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Genetic distance and ancestry proportion modify the association between maternal genetic risk score of type 2 diabetes and fetal growth. 遗传距离和祖先比例会改变母体 2 型糖尿病遗传风险评分与胎儿生长之间的关联。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-07-19 DOI: 10.1186/s40246-024-00645-1
Tesfa Dejenie Habtewold, Prabhavi Wijesiriwardhana, Richard J Biedrzycki, Fasil Tekola-Ayele

Background: Maternal genetic risk of type 2 diabetes (T2D) has been associated with fetal growth, but the influence of genetic ancestry is not yet fully understood. We aimed to investigate the influence of genetic distance (GD) and genetic ancestry proportion (GAP) on the association of maternal genetic risk score of T2D (GRST2D) with fetal weight and birthweight.

Methods: Multi-ancestral pregnant women (n = 1,837) from the NICHD Fetal Growth Studies - Singletons cohort were included in the current analyses. Fetal weight (in grams, g) was estimated from ultrasound measurements of fetal biometry, and birthweight (g) was measured at delivery. GRST2D was calculated using T2D-associated variants identified in the latest trans-ancestral genome-wide association study and was categorized into quartiles. GD and GAP were estimated using genotype data of four reference populations. GD was categorized into closest, middle, and farthest tertiles, and GAP was categorized as highest, medium, and lowest. Linear regression analyses were performed to test the association of GRST2D with fetal weight and birthweight, adjusted for covariates, in each GD and GAP category.

Results: Among women with the closest GD from African and Amerindigenous ancestries, the fourth and third GRST2D quartile was significantly associated with 5.18 to 7.48 g (weeks 17-20) and 6.83 to 25.44 g (weeks 19-27) larger fetal weight compared to the first quartile, respectively. Among women with middle GD from European ancestry, the fourth GRST2D quartile was significantly associated with 5.73 to 21.21 g (weeks 18-26) larger fetal weight. Furthermore, among women with middle GD from European and African ancestries, the fourth and second GRST2D quartiles were significantly associated with 117.04 g (95% CI = 23.88-210.20, p = 0.014) and 95.05 g (95% CI = 4.73-185.36, p = 0.039) larger birthweight compared to the first quartile, respectively. The absence of significant association among women with the closest GD from East Asian ancestry was complemented by a positive significant association among women with the highest East Asian GAP.

Conclusions: The association between maternal GRST2D and fetal growth began in early-second trimester and was influenced by GD and GAP. The results suggest the use of genetic GD and GAP could improve the generalizability of GRS.

背景:2型糖尿病(T2D)的母体遗传风险与胎儿生长有关,但遗传祖先的影响尚未完全明了。我们旨在研究遗传距离(GD)和遗传祖先比例(GAP)对母体 2 型糖尿病遗传风险评分(GRST2D)与胎儿体重和出生体重相关性的影响:本次分析纳入了 NICHD 胎儿生长研究 - 单胎队列中的多祖先孕妇(n = 1,837)。胎儿体重(以克为单位)根据胎儿生物测量的超声波测量结果估算,出生体重(以克为单位)则在分娩时测量。GRST2D使用最新的跨祖先全基因组关联研究中发现的T2D相关变异进行计算,并分为四等分。GD和GAP是利用四个参考人群的基因型数据估算的。GD分为最近、中间和最远三等分,GAP分为最高、中等和最低三等分。在对各GD和GAP类别的协变量进行调整后,对GRST2D与胎儿体重和出生体重的关系进行了线性回归分析:在GD最接近的非洲裔和美洲土著妇女中,GRST2D的第四和第三四分位数与第一四分位数相比,分别与胎儿体重增加5.18至7.48克(第17至20周)和6.83至25.44克(第19至27周)显著相关。在欧洲血统的中等 GD 孕妇中,GRST2D 四分位数的第四位与胎儿体重增加 5.73 至 21.21 克(第 18-26 周)显著相关。此外,在欧洲血统和非洲血统的中等 GD 孕妇中,与第一四分位数相比,第四和第二 GRST2D 四分位数分别与 117.04 克(95% CI = 23.88-210.20,p = 0.014)和 95.05 克(95% CI = 4.73-185.36,p = 0.039)较大的出生体重显著相关。与东亚血统最接近的 GD 妇女之间没有显着关联,而与东亚 GAP 最高的妇女之间存在正向显着关联:结论:母体 GRST2D 与胎儿生长的关系始于妊娠早期的第二个三个月,并受 GD 和 GAP 的影响。结果表明,使用遗传 GD 和 GAP 可以提高 GRS 的普适性。
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引用次数: 0
Identification of novel immune-related signatures for keloid diagnosis and treatment: insights from integrated bulk RNA-seq and scRNA-seq analysis. 为瘢痕疙瘩的诊断和治疗鉴定新型免疫相关特征:综合大量 RNA-seq 和 scRNA-seq 分析的启示。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-07-16 DOI: 10.1186/s40246-024-00647-z
Kui Xiao, Sisi Wang, Wenxin Chen, Yiping Hu, Ziang Chen, Peng Liu, Jinli Zhang, Bin Chen, Zhi Zhang, Xiaojian Li

Background: Keloid is a disease characterized by proliferation of fibrous tissue after the healing of skin tissue, which seriously affects the daily life of patients. However, the clinical treatment of keloids still has limitations, that is, it is not effective in controlling keloids, resulting in a high recurrence rate. Thus, it is urgent to identify new signatures to improve the diagnosis and treatment of keloids.

