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Polygenic risk score portability for common diseases across genetically diverse populations. 不同基因人群常见疾病的多基因风险评分可移植性。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-09-02 DOI: 10.1186/s40246-024-00664-y
Sonia Moreno-Grau, Manvi Vernekar, Arturo Lopez-Pineda, Daniel Mas-Montserrat, Míriam Barrabés, Consuelo D Quinto-Cortés, Babak Moatamed, Ming Ta Michael Lee, Zhenning Yu, Kensuke Numakura, Yuta Matsuda, Jeffrey D Wall, Alexander G Ioannidis, Nicholas Katsanis, Tomohiro Takano, Carlos D Bustamante

Background: Polygenic risk scores (PRS) derived from European individuals have reduced portability across global populations, limiting their clinical implementation at worldwide scale. Here, we investigate the performance of a wide range of PRS models across four ancestry groups (Africans, Europeans, East Asians, and South Asians) for 14 conditions of high-medical interest.

Methods: To select the best-performing model per trait, we first compared PRS performances for publicly available scores, and constructed new models using different methods (LDpred2, PRS-CSx and SNPnet). We used 285 K European individuals from the UK Biobank (UKBB) for training and 18 K, including diverse ancestries, for testing. We then evaluated PRS portability for the best models in Europeans and compared their accuracies with respect to the best PRS per ancestry. Finally, we validated the selected PRS models using an independent set of 8,417 individuals from Biobank of the Americas-Genomelink (BbofA-GL); and performed a PRS-Phewas.

Results: We confirmed a decay in PRS performances relative to Europeans when the evaluation was conducted using the best-PRS model for Europeans (51.3% for South Asians, 46.6% for East Asians and 39.4% for Africans). We observed an improvement in the PRS performances when specifically selecting ancestry specific PRS models (phenotype variance increase: 1.62 for Africans, 1.40 for South Asians and 0.96 for East Asians). Additionally, when we selected the optimal model conditional on ancestry for CAD, HDL-C and LDL-C, hypertension, hypothyroidism and T2D, PRS performance for studied populations was more comparable to what was observed in Europeans. Finally, we were able to independently validate tested models for Europeans, and conducted a PRS-Phewas, identifying cross-trait interplay between cardiometabolic conditions, and between immune-mediated components.

Conclusion: Our work comprehensively evaluated PRS accuracy across a wide range of phenotypes, reducing the uncertainty with respect to which PRS model to choose and in which ancestry group. This evaluation has let us identify specific conditions where implementing risk-prioritization strategies could have practical utility across diverse ancestral groups, contributing to democratizing the implementation of PRS.

背景:源自欧洲人的多基因风险评分(PRS)在全球人群中的可移植性较差,限制了其在全球范围内的临床应用。在此,我们研究了四个祖先群体(非洲人、欧洲人、东亚人和南亚人)的各种多基因风险评分模型在 14 种具有高度医学意义的疾病中的表现:为了选出每个性状中表现最好的模型,我们首先比较了公开分数的 PRS 表现,并使用不同的方法(LDpred2、PRS-CSx 和 SNPnet)构建了新模型。我们使用英国生物库 (UKBB) 中的 285 K 个欧洲人进行训练,并使用 18 K 个欧洲人(包括不同的祖先)进行测试。然后,我们评估了欧洲人最佳模型的 PRS 可移植性,并将其准确性与每个祖先的最佳 PRS 进行了比较。最后,我们使用来自美洲基因组链接生物库(BbofA-GL)的 8417 个独立个体验证了所选的 PRS 模型,并进行了 PRS-Phewas 分析:当使用欧洲人的最佳 PRS 模型进行评估时,我们证实相对于欧洲人的 PRS 性能有所下降(南亚人 51.3%,东亚人 46.6%,非洲人 39.4%)。我们观察到,在特别选择特定祖先的 PRS 模型时,PRS 的性能有所提高(表型方差增加:非洲人增加 1.62,南亚人增加 1.40,东亚人增加 0.96)。此外,当我们为 CAD、HDL-C 和 LDL-C、高血压、甲状腺机能减退和 T2D 选择了以血统为条件的最佳模型时,研究人群的 PRS 表现与在欧洲人中观察到的表现更为相似。最后,我们对欧洲人的测试模型进行了独立验证,并进行了 PRS-Phewas,确定了心血管代谢条件之间以及免疫介导成分之间的跨性状相互作用:我们的工作全面评估了各种表型的 PRS 准确性,减少了选择哪种 PRS 模型和哪个祖先群体的不确定性。这项评估让我们确定了在哪些特定条件下实施风险优先策略对不同的祖先群体具有实际效用,从而为 PRS 的民主化实施做出了贡献。
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引用次数: 0
Biological and clinical relevance of correlated expression levels of coding and long noncoding RNAs in HPV16 positive cervical cancers. HPV16 阳性宫颈癌中编码和长非编码 RNA 相关表达水平的生物学和临床意义。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-08-29 DOI: 10.1186/s40246-024-00660-2
Abhisikta Ghosh, Abarna Sinha, Arnab Ghosh, Somrita Roy, Sumana Mallick, Vinoth Kumar, Sonia Mathai, Jaydip Bhaumik, Asima Mukhopadhyay, Saugata Sen, Aditi Chandra, Arindam Maitra, Nidhan K Biswas, Partha P Majumder, Sharmila Sengupta

