本文介绍了Phenomics期刊2024年第一期收录文章合集，文章概览如下，请查收！

（Phenomics期刊2024年第一期封面图）

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DOI: 

https://doi.org/10.1007/s43657-023-00109-x

引用格式：

Qiao, H., Tan, J., Wen, S. et al. De Novo Dissecting the Three-Dimensional Facial Morphology of 2379 Han Chinese Individuals. Phenomics 4, 1–12 (2024). https://doi.org/10.1007/s43657-023-00109-x

该研究建立了手动标志点的面部形态学数据库，并对汉族人群的同质和异质形态学特征进行了表征。提供了显示汉族亚群分层的表型证据，这可能有助于汉族人群关联分析的研究设计。此外，群体分层的研究有助于理解精准医学的概念，为个性化的医学治疗提供支撑。

Abstract

Phenotypic diversity, especially that of facial morphology, has not been fully investigated in the Han Chinese, which is the largest ethnic group in the world. In this study, we systematically analyzed a total of 14,838 facial traits representing 15 categories with both a large-scale three-dimensional (3D) manual landmarking database and computer-aided facial segmented phenotyping in 2379 Han Chinese individuals. Our results illustrate that homogeneous and heterogeneous facial morphological traits exist among Han Chinese populations across the three geographical regions: Zhengzhou, Taizhou, and Nanning. We identified 1560 shared features from extracted phenotypes, which characterized well the basic facial morphology of the Han Chinese. In particular, heterogeneous phenotypes showing population structures corresponded to geographical subpopulations. The greatest facial variation among these geographical populations was the angle of glabella, left subalare, and right cheilion (p = 3.4 × 10−161). Interestingly, we found that Han Chinese populations could be classified into northern Han, central Han, and southern Han at the phenotypic level, and the facial morphological variation pattern of central Han Chinese was between the typical differentiation of northern and southern Han Chinese. This pattern was highly consistent with that revealed by the genetic data. These findings provide new insights into the analysis of multidimensional phenotypes as well as a valuable resource for further facial phenotype-genotype association studies in Han Chinese and East Asian populations.

A Heterozygous Phospholamban Variant (p.R14del) Leads to Left Ventricular Involvement and Heart Failure Phenotypes in Arrhythmogenic Right Ventricular Cardiomyopathy

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DOI: 

https://doi.org/10.1007/s43657-023-00126-w

引用格式：

Mo, H., Hua, X., Bao, M. et al. A Heterozygous Phospholamban Variant (p.R14del) Leads to Left Ventricular Involvement and Heart Failure Phenotypes in Arrhythmogenic Right Ventricular Cardiomyopathy. Phenomics 4, 13–23 (2024). https://doi.org/10.1007/s43657-023-00126-w

该研究旨在确定PLN基因致病突变引起的致心律失常性右室心肌病（ARVC）的患病率和临床特征，为PLN基因突变与ARVC之间的关联提供了宝贵的见解，有助于为ARVC患者制定更有效的诊断和治疗策略。

Abstract

This study aimed to determine the prevalence and clinical features of Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) caused by pathogenic mutations in the Phospholamban (PLN) gene. The study included 170 patients who had a confirmed diagnosis of ARVC and underwent PLN genetic screening using next-generation sequencing. The findings of this study provide valuable insights into the association between PLN mutations and ARVC, which can aid in the development of more effective diagnostic and treatment strategies for ARVC patients. Out of the patients evaluated, six had a rare pathogenic mutation in PLN with the same p.R14del variant. Family screening revealed that heterozygous carriers of p.R14del exhibited a definite ARVC phenotype. In clinical studies, individuals with the p.R14del mutation experienced a similar rate of malignant arrhythmia events as those with classic desmosome mutations. After adjusting for covariates, individuals with PLN mutations had a two point one seven times greater likelihood of experiencing transplant-related risks compared to those who did not possess PLN mutations (95% CI 1.08–6.82, p = 0.035). The accumulation of left ventricular fat and fibers is a pathological marker for ARVC patients with p.R14del mutations. In a cohort of 170 Chinese ARVC patients, three point five percent of probands had the PLN pathogenic variant (p.R14del) and all were female. Our data shows that PLN-related ARVC patients are at high risk for ventricular arrhythmias and heart failure, which requires clinical differentiation from classic ARVC. Furthermore, carrying the p.R14del mutation can be an independent prognostic risk factor in ARVC patients.