Method: Bulk RNA seq and scRNA seq data were downloaded from the GEO database. First, we used WGCNA and MEGENA to co-identify keloid/immune-related DEGs. Subsequently, we used three machine learning algorithms (Randomforest, SVM-RFE, and LASSO) to identify hub immune-related genes of keloid (KHIGs) and investigated the heterogeneous expression of KHIGs during fibroblast subpopulation differentiation using scRNA-seq. Finally, we used HE and Masson staining, quantitative reverse transcription-PCR, western blotting, immunohistochemical, and Immunofluorescent assay to investigate the dysregulated expression and the mechanism of retinoic acid in keloids.

Results: In the present study, we identified PTGFR, RBP5, and LIF as KHIGs and validated their diagnostic performance. Subsequently, we constructed a novel artificial neural network molecular diagnostic model based on the transcriptome pattern of KHIGs, which is expected to break through the current dilemma faced by molecular diagnosis of keloids in the clinic. Meanwhile, the constructed IG score can also effectively predict keloid risk, which provides a new strategy for keloid prevention. Additionally, we observed that KHIGs were also heterogeneously expressed in the constructed differentiation trajectories of fibroblast subtypes, which may affect the differentiation of fibroblast subtypes and thus lead to dysregulation of the immune microenvironment in keloids. Finally, we found that retinoic acid may treat or alleviate keloids by inhibiting RBP5 to differentiate pro-inflammatory fibroblasts (PIF) to mesenchymal fibroblasts (MF), which further reduces collagen secretion.

Conclusion: In summary, the present study provides novel immune signatures (PTGFR, RBP5, and LIF) for keloid diagnosis and treatment, and identifies retinoic acid as potential anti-keloid drugs. More importantly, we provide a new perspective for understanding the interactions between different fibroblast subtypes in keloids and the remodeling of their immune microenvironment.

背景:瘢痕疙瘩是一种以皮肤组织愈合后纤维组织增生为特征的疾病,严重影响患者的日常生活。然而,瘢痕疙瘩的临床治疗仍存在局限性,即不能有效控制瘢痕疙瘩,导致复发率较高。因此,确定新的特征以改善瘢痕疙瘩的诊断和治疗迫在眉睫:方法:从 GEO 数据库下载大量 RNA 序列和 scRNA 序列数据。首先,我们使用 WGCNA 和 MEGENA 共同鉴定瘢痕疙瘩/免疫相关 DEGs。随后,我们使用三种机器学习算法(Randomforest、SVM-RFE和LASSO)识别了瘢痕疙瘩的枢纽免疫相关基因(KHIGs),并利用scRNA-seq研究了成纤维细胞亚群分化过程中KHIGs的异质性表达。最后,我们采用HE和Masson染色、定量逆转录-PCR、Western印迹、免疫组织化学和免疫荧光检测等方法研究了维甲酸在瘢痕疙瘩中的表达失调及其机制:结果:在本研究中,我们确定了 PTGFR、RBP5 和 LIF 为 KHIGs,并验证了它们的诊断性能。随后,我们根据 KHIGs 的转录组模式构建了一个新的人工神经网络分子诊断模型,有望突破目前临床上瘢痕疙瘩分子诊断所面临的困境。同时,构建的IG评分还能有效预测瘢痕疙瘩的风险,为瘢痕疙瘩的预防提供了新策略。此外,我们还观察到,在构建的成纤维细胞亚型分化轨迹中,KHIGs也存在异质性表达,这可能会影响成纤维细胞亚型的分化,从而导致瘢痕疙瘩中免疫微环境的失调。最后,我们发现维甲酸可通过抑制 RBP5 使促炎症成纤维细胞(PIF)分化为间充质成纤维细胞(MF),从而进一步减少胶原蛋白的分泌,从而治疗或缓解瘢痕疙瘩:总之,本研究为瘢痕疙瘩的诊断和治疗提供了新的免疫特征(PTGFR、RBP5 和 LIF),并确定维甲酸为潜在的抗瘢痕疙瘩药物。更重要的是,我们为了解瘢痕疙瘩中不同成纤维细胞亚型之间的相互作用及其免疫微环境的重塑提供了一个新的视角。
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引用次数: 0
Post-implantation analysis of genomic variations in the progeny from developing fetus to birth. 从胎儿发育到出生,对后代基因组变异的植入后分析。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-07-15 DOI: 10.1186/s40246-024-00634-4
Yingming Zheng, Chuanping Lin, Wen-Jing Wang, Liya Wang, Yeqing Qian, Luna Mao, Baohua Li, Lijun Lou, Yuchan Mao, Na Li, Jiayong Zheng, Nan Jiang, Chaying He, Qijing Wang, Qing Zhou, Fang Chen, Fan Jin

