一级亲属患病风险增加两到四倍。由于 GGE 的大家庭非常罕见,因此国际研究重点关注使用全外显子组测序的散发性 GGE 患者,结果表明 GGE 具有高度遗传异质性,涉及罕见或超罕见变异。此外,大多数病例被怀疑具有多基因遗传模式。我们对来自苏丹的 20 个家庭进行了 SNP 微阵列和全外显子测序,重点研究了至少有四名患病成员的家庭。通过标准遗传过滤器和 Endeavour 算法对基因进行功能优先排序,筛选出 FAT1、DCHS1 或 ASTN2 基因中可能存在的易感变异。FAT1 和 DCHS1 是大脑发育过程中相互作用的粘附跨膜蛋白,而 ASTN2 则参与树突的发育。我们对家族性 GGE 的研究方法与对散发性病例的大规模合作研究是相辅相成的。我们的研究加强了这样的假设:即使在相对有限的地理区域内,GGE 也具有遗传异质性,而且主要是寡基因遗传,这一点得到了 GGE 家族低渗透性和我们在一个大型 JME 血统中开发的贝叶斯算法的支持。由于具有创始效应和内生性的人群适合研究常染色体隐性遗传病,因此也适合利用所报告的贝叶斯模型来破译复杂疾病的遗传成分。
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引用次数: 0
Global transcriptome modulation by xenobiotics: the role of alternative splicing in adaptive responses to chemical exposures. 异种生物对全球转录组的调节:替代剪接在对化学暴露的适应性反应中的作用。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-11-18 DOI: 10.1186/s40246-024-00694-6
Andrew J Annalora, Jacki L Coburn, Antony Jozic, Patrick L Iversen, Craig B Marcus

Background: Xenobiotic exposures can extensively influence the expression and alternative splicing of drug-metabolizing enzymes, including cytochromes P450 (CYPs), though their transcriptome-wide impact on splicing remains underexplored. This study used a well-characterized splicing event in the Cyp2b2 gene to validate a sandwich-cultured primary rat hepatocyte model for studying global splicing in vitro. Using endpoint PCR, RNA sequencing, and bioinformatics tools (rSeqDiff, rMATs, IGV), we analyzed differential gene expression and splicing in CYP and nuclear receptor genes, as well as the entire transcriptome, to understand how xenobiotic exposures shape alternative splicing and activate xenosensors.

Methods: Primary rat hepatocytes in sandwich culture were exposed to two methylenedioxybenzene (MDB) congeners and carbamazepine, with gene expression and splicing assessed. A 3D-clustergram integrating KEGG pathway analysis with differential gene expression provided distinct splicing landscapes for each xenobiotic, showing that splicing diversity does not always align with gene expression changes.

Results: Endpoint PCR revealed a Cyp2b2v to wild-type Cyp2b2 splicing ratio near 1:1 (100%) under most conditions, while RNA-seq showed a stable baseline closer to 40%. C6-MDB reduced this ratio to ~ 50% by PCR and ~ 39% by RNA-seq, showing slight method-dependent variations yet consistent trends. In contrast, exon 6 skipping in Cyp1a1 occurred only with MDB exposure, implicating AHR activation. Xenobiotic treatments also induced alternative splicing in defensome and stress-responsive genes, including the phase II enzyme Gstm3, Albumin, Orm1, and Fxyd1, highlighting their roles in xenobiotic response modulation. Significant splicing changes in factors such as SRSF1, SRSF7, and METTL3 suggest a coordinated feedback loop involving epitranscriptomic modulation and cross-talk within SR protein networks, refining splice site selection, transcript stability, and cellular fate.

Conclusions: This study demonstrates how xenobiotic structural features influence gene expression and splicing, revealing splicing patterns that expand our understanding of transcriptome diversity and function. By identifying regulatory mechanisms, including AHR activation, epitranscriptomic modulation, and crosstalk within SR protein networks, that shape adaptive responses to xenobiotic stress, this work offers insights into the splicing and transcriptional networks that maintain cellular homeostasis. These findings provide predictive biomarkers for toxic exposures and highlight the potential of splicing profiles as diagnostic tools for assessing the health impacts of chemical exposure.