Next-Generation Sequencing-Based Copy Number Variation Analysis in Chinese Patients with Primary Ciliary Dyskinesia Revealed Novel DNAH5 Copy Number Variations

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DOI：

https://doi.org/10.1007/s43657-023-00130-0

引用格式：

Chen, W., Guo, Z., Li, M. et al. Next-Generation Sequencing-Based Copy Number Variation Analysis in Chinese Patients with Primary Ciliary Dyskinesia Revealed Novel DNAH5 Copy Number Variations. Phenomics 4, 24–33 (2024). https://doi.org/10.1007/s43657-023-00130-0

该研究提供了中国PCD患者CNVs突变的详细描述，证实了CNVs在DNAH5基因引起的PCD中发挥了作用。

Abstract

Primary ciliary dyskinesia (PCD) is a rare disorder characterized by extensive genetic heterogeneity. However, in the genetic pathogenesis of PCD, copy number variation (CNV) has not received sufficient attention and has rarely been reported, especially in China. Next-generation sequencing (NGS) followed by targeted CNV analysis was used in patients highly suspected to have PCD with negative results in routine whole-exome sequencing (WES) analysis. Quantitative real-time polymerase chain reaction (qPCR) and Sanger sequencing were used to confirm these CNVs. To further characterize the ciliary phenotypes, high-speed video microscopy analysis (HSVA), transmission electron microscopy (TEM), and immunofluorescence (IF) analysis were used. Patient 1 (F1: II-1), a 0.6-year-old girl, came from a nonconsanguineous family-I. She presented with situs inversus totalis, neonatal respiratory distress, and sinusitis. The nasal nitric oxide level was markedly reduced. The respiratory cilia beat with reduced amplitude. TEM revealed shortened outer dynein arms (ODA) of cilia. chr5:13717907-13722661del spanning exons 71–72 was identified by NGS-based CNV analysis. Patient 2 (F2: IV-4), a 37-year-old man, and his eldest brother Patient 3 (F2: IV-2) came from a consanguineous family-II. Both had sinusitis, bronchiectasis and situs inversus totalis. The respiratory cilia of Patient 2 and Patient 3 were found to be uniformly immotile, with ODA defects. Two novel homozygous deletions chr5:13720087_13733030delinsGTTTTC and chr5:13649539_1 3707643del, spanning exons 69–71 and exons 77–79 were identified by NGS-based CNV analysis. Abnormalities in DNA copy number were confirmed by qPCR amplification. IF showed that the respiratory cilia of Patient 1 and Patient 2 were deficient in dynein axonemal heavy chain 5 (DNAH5) protein expression. This report identified three novel DNAH5 disease-associated variants by WES-based CNV analysis. Our study expands the genetic spectrum of PCD with DNAH5 in the Chinese population.

04

Investigating the Immunogenic Cell Death-Dependent Subtypes and Prognostic Signature of Triple-Negative Breast Cancer

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DOI：

https://doi.org/10.1007/s43657-023-00133-x

引用格式：

Shi, Y., Wu, Y., Li, F. et al. Investigating the Immunogenic Cell Death-Dependent Subtypes and Prognostic Signature of Triple-Negative Breast Cancer. Phenomics 4, 34–45 (2024). https://doi.org/10.1007/s43657-023-00133-x