The analysis of genomic variations in offspring after implantation has been infrequently studied. In this study, we aim to investigate the extent of de novo mutations in humans from developing fetus to birth. Using high-depth whole-genome sequencing, 443 parent-offspring trios were studied to compare the results of de novo mutations (DNMs) between different groups. The focus was on fetuses and newborns, with DNA samples obtained from the families' blood and the aspirated embryonic tissues subjected to deep sequencing. It was observed that the average number of total DNMs in the newborns group was 56.26 (54.17-58.35), which appeared to be lower than that the multifetal reduction group, which was 76.05 (69.70-82.40) (F = 2.42, P = 0.12). However, after adjusting for parental age and maternal pre-pregnancy body mass index (BMI), significant differences were found between the two groups. The analysis was further divided into single nucleotide variants (SNVs) and insertion/deletion of a small number of bases (indels), and it was discovered that the average number of de novo SNVs associated with the multifetal reduction group and the newborn group was 49.89 (45.59-54.20) and 51.09 (49.22-52.96), respectively. No significant differences were noted between the groups (F = 1.01, P = 0.32). However, a significant difference was observed for de novo indels, with a higher average number found in the multifetal reduction group compared to the newborn group (F = 194.17, P < 0.001). The average number of de novo indels among the multifetal reduction group and the newborn group was 26.26 (23.27-29.05) and 5.17 (4.82-5.52), respectively. To conclude, it has been observed that the quantity of de novo indels in the newborns experiences a significant decrease when compared to that in the aspirated embryonic tissues (7-9 weeks). This phenomenon is evident across all genomic regions, highlighting the adverse effects of de novo indels on the fetus and emphasizing the significance of embryonic implantation and intrauterine growth in human genetic selection mechanisms.

对植入胎儿后代基因组变异的分析研究并不多见。在这项研究中,我们旨在调查人类从胎儿发育到出生期间的新生突变程度。通过高深度全基因组测序,我们对 443 例父母-后代三人组进行了研究,以比较不同群体之间的从头突变(DNMs)结果。研究重点是胎儿和新生儿,对从家庭血液中获得的DNA样本和抽取的胚胎组织进行了深度测序。结果发现,新生儿组的 DNM 总数平均为 56.26(54.17-58.35)个,似乎低于多胎妊娠减少组的 76.05(69.70-82.40)个(F = 2.42,P = 0.12)。然而,在对父母年龄和母亲孕前体重指数(BMI)进行调整后,发现两组之间存在显著差异。分析进一步分为单核苷酸变异(SNVs)和少量碱基的插入/缺失(indels),发现与多胎妊娠减少组和新生儿组相关的从头SNVs平均数量分别为49.89(45.59-54.20)和51.09(49.22-52.96)。两组间无明显差异(F = 1.01,P = 0.32)。然而,在新生儿组中,多胎妊娠减少组与新生儿组相比,发现了更高的平均数量(F = 194.17,P = 0.32)。
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引用次数: 0
Pharmacogenetics in Italy: current landscape and future prospects 意大利的药物遗传学:现状与前景
IF 4.5 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-07-10 DOI: 10.1186/s40246-024-00612-w
Matteo Floris, Antonino Moschella, Myriam Alcalay, Annalaura Montella, Matilde Tirelli, Laura Fontana, Maria Laura Idda, Paolo Guarnieri, Mario Capasso, Corrado Mammì, Paola Nicoletti, Monica Miozzo
Pharmacogenetics investigates sequence of genes that affect drug response, enabling personalized medication. This approach reduces drug-induced adverse reactions and improves clinical effectiveness, making it a crucial consideration for personalized medical care. Numerous guidelines, drawn by global consortia and scientific organizations, codify genotype-driven administration for over 120 active substances. As the scientific community acknowledges the benefits of genotype-tailored therapy over traditionally agnostic drug administration, the push for its implementation into Italian healthcare system is gaining momentum. This evolution is influenced by several factors, including the improved access to patient genotypes, the sequencing costs decrease, the growing of large-scale genetic studies, the rising popularity of direct-to-consumer pharmacogenetic tests, and the continuous improvement of pharmacogenetic guidelines. Since EMA (European Medicines Agency) and AIFA (Italian Medicines Agency) provide genotype information on drug leaflet without clear and explicit clinical indications for gene testing, the regulation of pharmacogenetic testing is a pressing matter in Italy. In this manuscript, we have reviewed how to overcome the obstacles in implementing pharmacogenetic testing in the clinical practice of the Italian healthcare system. Our particular emphasis has been on germline testing, given the absence of well-defined national directives in contrast to somatic pharmacogenetics.
药物遗传学研究影响药物反应的基因序列,从而实现个性化用药。这种方法可以减少药物引起的不良反应,提高临床疗效,是个性化医疗的重要考虑因素。由全球联盟和科学组织制定的众多指南,对 120 多种活性物质的基因型驱动用药进行了编纂。随着科学界认识到基因型定制疗法比传统的不可知给药疗法更有优势,意大利医疗系统推动实施基因型定制疗法的势头也在不断增强。这一演变受到多个因素的影响,包括患者基因型获取途径的改善、测序成本的降低、大规模基因研究的增加、直接面向消费者的药物基因测试的日益普及以及药物基因指南的不断完善。由于 EMA(欧洲药品管理局)和 AIFA(意大利药品管理局)在药品说明书中提供基因型信息,但没有明确清晰的基因检测临床适应症,因此药物基因检测的监管在意大利已迫在眉睫。在本手稿中,我们回顾了如何克服障碍,在意大利医疗系统的临床实践中实施药物基因检测。与体细胞药物基因学相比,由于缺乏明确的国家指令,我们特别强调了种系检测。
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引用次数: 0
An investigation of the molecular characterization of the tripartite motif (TRIM) family and primary validation of TRIM31 in gastric cancer. 三方基序(TRIM)家族分子特征的研究以及 TRIM31 在胃癌中的初步验证。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-07-09 DOI: 10.1186/s40246-024-00631-7
Yixin Ding, Yangyang Lu, Jing Guo, Shuming Chen, Xiaoxi Han, Shibo Wang, Mengqi Zhang, Rui Wang, Jialin Song, Kongjia Wang, Wensheng Qiu, Weiwei Qi