背景:暴露于异种生物可广泛影响包括细胞色素 P450(CYPs)在内的药物代谢酶的表达和替代剪接,但它们对剪接的全转录组影响仍未得到充分探索。本研究利用 Cyp2b2 基因中一个特征明确的剪接事件来验证夹心培养的原代大鼠肝细胞模型,以研究体外全局剪接。利用终点 PCR、RNA 测序和生物信息学工具(rSeqDiff、rMATs、IGV),我们分析了 CYP 和核受体基因以及整个转录组的不同基因表达和剪接,以了解异生物暴露如何形成替代剪接和激活异种感应器:方法:将夹层培养的原代大鼠肝细胞暴露于两种亚甲基二氧苯(MDB)同系物和卡马西平,评估基因表达和剪接情况。整合了 KEGG 通路分析和差异基因表达的三维簇图为每种异生物提供了不同的剪接景观,表明剪接多样性并不总是与基因表达变化一致:结果:终点 PCR 显示,在大多数条件下,Cyp2b2v 与野生型 Cyp2b2 的剪接比率接近 1:1(100%),而 RNA-seq 显示的稳定基线接近 40%。通过 PCR 和 RNA-seq 测序,C6-MDB 将这一比例分别降低到约 50%和 39%,显示出轻微的方法依赖性变化,但趋势一致。相比之下,Cyp1a1 的外显子 6 跳越只发生在 MDB 暴露时,这与 AHR 激活有关。异生物处理还诱导了防御组和应激反应基因的替代剪接,包括II期酶Gstm3、白蛋白、Orm1和Fxyd1,突显了它们在异生物反应调节中的作用。SRSF1、SRSF7和METTL3等因子的剪接发生了显著变化,这表明在SR蛋白网络中存在一个协调的反馈回路,涉及表转录组学调控和交叉对话,完善了剪接位点选择、转录本稳定性和细胞命运:这项研究展示了异生物结构特征如何影响基因表达和剪接,揭示了剪接模式,从而拓展了我们对转录组多样性和功能的认识。通过确定包括 AHR 激活、表转录组调控和 SR 蛋白网络内的串扰在内的调控机制,这项工作提供了对维持细胞稳态的剪接和转录网络的深入了解,从而形成了对外生生物压力的适应性反应。这些发现为有毒物质暴露提供了预测性生物标志物,并凸显了剪接图谱作为评估化学物质暴露对健康影响的诊断工具的潜力。
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引用次数: 0
Analysis of public perceptions on the use of artificial intelligence in genomic medicine. 分析公众对人工智能在基因组医学中应用的看法。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-11-18 DOI: 10.1186/s40246-024-00686-6
Jack E Harrison, Fiona Lynch, Zornitza Stark, Danya F Vears

Purpose: Next generation sequencing has led to the creation of large pools of genomic data with analysis rather than data generation now the limiting factor. Artificial intelligence (AI) may be required to optimize the benefits of these data, but little is known about how the public feels about the use of AI in genomics.

Methods: We conducted focus groups with members of the Australian public. Participants were recruited via social media advertisements. We explored potential uses of AI in genomic medicine, the benefits, risks, and the possible social implications of its use.

Results: Participants (n = 34) largely felt comfortable with AI analysing their own genomic data and generally agreed about its benefits. Concerns were raised over data security, the potential for misdiagnosis, and bias AI may perpetuate. Many participants wanted checking mechanisms for when results were generated using AI.

Conclusions: The insights gained from these discussions help to understand public concerns around the use of AI in genomic medicine. Our findings can help to inform both policies around genomic AI and how to educate the public on its use.

目的:下一代测序技术产生了大量的基因组数据,现在限制因素是分析而不是数据生成。要优化这些数据的效益,可能需要人工智能(AI),但公众对在基因组学中使用人工智能的看法却知之甚少:我们与澳大利亚公众进行了焦点小组讨论。我们通过社交媒体广告招募参与者。我们探讨了人工智能在基因组医学中的潜在用途、使用人工智能的益处、风险以及可能产生的社会影响:结果:参与者(n = 34)对人工智能分析自己的基因组数据基本感到满意,并普遍认同人工智能的好处。但也有人对数据安全、误诊的可能性以及人工智能可能造成的偏见表示担忧。许多与会者希望在使用人工智能生成结果时能有检查机制:从这些讨论中获得的见解有助于了解公众对人工智能在基因组医学中应用的担忧。我们的发现有助于为有关基因组人工智能的政策以及如何教育公众使用人工智能提供信息。
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引用次数: 0
Ralationship between polymorphisms and diplotypes of HLA-G 3'UTR and fetuses with abnormal chromosomes or unexplained pregnancy loss (UPL). HLA-G 3'UTR 的多态性和二联型与胎儿染色体异常或不明原因妊娠损失(UPL)之间的关系。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-11-17 DOI: 10.1186/s40246-024-00695-5
Danping Xu, Yiyang Zhu, Jun Wang, Heqin Guan, Xiuzhen Shen

Objectives: Human leukocyte antigen G (HLA-G) plays a crucial role in pregnancy. Pregnancy loss (PL) is caused by a variety of causes, such as fetal chromosomal abnormalities, maternal hypertension and diabetes, immune causes, spontaneous immune diseases, infections, unknown causes, etc. This study reports on the association of fetal HLA-G 3'UTR polymorphisms and diplotypes with chromosomally abnormal fetuses (CAF) or unexplained pregnancy loss (UPL).