在这项研究中，作者成功验证了TNBC中失调的ICD过程，并确定了两种ICD依赖亚型，这两种亚型在肿瘤免疫微环境（TIME）和癌症标志特征上展现出显著的特征。Cluster 1和Cluster 2分别对应于免疫的“冷”和“热”表型。此外，作者开发了ICD评分标签，该标签显示了预后功效，为癌症患者的治疗提供了新的见解。然而，作者仍需进一步的数据来全面评估其在预后中的价值。此外，需要更多的研究来预测TNBC患者治疗中的预期益处。这项研究为我们深入理解TNBC的异质性提供了重要线索，并为未来的治疗和预测模型的发展提供了有益的信息。然而，鉴于临床数据的多样性，研究者在进一步的实验和大规模病例研究中可能需要更广泛的数据验证和进一步探索。这将有助于确保ICD评分的准确性和可靠性，为患者提供更加精准的治疗方案。

Abstract

Recently, immunotherapy has emerged as a promising and effective method for treating triple-negative breast cancer (TNBC). However, challenges still persist. Immunogenic cell death (ICD) is considered a prospective treatment and potential combinational treatment strategy as it induces an anti-tumor immune response by presenting the antigenic epitopes of dead cells. Nevertheless, the ICD process in TNBC and its impact on disease progression and the response to immunotherapy are not well understood. In this study, we observed dysregulation of the ICD process and verified the altered expression of prognostic ICD genes in TNBC through quantitative real-time polymerase chain reaction (qRT-PCR) analysis. To investigate the potential role of the ICD process in TNBC progression, we determined the ICD-dependent subtypes, and two were identified. Analysis of their distinct tumor immune microenvironment (TIME) and cancer hallmark features revealed that Cluster 1 and 2 corresponded to the immune “cold” and “hot” phenotypes, respectively. In addition, we constructed the prognostic signature ICD score of TNBC patients and demonstrated its clinical independence and generalizability. The ICD score could also serve as a potential biomarker for immune checkpoint blockade and may aid in the identification of targeted effective agents for individualized clinical strategies.

05

Allergic Phenotypes and Sarcopenia: Evidence from Observational Studies and Mendelian Randomization Analysis

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DOI：

https://doi.org/10.1007/s43657-023-00110-4

引用格式：

Tang, Z., Zhou, G., Xiao, Y. et al. Allergic Phenotypes and Sarcopenia: Evidence from Observational Studies and Mendelian Randomization Analysis. Phenomics 4, 46–50 (2024). https://doi.org/10.1007/s43657-023-00110-4

尽管慢性炎症与肌少症、衰老的关联以及作用已经较为明确，但变态反应性疾病是否会对肌少症相关衰老以及二者是否存在因果关联尚无报道。这项课题通过综合多项队列数据以及多种设计，从流行病学角度深入探究了变态反应性疾病与肌少症的关系，首次提出患有AD、哮喘等变态反应性疾病可增加肌少症的发病风险，且存在因果关系。这些结果将提高过敏人群预防衰老相关疾病或老年综合征的意识。

Abstract

Commonly affected in early-life population, the impact of allergic phenotypes on mid- or late-life health is less discussed. This study is to explore the association of allergic phenotypes including atopic dermatitis (AD), asthma, eosinophils count (EC), and sarcopenia. We conducted observational studies and mendelian randomization (MR) analysis based on UK Biobank (UKB), the China Health and Retirement Longitudinal Study (CHARLS) and data from genome-wide association study (GWAS). Based on the UKB data, AD, asthma and EC were positively correlated with pre-sarcopenia and decreased skeletal muscle mass index and hand grip in fully adjusted model. Asthma and EC were significantly associated with sarcopenia while AD was marginally associated (p = 0.095). Based on the CHARLS cohort, asthma significantly added 109.4% risk for pre-sarcopenia in adjusted model (relative risk = 2.094; p = 0.002), respectively. Both asthma (β = 0.100, p = 0.006) and EC (β = 0.023, p = 0.017) exerted significantly casual effects on pre-sarcopenia. However, as for sarcopenia, merely EC exhibited a significantly casual effect (β = 0.005, p = 0.048). Significant casual effects of AD (β = – 0.027, p = 0.003), asthma (β = – 0.029, p = 0.027) and EC (β = – 0.041, p < 0.001) on decreased appendicular lean mass (ALM) were observed using the inverse-variance weighted method and the Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) method. Our results revealed a contributory role of AD, asthma and EC on sarcopenia, especially in terms of decreased ALM, an indicator for sarcopenia diagnosis. The findings of our study will raise the awareness of preventing aging-related disorders or geriatric syndromes among allergic populations.