Most TRIM family members characterized by the E3-ubiquitin ligases, participate in ubiquitination and tumorigenesis. While there is a dearth of a comprehensive investigation for the entire family in gastric cancer (GC). By combining the TCGA and GEO databases, common TRIM family members (TRIMs) were obtained to investigate gene expression, gene mutations, and clinical prognosis. On the basis of TRIMs, a consensus clustering analysis was conducted, and a risk assessment system and prognostic model were developed. Particularly, TRIM31 with clinical prognostic and diagnostic value was chosen for single-gene bioinformatics analysis, in vitro experimental validation, and immunohistochemical analysis of clinical tissue microarrays. The combined dataset consisted of 66 TRIMs, of which 52 were differentially expressed and 43 were differentially prognostic. Significant survival differences existed between the gene clusters obtained by consensus clustering analysis. Using 4 differentially expressed genes identified by multivariate Cox regression and LASSO regression, a risk scoring system was developed. Higher risk scores were associated with a poorer prognosis, suppressive immune cell infiltration, and drug resistance. Transcriptomic data and clinical sample tissue microarrays confirmed that TRIM31 was highly expressed in GC and associated with a poor prognosis. Pathway enrichment analysis, cell migration and colony formation assay, EdU assay, reactive oxygen species (ROS) assay, and mitochondrial membrane potential assay revealed that TRIM31 may be implicated in cell cycle regulation and oxidative stress-related pathways, contribute to gastric carcinogenesis. This study investigated the whole functional and expression profile and a risk score system based on the TRIM family in GC. Further investigation centered around TRIM31 offers insight into the underlying mechanisms of action exhibited by other members of its family in the context of GC.

大多数 TRIM 家族成员都是 E3 泛素连接酶,参与泛素化和肿瘤发生。但目前还缺乏对胃癌(GC)中整个家族成员的全面调查。通过结合TCGA和GEO数据库,我们获得了常见的TRIM家族成员(TRIMs),以研究基因表达、基因突变和临床预后。在TRIMs的基础上,进行了共识聚类分析,并建立了风险评估系统和预后模型。特别是选择了具有临床预后和诊断价值的 TRIM31 进行单基因生物信息学分析、体外实验验证和临床组织芯片免疫组化分析。合并数据集包括 66 个 TRIMs,其中 52 个具有差异表达,43 个具有差异预后。通过共识聚类分析获得的基因簇之间存在显著的生存差异。利用多元 Cox 回归和 LASSO 回归确定的 4 个差异表达基因,建立了一个风险评分系统。较高的风险评分与较差的预后、抑制性免疫细胞浸润和耐药性有关。转录组数据和临床样本组织芯片证实,TRIM31在GC中高表达,并与不良预后相关。通路富集分析、细胞迁移和集落形成测定、EdU测定、活性氧(ROS)测定和线粒体膜电位测定显示,TRIM31可能与细胞周期调控和氧化应激相关通路有关,并导致胃癌的发生。本研究调查了 TRIM31 家族在胃癌中的整个功能和表达谱以及基于 TRIM31 家族的风险评分系统。围绕 TRIM31 开展的进一步研究有助于深入了解其家族其他成员在胃癌中的潜在作用机制。
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引用次数: 0
Association of lipid-lowering drugs with risk of sarcopenia: a drug target mendelian randomization study and meta-analysis. 降脂药物与肌肉疏松症风险的关系:一项药物靶点孟德尔随机化研究和荟萃分析。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-07-03 DOI: 10.1186/s40246-024-00643-3
Jiaxin Li, Chenyang Zang, Hui Lv, Zheng Xiao, Peihong Li, Bo Xiao, Luo Zhou

Background: Lipid-lowering drugs are widely used among the elderly, with some studies suggesting links to muscle-related symptoms. However, the causality remains uncertain.

Methods: Using the Mendelian randomization (MR) approach, we assessed the causal effects of genetically proxied reduced low-density lipoprotein cholesterol (LDL-C) through inhibitions of hydroxy-methyl-glutaryl-CoA reductase (HMGCR), proprotein convertase subtilisin/kexin type 9 (PCSK9), and Niemann-Pick C1-like 1 (NPC1L1) on sarcopenia-related traits, including low hand grip strength, appendicular lean mass, and usual walking pace. A meta-analysis was conducted to combine the causal estimates from different consortiums.

Results: Using LDL-C pooled data predominantly from UK Biobank, genetically proxied inhibition of HMGCR was associated with higher appendicular lean mass (beta = 0.087, P = 7.56 × 10- 5) and slower walking pace (OR = 0.918, P = 6.06 × 10- 9). In contrast, inhibition of PCSK9 may reduce appendicular lean mass (beta = -0.050, P = 1.40 × 10- 3), while inhibition of NPC1L1 showed no causal impact on sarcopenia-related traits. These results were validated using LDL-C data from Global Lipids Genetics Consortium, indicating that HMGCR inhibition may increase appendicular lean mass (beta = 0.066, P = 2.17 × 10- 3) and decelerate walking pace (OR = 0.932, P = 1.43 × 10- 6), whereas PCSK9 inhibition could decrease appendicular lean mass (beta = -0.048, P = 1.69 × 10- 6). Meta-analysis further supported the robustness of these causal associations.