Methods: A total of 552 specimens were collected and grouped by next-generation sequencing technology (NGS) and fetal survival: UPL (112 cases), CAF (170 cases) and control (258 cases). The polymorphisms of HLA-G 3'UTR in all samples were detected by Sanger sequencing. The genotypes, haplotypes and diplotypes of HLA-G 3'UTR were analyzed. The classification and regression tree (CART) analysis was used to evaluate the role of HLA-G diplotypes in predicting fetal outcomes. The correlations between CAF or UPL and maternal age, paternal age, times of miscarrage, times of delivery were analyzed by logistic regression.

Results: The frequencies of HLA-G + 2960del/del and + 3035CC genotypes were remarkablly increased in CAF than those in control group. The frequencies of HLA-G + 2960ins/del, + 3010CC, + 3035TC, + 3142GG, + 3187AA in CAF were significantly lower than those in normal fetuses. Through genetic models and logistic regression analysis, the dominant model of HLA-G 3'UTR genotypes [such as + 2960 (OR = 1.27, 95% CI = 1.05-1.54, p = 0.016), + 3010 (OR = 0.78, 95% CI = 0.63-0.97, p = 0.026), + 3035 (OR = 1.22, 95% CI = 1.00-1.49, p = 0.047), + 3142 (OR = 0.76, 95% CI = 0.62-0.95, p = 0.014) and + 3187 (OR = 0.80, 95% CI = 0.65-0.99, p = 0.041)] were dramatically associated with CAF. However, the frequencies of HLA-G + 3010GC, + 3142GC and + 3187AG in fetuses with UPL were memorably decreased than those in normal fetuses. No significant difference was found in the frequencies of HLA-G haplotypes in all groups. However, the frequency of UTR-1 positive specimens in CAF was significantly higher than that in UPL and control group. At the same time, the frequency of UTR-1/UTR-3 diplotypes in CAF was observably higher than that in UPL and control group, while the UTR-1/UTR-7 frequency in UPL was signally lower than that in control group. Multivariate logistic regression analysis indicated that positive HLA-G UTR-1 (OR = 1.8, 95% CI = 1.16-2.81, p = 0.009), times of abortion (OR = 1.23, 95% CI = 1.02-1.50, p = 0.035), and times of delivery (OR = 0.31, 95% CI = 0.20-0.48, p < 0.001) were correlated with CAF.

Conclusions: This study suggests that HLA-G 3'UTR polymorphisms and diplotypes play an important role in the process of successful pregnancy of the embryos with abnormal chromosomes after fertilization. At the same time, Different alleles or diplotypes also affect the development of embryos with UPL.