06

Circulating Lipoproteins Mediate the Association Between Cardiovascular Risk Factors and Cognitive Decline: A Community-Based Cohort Study

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DOI：

https://doi.org/10.1007/s43657-023-00120-2

引用格式：

Li, J., Huang, Q., Wang, Y. et al. Circulating Lipoproteins Mediate the Association Between Cardiovascular Risk Factors and Cognitive Decline: A Community-Based Cohort Study. Phenomics 4, 51–55 (2024). https://doi.org/10.1007/s43657-023-00120-2

该研究基于泰州脑影像队列，利用代谢组学技术全面分析了循环代谢物水平在心血管健康评分与认知下降关联中的作用。围绕不同脂蛋白亚类和组分的详细讨论扩展了我们对传统临床血脂指标的理解。研究结果表明，对心血管危险因素的宣教和管理可能会带来心血管疾病之外的公共健康收益。研究同时还发现循环脂蛋白是心血管危险因素与老年人群认知功能下降的重要中介因素，这也提示了未来其作为痴呆早期筛查和防控的关键靶标的潜力。

Abstract

Cardiovascular health metrics are now widely recognized as modifiable risk factors for cognitive decline and dementia. Metabolic perturbations might play roles in the linkage of cardiovascular diseases and dementia. Circulating metabolites profiling by metabolomics may improve understanding of the potential mechanism by which cardiovascular risk factors contribute to cognitive decline. In a prospective community-based cohort in China (n = 725), 312 serum metabolic phenotypes were quantified, and cardiovascular health score was calculated including smoking, exercise, sleep, diet, body mass index, blood pressure, and blood glucose. Cognitive function assessments were conducted in baseline and follow-up visits to identify longitudinal cognitive decline. A better cardiovascular health was significantly associated with lower risk of concentration decline and orientation decline (hazard ratio (HR): 0.84–0.90; p < 0.05). Apolipoprotein-A1, high-density lipoprotein (HDL) cholesterol, cholesterol ester, and phospholipid concentrations were significantly associated with a lower risk of longitudinal memory and orientation decline (p < 0.05 and adjusted-p < 0.20). Mediation analysis suggested that the negative association between health status and the risk of orientation decline was partly mediated by cholesterol ester and total lipids in HDL-2 and -3 (proportion of mediation: 7.68–8.21%, both p < 0.05). Cardiovascular risk factors were associated with greater risks of cognitive decline, which were found to be mediated by circulating lipoproteins, particularly the medium-size HDL components. These findings underscore the potential of utilizing lipoproteins as targets for early stage dementia screening and intervention.

Multimodal Omics Approaches to Aging and Age-Related Diseases

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DOI：

https://doi.org/10.1007/s43657-023-00125-x

引用格式：

Ji, Q., Jiang, X., Wang, M. et al. Multimodal Omics Approaches to Aging and Age-Related Diseases. Phenomics 4, 56–71 (2024). https://doi.org/10.1007/s43657-023-00125-x

该研究综述了多模态组学方法的分类和进展，报道了其在衰老研究领域应用的文章数量迅速增长，并概述了基于组学技术的年龄相关疾病临床治疗的新进展。

Abstract

Aging is associated with a progressive decline in physiological capacities and an increased risk of aging-associated disorders. An increasing body of experimental evidence shows that aging is a complex biological process coordinately regulated by multiple factors at different molecular layers. Thus, it is difficult to delineate the overall systematic aging changes based on single-layer data. Instead, multimodal omics approaches, in which data are acquired and analyzed using complementary omics technologies, such as genomics, transcriptomics, and epigenomics, are needed for gaining insights into the precise molecular regulatory mechanisms that trigger aging. In recent years, multimodal omics sequencing technologies that can reveal complex regulatory networks and specific phenotypic changes have been developed and widely applied to decode aging and age-related diseases. This review summarizes the classification and progress of multimodal omics approaches, as well as the rapidly growing number of articles reporting on their application in the field of aging research, and outlines new developments in the clinical treatment of age-related diseases based on omics technologies.