Conclusions: Genetically proxied HMGCR inhibition may increase muscle mass but compromise muscle function, PCSK9 inhibition could result in reduced muscle mass, while NPC1L1 inhibition is not associated with sarcopenia-related traits and this class of drugs may serve as viable alternatives to sarcopenia individuals or those at an elevated risk.

背景:降脂药在老年人中被广泛使用,一些研究表明它与肌肉相关症状有关。然而,其因果关系仍不确定:方法:我们使用孟德尔随机化(MR)方法,评估了通过抑制羟甲基戊二酰-CoA 还原酶(HMGCR)、9 型枯草蛋白酶/kexin 型丙蛋白转换酶(PCSK9)和 Niemann-Pick C1-like 1(NPC1L1)来降低低密度脂蛋白胆固醇(LDL-C)对肌肉疏松症相关特征的因果效应,包括低手握力、阑尾瘦体重和通常步行速度。我们进行了一项荟萃分析,以合并来自不同联盟的因果关系估计值:结果:利用主要来自英国生物库的低密度脂蛋白胆固醇集合数据,HMGCR的基因替代抑制与较高的闌尾瘦体重(β=0.087,P=7.56 × 10-5)和较慢的步行速度(OR=0.918,P=6.06 × 10-9)相关。与此相反,抑制 PCSK9 可减少阑尾瘦体重(β = -0.050,P = 1.40 × 10-3),而抑制 NPC1L1 则对肌肉疏松症相关特征没有因果影响。这些结果通过全球血脂遗传学联合会的低密度脂蛋白胆固醇数据得到了验证,表明抑制 HMGCR 可增加阑尾瘦体重(β = 0.066,P = 2.17 × 10-3)并减慢步行速度(OR = 0.932,P = 1.43 × 10-6),而抑制 PCSK9 可减少阑尾瘦体重(β = -0.048,P = 1.69 × 10-6)。元分析进一步证实了这些因果关系的稳健性:结论:基因替代的 HMGCR 抑制可增加肌肉质量,但会损害肌肉功能;PCSK9 抑制可导致肌肉质量减少;而 NPC1L1 抑制与肌肉疏松症相关特征无关。
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引用次数: 0
A novel variant in GAS2 is associated with autosomal dominant nonsyndromic hearing impairment in a Chinese family. 在一个中国家庭中,GAS2的一个新变体与常染色体显性非综合征性听力障碍有关。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-07-02 DOI: 10.1186/s40246-024-00628-2
Luping Zhang, Danya Zheng, Lian Xu, Han Wang, Shuqiang Zhang, Jianhua Shi, Nana Jin

Knockout of GAS2 (growth arrest-specific protein 2), causes disorganization and destabilization of microtubule bundles in supporting cells of the cochlear duct, leading to hearing loss in vivo. However, the molecular mechanism through which GAS2 variant results in hearing loss remains unknown. By Whole-exome sequencing, we identified a novel heterozygous splicing variant in GAS2 (c.616-2 A > G) as the only candidate mutation segregating with late-onset and progressive nonsyndromic hearing loss (NSHL) in a large dominant family. This splicing mutation causes an intron retention and produces a C-terminal truncated protein (named GAS2mu). Mechanistically, the degradation of GAS2mu via the ubiquitin-proteasome pathway is enhanced, and cells expressing GAS2mu exhibit disorganized microtubule bundles. Additionally, GAS2mu further promotes apoptosis by increasing the Bcl-xS/Bcl-xL ratio instead of through the p53-dependent pathway as wild-type GAS2 does, indicating that GAS2mu acts as a toxic molecule to exacerbate apoptosis. Our findings demonstrate that this novel variant of GAS2 promotes its own protein degradation, microtubule disorganization and cellular apoptosis, leading to hearing loss in carriers. This study expands the spectrum of GAS2 variants and elucidates the underlying pathogenic mechanisms, providing a foundation for future investigations of new therapeutic strategies to prevent GAS2-associated progressive hearing loss.

基因敲除 GAS2(生长停滞特异性蛋白 2)会导致耳蜗导管支持细胞中微管束的混乱和不稳定,从而导致体内听力损失。然而,GAS2 变体导致听力损失的分子机制仍然未知。通过全外显子组测序,我们在一个大型显性家族中发现了 GAS2 的一个新的杂合剪接变异(c.616-2 A > G),它是与晚发性和进行性非综合征性听力损失(NSHL)分离的唯一候选突变。这种剪接突变导致内含子保留,并产生 C 端截短蛋白(命名为 GAS2mu)。从机理上讲,GAS2mu 通过泛素-蛋白酶体途径的降解作用增强,表达 GAS2mu 的细胞表现出微管束紊乱。此外,GAS2mu 还通过增加 Bcl-xS/Bcl-xL 的比例进一步促进细胞凋亡,而不是像野生型 GAS2 那样通过 p53 依赖性途径,这表明 GAS2mu 是一种加剧细胞凋亡的毒性分子。我们的研究结果表明,GAS2 的这种新型变体会促进自身蛋白降解、微管紊乱和细胞凋亡,从而导致携带者听力损失。这项研究扩大了GAS2变体的范围,阐明了其潜在的致病机制,为今后研究新的治疗策略以预防GAS2相关的渐进性听力损失奠定了基础。
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引用次数: 0
Unveiling the molecular landscape of cognitive aging: insights from polygenic risk scores, DNA methylation, and gene expression. 揭示认知老化的分子图谱:从多基因风险评分、DNA 甲基化和基因表达中获得启示。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-07-02 DOI: 10.1186/s40246-024-00640-6
Sonya Neto, Andreia Reis, Miguel Pinheiro, Margarida Ferreira, Vasco Neves, Teresa Costa Castanho, Nadine Santos, Ana João Rodrigues, Nuno Sousa, Manuel A S Santos, Gabriela R Moura