目的:人类白细胞抗原 G(HLA-G)在妊娠中起着至关重要的作用。妊娠丢失(PL)由多种原因引起,如胎儿染色体异常、母体高血压和糖尿病、免疫原因、自发性免疫疾病、感染、不明原因等。本研究报告了胎儿 HLA-G 3'UTR 多态性和双型与染色体异常胎儿(CAF)或不明原因妊娠丢失(UPL)的相关性:方法:共收集了 552 份标本,并根据新一代测序技术(NGS)和胎儿存活情况进行分组:UPL(112 例)、CAF(170 例)和对照(258 例)。所有样本的 HLA-G 3'UTR 多态性均通过 Sanger 测序法检测。分析了 HLA-G 3'UTR 的基因型、单倍型和双倍型。采用分类和回归树(CART)分析评估 HLA-G 双倍型在预测胎儿结局中的作用。通过逻辑回归分析了CAF或UPL与产妇年龄、父亲年龄、流产时间、分娩时间之间的相关性:结果:HLA-G + 2960del/del 和 + 3035CC 基因型在 CAF 中的频率明显高于对照组。CAF 中 HLA-G + 2960ins/del、+ 3010CC、+ 3035TC、+ 3142GG、+ 3187AA 的频率明显低于正常胎儿。通过遗传模型和逻辑回归分析,HLA-G 3'UTR 基因型的显性模型[如 + 2960(OR = 1.27,95% CI = 1.05-1.54,p = 0.016)、+ 3010(OR = 0.78,95% CI = 0.63-0.97,p = 0.026)、+ 3035(OR = 1.22,95% CI = 1.00-1.49,p = 0.047)、+ 3142(OR = 0.76,95% CI = 0.62-0.95,p = 0.014)和+ 3187(OR = 0.80,95% CI = 0.65-0.99,p = 0.041)]与 CAF 显著相关。然而,与正常胎儿相比,UPL 胎儿的 HLA-G + 3010GC、+ 3142GC 和 + 3187AG 的频率明显下降。所有组别的 HLA-G 单倍型频率均无明显差异。然而,CAF 中 UTR-1 阳性标本的频率明显高于 UPL 和对照组。同时,CAF 中 UTR-1/UTR-3 双倍型的频率明显高于 UPL 和对照组,而 UPL 中 UTR-1/UTR-7 的频率明显低于对照组。多变量逻辑回归分析表明,HLA-G UTR-1 阳性(OR = 1.8,95% CI = 1.16-2.81,P = 0.009)、流产次数(OR = 1.23,95% CI = 1.02-1.50,P = 0.035)和分娩次数(OR = 0.31,95% CI = 0.20-0.48,P 结论:HLA-G 3-配型的阳性率与流产次数、流产次数和分娩次数有关:本研究表明,HLA-G 3'UTR 多态性和二联型在受精后染色体异常胚胎的成功妊娠过程中起着重要作用。同时,不同的等位基因或二联型也会影响 UPL 胚胎的发育。
{"title":"Ralationship between polymorphisms and diplotypes of HLA-G 3'UTR and fetuses with abnormal chromosomes or unexplained pregnancy loss (UPL).","authors":"Danping Xu, Yiyang Zhu, Jun Wang, Heqin Guan, Xiuzhen Shen","doi":"10.1186/s40246-024-00695-5","DOIUrl":"10.1186/s40246-024-00695-5","url":null,"abstract":"<p><strong>Objectives: </strong>Human leukocyte antigen G (HLA-G) plays a crucial role in pregnancy. Pregnancy loss (PL) is caused by a variety of causes, such as fetal chromosomal abnormalities, maternal hypertension and diabetes, immune causes, spontaneous immune diseases, infections, unknown causes, etc. This study reports on the association of fetal HLA-G 3'UTR polymorphisms and diplotypes with chromosomally abnormal fetuses (CAF) or unexplained pregnancy loss (UPL).</p><p><strong>Methods: </strong>A total of 552 specimens were collected and grouped by next-generation sequencing technology (NGS) and fetal survival: UPL (112 cases), CAF (170 cases) and control (258 cases). The polymorphisms of HLA-G 3'UTR in all samples were detected by Sanger sequencing. The genotypes, haplotypes and diplotypes of HLA-G 3'UTR were analyzed. The classification and regression tree (CART) analysis was used to evaluate the role of HLA-G diplotypes in predicting fetal outcomes. The correlations between CAF or UPL and maternal age, paternal age, times of miscarrage, times of delivery were analyzed by logistic regression.</p><p><strong>Results: </strong>The frequencies of HLA-G + 2960del/del and + 3035CC genotypes were remarkablly increased in CAF than those in control group. The frequencies of HLA-G + 2960ins/del, + 3010CC, + 3035TC, + 3142GG, + 3187AA in CAF were significantly lower than those in normal fetuses. Through genetic models and logistic regression analysis, the dominant model of HLA-G 3'UTR genotypes [such as + 2960 (OR = 1.27, 95% CI = 1.05-1.54, p = 0.016), + 3010 (OR = 0.78, 95% CI = 0.63-0.97, p = 0.026), + 3035 (OR = 1.22, 95% CI = 1.00-1.49, p = 0.047), + 3142 (OR = 0.76, 95% CI = 0.62-0.95, p = 0.014) and + 3187 (OR = 0.80, 95% CI = 0.65-0.99, p = 0.041)] were dramatically associated with CAF. However, the frequencies of HLA-G + 3010GC, + 3142GC and + 3187AG in fetuses with UPL were memorably decreased than those in normal fetuses. No significant difference was found in the frequencies of HLA-G haplotypes in all groups. However, the frequency of UTR-1 positive specimens in CAF was significantly higher than that in UPL and control group. At the same time, the frequency of UTR-1/UTR-3 diplotypes in CAF was observably higher than that in UPL and control group, while the UTR-1/UTR-7 frequency in UPL was signally lower than that in control group. Multivariate logistic regression analysis indicated that positive HLA-G UTR-1 (OR = 1.8, 95% CI = 1.16-2.81, p = 0.009), times of abortion (OR = 1.23, 95% CI = 1.02-1.50, p = 0.035), and times of delivery (OR = 0.31, 95% CI = 0.20-0.48, p < 0.001) were correlated with CAF.</p><p><strong>Conclusions: </strong>This study suggests that HLA-G 3'UTR polymorphisms and diplotypes play an important role in the process of successful pregnancy of the embryos with abnormal chromosomes after fertilization. At the same time, Different alleles or diplotypes also affect the development of embryos with UPL.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"18 1","pages":"126"},"PeriodicalIF":3.8,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11572094/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142647624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Methyltransferase-like 3 represents a prospective target for the diagnosis and treatment of kidney diseases. 甲基转移酶样 3 是诊断和治疗肾脏疾病的前瞻性靶点。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-11-14 DOI: 10.1186/s40246-024-00692-8
Bin Song, Xiaolong Wu, Yan Zeng