08

The Protocol of Ultrasonic Backscatter Measurements of Musculoskeletal Properties

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DOI：

https://doi.org/10.1007/s43657-023-00122-0

引用格式：

Bi, D., Shi, L., Li, B. et al. The Protocol of Ultrasonic Backscatter Measurements of Musculoskeletal Properties. Phenomics 4, 72–80 (2024). https://doi.org/10.1007/s43657-023-00122-0

该研究介绍了基于新型超声反向散射骨诊断（UBBD）仪器的肌肉骨骼特性超声反向散射测量方案。UBBD仪器的标准化反向散射测量方案可能具有评估肌肉骨骼特征的潜力，有助于促进反向散射技术在肌肉骨骼疾病临床诊断中的应用。

Abstract

This study aims to introduce the protocol for ultrasonic backscatter measurements of musculoskeletal properties based on a novel ultrasonic backscatter bone diagnostic (UBBD) instrument. Dual-energy X-ray absorptiometry (DXA) can be adopted to measure bone mineral density (BMD) in the hip, spine, legs and the whole body. The muscle and fat mass in the legs and the whole body can be also calculated by DXA body composition analysis. Based on the proposed protocol for backscatter measurements by UBBD, ultrasonic backscatter signals can be measured in vivo, deriving three backscatter parameters [apparent integral backscatter (AIB), backscatter signal peak amplitude (BSPA) and the corresponding arrival time (BSPT)]. AIB may provide important diagnostic information about bone properties. BSPA and BSPT may be important indicators of muscle and fat properties. The standardized backscatter measurement protocol of the UBBD instrument may have the potential to evaluate musculoskeletal characteristics, providing help for promoting the application of the backscatter technique in the clinical diagnosis of musculoskeletal disorders (MSDs), such as osteoporosis and muscular atrophy.

09

Analysis of the Immune Response by Standardized Whole-Blood Stimulation with Metabolism Modulation

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DOI：

https://doi.org/10.1007/s43657-023-00114-0

引用格式：

Zhao, J., Han, X., Li, H. et al. Analysis of the Immune Response by Standardized Whole-Blood Stimulation with Metabolism Modulation. Phenomics 4, 81–89 (2024). https://doi.org/10.1007/s43657-023-00114-0

该研究为人体免疫功能评估提供了系统优化的全血刺激标准操作流程，并为探索免疫应答和代谢状态之间的关系提供了方案。旨在更好地研究人体免疫应答的特征，实现人体免疫表型的深度刻画。

Abstract

The immune system defends the body from infection and plays a vital role in a wide range of health conditions. Metabolism affects a series of physiological processes, including those linked to the function of human immune system. Cellular metabolism modulates immune cell activation and cytokine production. Understanding the relationship between metabolism and immune response has important implications for the development of immune-based therapeutics. However, the deployment of large-scale functional assays to investigate the metabolic regulation of immune response has been limited by the lack of standardized procedures. Here, we present a protocol for the analysis of immune response using standardized whole-blood stimulation with metabolism modulation. Diverse immune stimuli including pattern recognition receptor (PRR) ligands and microbial stimuli were incubated with fresh human whole blood. The metabolic inhibitors were used to modulate metabolic status in the immune cells. The variable immune responses after metabolic interventions were evaluated. We described in detail the main steps involved in the whole-blood stimulation and cytokines quantification, namely, collection and treatment of whole blood, preparation of samples and controls, cytokines detection, and stimulation with metabolic interventions. The metabolic inhibitors for anabolic pathways and catabolic pathways exert selective effects on the production of cytokines from immune cells. In addition to a robust and accurate assessment of immune response in cohort studies, the standardized whole-blood stimulation with metabolic regulation might provide new insights for modulating immunity.

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