Background: Aging represents a significant risk factor for the occurrence of cerebral small vessel disease, associated with white matter (WM) lesions, and to age-related cognitive alterations, though the precise mechanisms remain largely unknown. This study aimed to investigate the impact of polygenic risk scores (PRS) for WM integrity, together with age-related DNA methylation, and gene expression alterations, on cognitive aging in a cross-sectional healthy aging cohort. The PRSs were calculated using genome-wide association study (GWAS) summary statistics for magnetic resonance imaging (MRI) markers of WM integrity, including WM hyperintensities, fractional anisotropy (FA), and mean diffusivity (MD). These scores were utilized to predict age-related cognitive changes and evaluate their correlation with structural brain changes, which distinguish individuals with higher and lower cognitive scores. To reduce the dimensionality of the data and identify age-related DNA methylation and transcriptomic alterations, Sparse Partial Least Squares-Discriminant Analysis (sPLS-DA) was used. Subsequently, a canonical correlation algorithm was used to integrate the three types of omics data (PRS, DNA methylation, and gene expression data) and identify an individual "omics" signature that distinguishes subjects with varying cognitive profiles.

Results: We found a positive association between MD-PRS and long-term memory, as well as a correlation between MD-PRS and structural brain changes, effectively discriminating between individuals with lower and higher memory scores. Furthermore, we observed an enrichment of polygenic signals in genes related to both vascular and non-vascular factors. Age-related alterations in DNA methylation and gene expression indicated dysregulation of critical molecular features and signaling pathways involved in aging and lifespan regulation. The integration of multi-omics data underscored the involvement of synaptic dysfunction, axonal degeneration, microtubule organization, and glycosylation in the process of cognitive aging.

Conclusions: These findings provide valuable insights into the biological mechanisms underlying the association between WM coherence and cognitive aging. Additionally, they highlight how age-associated DNA methylation and gene expression changes contribute to cognitive aging.

背景:衰老是发生脑小血管疾病(与白质(WM)病变有关)和与年龄有关的认知改变的一个重要风险因素,但其确切机制在很大程度上仍然未知。本研究旨在调查白质完整性的多基因风险评分(PRS)以及与年龄相关的 DNA 甲基化和基因表达改变对横断面健康老年队列中认知老化的影响。PRS是利用全基因组关联研究(GWAS)对WM完整性的磁共振成像(MRI)标记物(包括WM高密度、分数各向异性(FA)和平均弥散度(MD))的汇总统计计算得出的。这些分数被用来预测与年龄相关的认知变化,并评估它们与大脑结构变化的相关性,从而区分认知分数较高和较低的个体。为了降低数据维度并识别与年龄相关的 DNA 甲基化和转录组变化,研究人员使用了稀疏偏最小二乘法判别分析(sPLS-DA)。随后,我们使用了一种典型相关算法来整合三种类型的 omics 数据(PRS、DNA 甲基化和基因表达数据),并识别出一种个体 "omics "特征,以区分具有不同认知特征的受试者:结果:我们发现 MD-PRS 与长期记忆之间存在正相关,MD-PRS 与大脑结构变化之间也存在相关性,可有效区分记忆得分较低和较高的个体。此外,我们还观察到与血管和非血管因素相关的基因中富含多基因信号。DNA 甲基化和基因表达中与年龄相关的改变表明,参与衰老和寿命调节的关键分子特征和信号通路出现失调。多组学数据的整合强调了认知老化过程中突触功能障碍、轴突变性、微管组织和糖基化的参与:这些发现为了解WM连贯性与认知衰老之间关联的生物机制提供了宝贵的见解。此外,这些研究还强调了与年龄相关的 DNA 甲基化和基因表达变化是如何导致认知衰老的。
{"title":"Unveiling the molecular landscape of cognitive aging: insights from polygenic risk scores, DNA methylation, and gene expression.","authors":"Sonya Neto, Andreia Reis, Miguel Pinheiro, Margarida Ferreira, Vasco Neves, Teresa Costa Castanho, Nadine Santos, Ana João Rodrigues, Nuno Sousa, Manuel A S Santos, Gabriela R Moura","doi":"10.1186/s40246-024-00640-6","DOIUrl":"10.1186/s40246-024-00640-6","url":null,"abstract":"<p><strong>Background: </strong>Aging represents a significant risk factor for the occurrence of cerebral small vessel disease, associated with white matter (WM) lesions, and to age-related cognitive alterations, though the precise mechanisms remain largely unknown. This study aimed to investigate the impact of polygenic risk scores (PRS) for WM integrity, together with age-related DNA methylation, and gene expression alterations, on cognitive aging in a cross-sectional healthy aging cohort. The PRSs were calculated using genome-wide association study (GWAS) summary statistics for magnetic resonance imaging (MRI) markers of WM integrity, including WM hyperintensities, fractional anisotropy (FA), and mean diffusivity (MD). These scores were utilized to predict age-related cognitive changes and evaluate their correlation with structural brain changes, which distinguish individuals with higher and lower cognitive scores. To reduce the dimensionality of the data and identify age-related DNA methylation and transcriptomic alterations, Sparse Partial Least Squares-Discriminant Analysis (sPLS-DA) was used. Subsequently, a canonical correlation algorithm was used to integrate the three types of omics data (PRS, DNA methylation, and gene expression data) and identify an individual \"omics\" signature that distinguishes subjects with varying cognitive profiles.</p><p><strong>Results: </strong>We found a positive association between MD-PRS and long-term memory, as well as a correlation between MD-PRS and structural brain changes, effectively discriminating between individuals with lower and higher memory scores. Furthermore, we observed an enrichment of polygenic signals in genes related to both vascular and non-vascular factors. Age-related alterations in DNA methylation and gene expression indicated dysregulation of critical molecular features and signaling pathways involved in aging and lifespan regulation. The integration of multi-omics data underscored the involvement of synaptic dysfunction, axonal degeneration, microtubule organization, and glycosylation in the process of cognitive aging.</p><p><strong>Conclusions: </strong>These findings provide valuable insights into the biological mechanisms underlying the association between WM coherence and cognitive aging. Additionally, they highlight how age-associated DNA methylation and gene expression changes contribute to cognitive aging.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11221141/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141491739","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
The cuproptosis-related signature predicts the prognosis and immune microenvironments of primary diffuse gliomas: a comprehensive analysis. 杯突相关特征可预测原发性弥漫性胶质瘤的预后和免疫微环境:一项综合分析。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-07-02 DOI: 10.1186/s40246-024-00636-2
Tao Chang, Yihan Wu, Xiaodong Niu, Zhiwei Guo, Jiahao Gan, Xiang Wang, Yanhui Liu, Qi Pan, Qing Mao, Yuan Yang