Kidney disease is marked by complex pathological mechanisms and significant therapeutic hurdles, resulting in high morbidity and mortality rates globally. A deeper understanding of the fundamental processes involved can aid in identifying novel therapeutic targets and improving treatment efficacy. Current comprehensive data analyses indicate the involvement of methyltransferase-like 3 (METTL3) and its role in RNA N6-methyladenosine methylation in various renal pathologies, including acute kidney injury, renal fibrosis, and chronic kidney disease. However, there is a paucity of thorough reviews that clarify the functional mechanisms of METTL3 and evaluate its importance in enhancing therapeutic outcomes. This review seeks to systematically examine the roles, mechanisms, and potential clinical applications of METTL3 in renal diseases. The findings presented suggest that METTL3 is implicated in the etiology and exacerbation of kidney disorders, affecting their onset, progression, malignancy, and responsiveness to chemotherapeutic agents through the regulation of specific genetic pathways. In conclusion, this review underscores a detrimental correlation between METTL3 and kidney diseases, highlighting the therapeutic promise of targeting METTL3. Additionally, it offers critical insights for researchers concerning the diagnosis, prognosis, and treatment strategies for renal conditions.

肾脏疾病病理机制复杂,治疗难度大,导致全球发病率和死亡率居高不下。深入了解其中的基本过程有助于确定新的治疗靶点并提高治疗效果。目前的综合数据分析表明,甲基转移酶样 3(METTL3)及其在 RNA N6-甲基腺苷甲基化中的作用参与了各种肾脏病理,包括急性肾损伤、肾脏纤维化和慢性肾病。然而,阐明 METTL3 的功能机制并评估其在提高治疗效果方面的重要性的详尽综述并不多见。本综述旨在系统研究 METTL3 在肾脏疾病中的作用、机制和潜在的临床应用。研究结果表明,METTL3 与肾脏疾病的病因和恶化有关,它通过调节特定的遗传途径影响肾脏疾病的发病、进展、恶性程度以及对化疗药物的反应性。总之,这篇综述强调了 METTL3 与肾脏疾病之间的有害关联,突出了靶向 METTL3 的治疗前景。此外,它还为研究人员提供了有关肾脏疾病诊断、预后和治疗策略的重要见解。
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引用次数: 0
Shared genetics between breast cancer and predisposing diseases identifies novel breast cancer treatment candidates. 乳腺癌与易患疾病之间的共同遗传学发现了新型乳腺癌候选治疗方法。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-11-14 DOI: 10.1186/s40246-024-00688-4
Panagiotis N Lalagkas, Rachel D Melamed

Background: Current effective breast cancer treatment options have severe side effects, highlighting a need for new therapies. Drug repurposing can accelerate improvements to care, as FDA-approved drugs have known safety and pharmacological profiles. Some drugs for other conditions, such as metformin, an antidiabetic, have been tested in clinical trials for repurposing for breast cancer. Here, we exploit the genetics of breast cancer and linked predisposing diseases to propose novel drug repurposing opportunities. We hypothesize that if a predisposing disease contributes to breast cancer pathology, identifying the pleiotropic genes related to the risk of cancer could prioritize drugs, among all drugs treating a predisposing disease. We aim to develop a method to not only prioritize drugs for repurposing, but also to highlight shared etiology explaining repurposing.

Methods: We compile breast cancer's predisposing diseases from literature. For each predisposing disease, we use GWAS summary statistics data to identify genes in loci showing genetic correlation with breast cancer. Then, we use a network approach to link these shared genes to canonical pathways. Similarly, for all drugs treating the predisposing disease, we link their targets to pathways. In this manner, we are able to prioritize a list of drugs based on each predisposing disease, with each drug linked to a set of implicating pathways. Finally, we evaluate our recommendations against drugs currently under investigation for breast cancer.

Results: We identify 84 loci harboring mutations with positively correlated effects between breast cancer and its predisposing diseases; these contain 194 identified shared genes. Out of the 112 drugs indicated for the predisposing diseases, 74 drugs can be linked to shared genes via pathways (candidate drugs for repurposing). Fifteen out of these candidate drugs are already in advanced clinical trial phases or approved for breast cancer (OR = 9.28, p = 7.99e-03, one-sided Fisher's exact test), highlighting the ability of our approach to identify likely successful candidate drugs for repurposing.

Conclusions: Our novel approach accelerates drug repurposing for breast cancer by leveraging shared genetics with its known predisposing diseases. The result provides 59 novel candidate drugs alongside biological insights supporting each recommendation.

背景:目前有效的乳腺癌治疗方案存在严重的副作用,这凸显了对新疗法的需求。由于美国食品及药物管理局批准的药物具有已知的安全性和药理学特征,因此药物再利用可以加快改善治疗。一些治疗其他疾病的药物,如二甲双胍(一种抗糖尿病药物),已在临床试验中接受了乳腺癌再利用的测试。在这里,我们利用乳腺癌的遗传学和相关易感疾病,提出了新的药物再利用机会。我们假设,如果易患疾病是乳腺癌病理的诱因,那么找出与癌症风险相关的多效基因,就能在所有治疗易患疾病的药物中优先选择药物。我们的目标是开发出一种方法,不仅能确定药物再利用的优先次序,还能突出解释再利用的共同病因:方法:我们从文献中整理出乳腺癌的易感疾病。对于每种易患疾病,我们利用 GWAS 的汇总统计数据来确定与乳腺癌有遗传相关性的基因位点。然后,我们使用网络方法将这些共享基因与典型通路联系起来。同样,对于治疗易患疾病的所有药物,我们将其靶点与通路联系起来。这样,我们就能根据每种易患疾病列出药物的优先级,并将每种药物与一系列相关途径联系起来。最后,我们对照目前正在研究的乳腺癌药物对我们的建议进行了评估:结果:我们确定了乳腺癌及其易感疾病之间存在正相关效应突变的 84 个位点,其中包含 194 个已确定的共享基因。在针对易患疾病的 112 种药物中,有 74 种药物可通过途径与共有基因建立联系(候选药物再利用)。在这些候选药物中,有 15 种药物已进入晚期临床试验阶段或已获批用于乳腺癌(OR = 9.28,p = 7.99e-03,单侧费雪精确检验),这凸显了我们的方法有能力识别出可能成功的候选药物,以进行再利用:我们的新方法利用乳腺癌与已知易感疾病的共同遗传学,加快了乳腺癌药物的再利用。结果提供了 59 种新型候选药物以及支持每种推荐药物的生物学见解。
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引用次数: 0
Identification and characterization of novel ferroptosis-related genes in acute myocardial infarction. 急性心肌梗死中新型铁蛋白沉积相关基因的鉴定和特征描述
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-11-13 DOI: 10.1186/s40246-024-00693-7
Qiaoyu Zhou, Ruizheng Shi, Jia Liu, Zhaoya Liu

Background: Acute myocardial infarction (AMI) is a leading cause of death and morbidity worldwide. Ferroptosis, a form of regulated cell death, plays a critical role in modulating immune functions during AMI. This study aimed to identify ferroptosis-related hub genes that could serve as potential therapeutic targets in the progression of AMI.

Methods: Bioinformatics was used to identify overlapping genes associated with ferroptosis and the infiltration of 22 immune cells by Cell-type Identification by Estimating Relative Subsets of RNA Transcript (CIBERSORT) analysis. The expression of ferroptosis-related genes in AMI was validated across independent datasets, clinical samples, and in vitro cellular experiments. The predictive value for heart failure was evaluated in the first dimension of principal component analysis (PCA) using receiver operating characteristic (ROC) analysis.

Results: The study identified 11 key ferroptosis-related genes significantly correlated with immune cell abundance. CIBERSORT analysis highlighted immune dysregulation in AMI. JDP2, DUSP1, TLR4, NFS1, and SLC1A5 were identified as potential biomarkers for AMI progression. Additionally, JDP2, DUSP1, and DDIT4 demonstrated strong predictive value for long-term heart failure.

Conclusion: This study highlights the potential association of ferroptosis-related genes with the pathogenesis of AMI, suggesting a role in the molecular mechanisms that may underlie acute coronary events.