Background: Evidence has revealed a connection between cuproptosis and the inhibition of tumor angiogenesis. While the efficacy of a model based on cuproptosis-related genes (CRGs) in predicting the prognosis of peripheral organ tumors has been demonstrated, the impact of CRGs on the prognosis and the immunological landscape of gliomas remains unexplored.

Methods: We screened CRGs to construct a novel scoring tool and developed a prognostic model for gliomas within the various cohorts. Afterward, a comprehensive exploration of the relationship between the CRG risk signature and the immunological landscape of gliomas was undertaken from multiple perspectives.

Results: Five genes (NLRP3, ATP7B, SLC31A1, FDX1, and GCSH) were identified to build a CRG scoring system. The nomogram, based on CRG risk and other signatures, demonstrated a superior predictive performance (AUC of 0.89, 0.92, and 0.93 at 1, 2, and 3 years, respectively) in the training cohort. Furthermore, the CRG score was closely associated with various aspects of the immune landscape in gliomas, including immune cell infiltration, tumor mutations, tumor immune dysfunction and exclusion, immune checkpoints, cytotoxic T lymphocyte and immune exhaustion-related markers, as well as cancer signaling pathway biomarkers and cytokines.

Conclusion: The CRG risk signature may serve as a robust biomarker for predicting the prognosis and the potential viability of immunotherapy responses. Moreover, the key candidate CRGs might be promising targets to explore the underlying biological background and novel therapeutic interventions in gliomas.