背景:急性心肌梗死(AMI)是全球死亡和发病的主要原因。铁蛋白沉积是一种调节细胞死亡的形式,在调节急性心肌梗死期间的免疫功能方面起着至关重要的作用。本研究旨在确定与铁突变相关的枢纽基因,这些基因可作为急性心肌梗死进展过程中的潜在治疗靶点:方法:通过估算RNA转录本相对子集的细胞类型鉴定(CIBERSORT)分析,使用生物信息学方法鉴定与铁沉降和22种免疫细胞浸润相关的重叠基因。在独立数据集、临床样本和体外细胞实验中验证了急性心肌梗死中铁蛋白沉积相关基因的表达。在主成分分析(PCA)的第一个维度中,利用接收者操作特征(ROC)分析评估了心衰的预测价值:结果:研究发现了 11 个与铁蛋白沉积相关的关键基因,这些基因与免疫细胞的丰度密切相关。CIBERSORT分析强调了AMI中的免疫失调。JDP2、DUSP1、TLR4、NFS1和SLC1A5被确定为AMI进展的潜在生物标志物。此外,JDP2、DUSP1 和 DDIT4 对长期心力衰竭有很强的预测价值:本研究强调了铁蛋白沉积相关基因与急性心肌梗死发病机制的潜在联系,表明这些基因在可能导致急性冠状动脉事件的分子机制中发挥作用。
{"title":"Identification and characterization of novel ferroptosis-related genes in acute myocardial infarction.","authors":"Qiaoyu Zhou, Ruizheng Shi, Jia Liu, Zhaoya Liu","doi":"10.1186/s40246-024-00693-7","DOIUrl":"10.1186/s40246-024-00693-7","url":null,"abstract":"<p><strong>Background: </strong>Acute myocardial infarction (AMI) is a leading cause of death and morbidity worldwide. Ferroptosis, a form of regulated cell death, plays a critical role in modulating immune functions during AMI. This study aimed to identify ferroptosis-related hub genes that could serve as potential therapeutic targets in the progression of AMI.</p><p><strong>Methods: </strong>Bioinformatics was used to identify overlapping genes associated with ferroptosis and the infiltration of 22 immune cells by Cell-type Identification by Estimating Relative Subsets of RNA Transcript (CIBERSORT) analysis. The expression of ferroptosis-related genes in AMI was validated across independent datasets, clinical samples, and in vitro cellular experiments. The predictive value for heart failure was evaluated in the first dimension of principal component analysis (PCA) using receiver operating characteristic (ROC) analysis.</p><p><strong>Results: </strong>The study identified 11 key ferroptosis-related genes significantly correlated with immune cell abundance. CIBERSORT analysis highlighted immune dysregulation in AMI. JDP2, DUSP1, TLR4, NFS1, and SLC1A5 were identified as potential biomarkers for AMI progression. Additionally, JDP2, DUSP1, and DDIT4 demonstrated strong predictive value for long-term heart failure.</p><p><strong>Conclusion: </strong>This study highlights the potential association of ferroptosis-related genes with the pathogenesis of AMI, suggesting a role in the molecular mechanisms that may underlie acute coronary events.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"18 1","pages":"123"},"PeriodicalIF":3.8,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11562590/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142619320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Minigene-based splice assays provide new insights on intronic variants of the PKHD1 gene. 基于微型基因的剪接测定为了解 PKHD1 基因的内含子变异提供了新的视角。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-11-09 DOI: 10.1186/s40246-024-00675-9
Yiyin Zhang, Ran Zhang, Xiaomeng Shi, Xuyan Liu, Changying Li, Yan Zhang, Zhi Wang, Dan Qiao, Fengjiao Pan, Bingying Zhang, Ning Xu, Bingzi Dong, Leping Shao

Background: Autosomal Recessive Polycystic Kidney Disease (ARPKD) is a rare hereditary disorder caused by variants in PKHD1. Currently, aberrant splicing has been reported to play important roles in genetic disease. Our goal is to analyze intronic variants in PKHD1 at the mRNA level.

Results: The 12 candidate variants were introduced into the corresponding minigene and functionally assayed in HEK 293T and Hela cells. We identified 11 variants that induce splicing alterations, resulting in various consequences such as skipping of exons, intron retention and protein truncation.

Conclusions: This underlined the importance of mRNA-level assessment for genetic diagnostics in related genetic disorders.

背景:常染色体隐性遗传多囊肾病(ARPKD)是一种罕见的遗传性疾病,由 PKHD1 变异引起。目前,异常剪接已被报道在遗传病中发挥重要作用。我们的目标是在 mRNA 水平分析 PKHD1 的内含子变异:结果:我们将 12 个候选变体引入相应的迷你基因,并在 HEK 293T 和 Hela 细胞中进行了功能测试。我们发现了 11 个可诱导剪接改变的变异体,它们会导致各种后果,如跳过外显子、内含子保留和蛋白质截断:这突显了 mRNA 水平评估对相关遗传疾病基因诊断的重要性。
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引用次数: 0
Development of oxidative stress- and ferroptosis-related prognostic signature in gastric cancer and identification of CDH19 as a novel biomarker. 开发胃癌氧化应激和铁蛋白沉积相关预后特征并确定 CDH19 为新型生物标记物
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-11-05 DOI: 10.1186/s40246-024-00682-w
Shibo Wang, Siyi Zhang, Xiaoxuan Li, Chuanyu Leng, Xiangxue Li, Jing Lv, Shufen Zhao, Wensheng Qiu, Jing Guo

Background: Ferroptosis is a unique mode of cell death that is iron-dependent and associated with oxidative stress and lipid peroxidation. Oxidative stress and ferroptosis are essential mechanisms leading to metabolic abnormalities in cells and have been popular areas in cancer research.

Methods: Initially, 76 oxidative stress and ferroptosis-related genes (OFRGs) were acquired by intersecting the gene sets from oxidative stress and ferroptosis. Afterwards, optimal OFRGs were screened using PPI networks, and individuals were separated into two OFRG subtypes (K = 2). Subsequently, we successfully constructed and verified a prognostic signature comprising SLC7A2, Cadherin 19 (CDH19), and CCN1. To further uncover potential biomarkers of gastric cancer (GC), we examined the expression level of CDH19, investigated the effects of knocking down CDH19 on the biological behavior of GC cells, and explored whether CDH19 is involved in ferroptosis and oxidative stress processes.

Results: According to the findings, individuals in the low-risk scoring group have less infiltration of immune suppressive cells, fewer occurrences of immune escape and dysfunction, greater efficacy in chemotherapy and immunotherapy, and better survival outcomes. The qRT-PCR assay indicated that CDH19 expression was significantly higher in GC cells. Through experiments, we demonstrated that knocking down CDH19 can affect the transcription levels of ACSL4 and GPX4, increase intracellular iron ion concentration and accumulation of reactive oxygen species (ROS), and inhibit the proliferation and migration of GC cells.

Conclusion: We developed an OFRG-related signature to predict the prognosis and treatment responsiveness of individuals with GC and identified CDH19 as a possible therapeutic target for GC.

背景:铁变性是一种独特的细胞死亡模式,它依赖于铁,并与氧化应激和脂质过氧化有关。氧化应激和铁氧化是导致细胞代谢异常的重要机制,一直是癌症研究的热门领域:方法:最初,通过交叉氧化应激和铁变态反应的基因集,获得了 76 个氧化应激和铁变态反应相关基因(OFRGs)。随后,利用 PPI 网络筛选出最佳 OFRGs,并将个体分为两个 OFRG 亚型(K = 2)。随后,我们成功构建并验证了由 SLC7A2、Cadherin 19 (CDH19) 和 CCN1 组成的预后特征。为了进一步发现胃癌(GC)的潜在生物标志物,我们检测了CDH19的表达水平,研究了敲除CDH19对GC细胞生物学行为的影响,并探讨了CDH19是否参与了铁变态反应和氧化应激过程:结果:研究结果显示,低危评分组患者的免疫抑制细胞浸润较少,免疫逃逸和免疫功能失调的发生率较低,化疗和免疫治疗的疗效较好,生存预后较好。qRT-PCR检测表明,CDH19在GC细胞中的表达量明显较高。通过实验,我们证明了敲除 CDH19 可影响 ACSL4 和 GPX4 的转录水平,增加细胞内铁离子浓度和活性氧(ROS)的积累,抑制 GC 细胞的增殖和迁移:我们建立了一个与 OFRG 相关的特征来预测 GC 患者的预后和治疗反应性,并确定 CDH19 为 GC 的可能治疗靶点。
{"title":"Development of oxidative stress- and ferroptosis-related prognostic signature in gastric cancer and identification of CDH19 as a novel biomarker.","authors":"Shibo Wang, Siyi Zhang, Xiaoxuan Li, Chuanyu Leng, Xiangxue Li, Jing Lv, Shufen Zhao, Wensheng Qiu, Jing Guo","doi":"10.1186/s40246-024-00682-w","DOIUrl":"10.1186/s40246-024-00682-w","url":null,"abstract":"<p><strong>Background: </strong>Ferroptosis is a unique mode of cell death that is iron-dependent and associated with oxidative stress and lipid peroxidation. Oxidative stress and ferroptosis are essential mechanisms leading to metabolic abnormalities in cells and have been popular areas in cancer research.</p><p><strong>Methods: </strong>Initially, 76 oxidative stress and ferroptosis-related genes (OFRGs) were acquired by intersecting the gene sets from oxidative stress and ferroptosis. Afterwards, optimal OFRGs were screened using PPI networks, and individuals were separated into two OFRG subtypes (K = 2). Subsequently, we successfully constructed and verified a prognostic signature comprising SLC7A2, Cadherin 19 (CDH19), and CCN1. To further uncover potential biomarkers of gastric cancer (GC), we examined the expression level of CDH19, investigated the effects of knocking down CDH19 on the biological behavior of GC cells, and explored whether CDH19 is involved in ferroptosis and oxidative stress processes.</p><p><strong>Results: </strong>According to the findings, individuals in the low-risk scoring group have less infiltration of immune suppressive cells, fewer occurrences of immune escape and dysfunction, greater efficacy in chemotherapy and immunotherapy, and better survival outcomes. The qRT-PCR assay indicated that CDH19 expression was significantly higher in GC cells. Through experiments, we demonstrated that knocking down CDH19 can affect the transcription levels of ACSL4 and GPX4, increase intracellular iron ion concentration and accumulation of reactive oxygen species (ROS), and inhibit the proliferation and migration of GC cells.</p><p><strong>Conclusion: </strong>We developed an OFRG-related signature to predict the prognosis and treatment responsiveness of individuals with GC and identified CDH19 as a possible therapeutic target for GC.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"18 1","pages":"121"},"PeriodicalIF":3.8,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11536560/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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Human Genomics
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