背景:有证据显示杯突与抑制肿瘤血管生成之间存在联系。虽然基于杯突相关基因(CRGs)的模型在预测外周器官肿瘤预后方面的有效性已得到证实,但CRGs对神经胶质瘤预后和免疫格局的影响仍有待探索:方法:我们筛选了CRGs,构建了一个新的评分工具,并在不同队列中开发了胶质瘤预后模型。随后,我们从多个角度全面探讨了CRG风险特征与胶质瘤免疫格局之间的关系:结果:确定了五个基因(NLRP3、ATP7B、SLC31A1、FDX1 和 GCSH),从而建立了 CRG 评分系统。在训练队列中,基于 CRG 风险和其他特征的提名图显示出卓越的预测性能(1 年、2 年和 3 年的 AUC 分别为 0.89、0.92 和 0.93)。此外,CRG评分与胶质瘤中免疫状况的各个方面密切相关,包括免疫细胞浸润、肿瘤突变、肿瘤免疫功能障碍和排斥、免疫检查点、细胞毒性T淋巴细胞和免疫耗竭相关标记物以及癌症信号通路生物标记物和细胞因子:CRG风险特征可作为预测预后和免疫治疗反应潜在可行性的可靠生物标志物。此外,关键候选CRG可能是探索胶质瘤潜在生物学背景和新型治疗干预的有希望的靶点。
{"title":"The cuproptosis-related signature predicts the prognosis and immune microenvironments of primary diffuse gliomas: a comprehensive analysis.","authors":"Tao Chang, Yihan Wu, Xiaodong Niu, Zhiwei Guo, Jiahao Gan, Xiang Wang, Yanhui Liu, Qi Pan, Qing Mao, Yuan Yang","doi":"10.1186/s40246-024-00636-2","DOIUrl":"10.1186/s40246-024-00636-2","url":null,"abstract":"<p><strong>Background: </strong>Evidence has revealed a connection between cuproptosis and the inhibition of tumor angiogenesis. While the efficacy of a model based on cuproptosis-related genes (CRGs) in predicting the prognosis of peripheral organ tumors has been demonstrated, the impact of CRGs on the prognosis and the immunological landscape of gliomas remains unexplored.</p><p><strong>Methods: </strong>We screened CRGs to construct a novel scoring tool and developed a prognostic model for gliomas within the various cohorts. Afterward, a comprehensive exploration of the relationship between the CRG risk signature and the immunological landscape of gliomas was undertaken from multiple perspectives.</p><p><strong>Results: </strong>Five genes (NLRP3, ATP7B, SLC31A1, FDX1, and GCSH) were identified to build a CRG scoring system. The nomogram, based on CRG risk and other signatures, demonstrated a superior predictive performance (AUC of 0.89, 0.92, and 0.93 at 1, 2, and 3 years, respectively) in the training cohort. Furthermore, the CRG score was closely associated with various aspects of the immune landscape in gliomas, including immune cell infiltration, tumor mutations, tumor immune dysfunction and exclusion, immune checkpoints, cytotoxic T lymphocyte and immune exhaustion-related markers, as well as cancer signaling pathway biomarkers and cytokines.</p><p><strong>Conclusion: </strong>The CRG risk signature may serve as a robust biomarker for predicting the prognosis and the potential viability of immunotherapy responses. Moreover, the key candidate CRGs might be promising targets to explore the underlying biological background and novel therapeutic interventions in gliomas.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11220998/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141491738","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
EU surveys insights: analytical tools, future directions, and the essential requirement for reference materials in wastewater monitoring of SARS-CoV-2, antimicrobial resistance and beyond. 欧盟调查见解:SARS-CoV-2、抗菌药耐药性及其他废水监测中的分析工具、未来方向和对参考材料的基本要求。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-06-27 DOI: 10.1186/s40246-024-00641-5
Valentina Paracchini, Mauro Petrillo, Anandasagari Arcot Rajashekar, Piotr Robuch, Ursula Vincent, Philippe Corbisier, Simona Tavazzi, Barbara Raffael, Elisabetta Suffredini, Giuseppina La Rosa, Bernd Manfred Gawlik, Antonio Marchini

Background: Wastewater surveillance (WWS) acts as a vigilant sentinel system for communities, analysing sewage to protect public health by detecting outbreaks and monitoring trends in pathogens and contaminants. To achieve a thorough comprehension of present and upcoming practices and to identify challenges and opportunities for standardisation and improvement in WWS methodologies, two EU surveys were conducted targeting over 750 WWS laboratories across Europe and other regions. The first survey explored a diverse range of activities currently undertaken or planned by laboratories. The second survey specifically targeted methods and quality controls utilised for SARS-CoV-2 surveillance.

Results: The findings of the two surveys provide a comprehensive insight into the procedures and methodologies applied in WWS. In Europe, WWS primarily focuses on SARS-CoV-2 with 99% of the survey participants dedicated to this virus. However, the responses highlighted a lack of standardisation in the methodologies employed for monitoring SARS-CoV-2. The surveillance of other pathogens, including antimicrobial resistance, is currently fragmented and conducted by only a limited number of laboratories. Notably, these activities are anticipated to expand in the future. Survey replies emphasise the collective recognition of the need to enhance the accuracy of results in WWS practices, reflecting a shared commitment to advancing precision and effectiveness in WWS methodologies.

Conclusions: These surveys identified a lack of standardised common procedures in WWS practices and the need for quality standards and reference materials to enhance the accuracy and reliability of WWS methods in the future. In addition, it is important to broaden surveillance efforts beyond SARS-CoV-2 to include other emerging pathogens and antimicrobial resistance to ensure a comprehensive approach to protecting public health.

背景:污水监测(WWS)是社区的警戒哨系统,通过分析污水来检测疫情并监测病原体和污染物的趋势,从而保护公众健康。为了全面了解当前和未来的做法,并确定 WWS 方法标准化和改进所面临的挑战和机遇,欧盟针对欧洲和其他地区的 750 多个 WWS 实验室开展了两项调查。第一项调查探讨了实验室目前正在开展或计划开展的各种活动。第二项调查专门针对用于 SARS-CoV-2 监测的方法和质量控制:这两项调查的结果使人们对 WWS 所采用的程序和方法有了全面的了解。在欧洲,WWS 主要关注的是 SARS-CoV-2 病毒,99% 的调查参与者都致力于该病毒的监测。然而,调查结果显示,监测 SARS-CoV-2 所采用的方法缺乏标准化。目前,对其他病原体(包括抗菌素耐药性)的监测是分散的,只有少数实验室进行监测。值得注意的是,这些活动预计今后会扩大。调查答复强调,大家都认识到有必要提高 WWS 实践结果的准确性,这反映出大家都致力于提高 WWS 方法的准确性和有效性:这些调查发现,世界水资源统计实践中缺乏标准化的通用程序,需要质量标准和参考资料来提高世界水资源统计方法的准确性和可靠性。此外,重要的是要将监测工作从 SARS-CoV-2 扩展到其他新出现的病原体和抗菌素耐药性,以确保以全面的方法保护公众健康。
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引用次数: 0
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Human Genomics
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