Human papillomavirus (HPV) drives cervical cancer (CaCx) pathogenesis and viral oncoproteins jeopardize global gene expression in such cancers. In this study, our aim was to identify differentially expressed coding (DEcGs) and long noncoding RNA genes (DElncGs) specifically sense intronic and Natural Antisense Transcripts as they are located in the genic regions and may have a direct influence on the expression pattern of their neighbouring coding genes. We compared HPV16-positive CaCx patients (N = 44) with HPV-negative normal individuals (N = 34) by employing strand-specific RNA-seq and determined the relationships between DEcGs and DElncGs and their clinical implications. By performing Gene set enrichment and protein-protein interaction (PPI) analyses of DEcGs, we identified enrichment of processes crucial for abortive virus life cycle and cancer progression. The DEcGs formed 16 gene clusters which we identified through Molecular Complex Detection (MCODE) plugin of Cytoscape. All the gene clusters portrayed cancer-related functions. We recorded significantly correlated expression levels of 79 DElncGs with DEcGs at proximal genomic loci based on Pearson's Correlation coefficients. Of these gene pairs, 24 pairs portrayed significantly altered correlation coefficients among patients, compared to normal individuals. Of these, 6 DEcGs of 6 such gene pairs, belonged to 5 of the identified gene clusters, one of which was survival-associated. Out of the 24 correlated DEcG: DElncG pairs, we identified 3 pairs, where expression of both members was significantly associated with patient overall survival. The findings justify the cooperative roles of these gene pairs, in patient prognostication, thereby bearing immense potential for translation. Thus, elucidation of correlative strengths between paired DElncGs and DEcGs in patient and normal samples, could serve as a foundation for identification of therapeutic and prognostic targets of HPV16-positive CaCx.

人类乳头瘤病毒(HPV)是宫颈癌(CaCx)的致病因素,而病毒癌蛋白会危及此类癌症的全局基因表达。在这项研究中,我们的目的是识别差异表达的编码基因(DEcGs)和长非编码 RNA 基因(DElncGs),这些基因特异性地感知内含子和天然反义转录本,因为它们位于基因区,可能直接影响邻近编码基因的表达模式。我们通过链特异性 RNA-seq,比较了 HPV16 阳性的 CaCx 患者(44 人)和 HPV 阴性的正常人(34 人),确定了 DEcGs 和 DElncGs 之间的关系及其临床意义。通过对DEcGs进行基因组富集和蛋白-蛋白相互作用(PPI)分析,我们发现了对中止病毒生命周期和癌症进展至关重要的富集过程。通过Cytoscape的分子复合体检测(MCODE)插件,我们发现DEcGs形成了16个基因簇。所有基因簇都具有癌症相关功能。根据皮尔逊相关系数,我们记录了79个DElncGs与DEcGs在近端基因组位点上的明显相关表达水平。在这些基因对中,与正常人相比,24对基因对在患者中的相关系数有明显变化。其中,6 个基因对中的 6 个 DEcGs 属于 5 个已确定的基因簇,其中一个与生存相关。在 24 个相关的 DEcG:DElncG 对中,我们发现有 3 对基因对的两个成员的表达都与患者的总生存期显著相关。这些发现证明了这些基因对在患者预后中的合作作用,因此具有巨大的转化潜力。因此,阐明患者和正常样本中成对 DElncGs 和 DEcGs 之间的相关性,可以为确定 HPV16 阳性 CaCx 的治疗和预后靶点奠定基础。
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引用次数: 0
Variant Impact Predictor database (VIPdb), version 2: trends from three decades of genetic variant impact predictors. 变异影响预测数据库(VIPdb),第 2 版:三十年来遗传变异影响预测的趋势。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-08-28 DOI: 10.1186/s40246-024-00663-z
Yu-Jen Lin, Arul S Menon, Zhiqiang Hu, Steven E Brenner

Background: Variant interpretation is essential for identifying patients' disease-causing genetic variants amongst the millions detected in their genomes. Hundreds of Variant Impact Predictors (VIPs), also known as Variant Effect Predictors (VEPs), have been developed for this purpose, with a variety of methodologies and goals. To facilitate the exploration of available VIP options, we have created the Variant Impact Predictor database (VIPdb).

Results: The Variant Impact Predictor database (VIPdb) version 2 presents a collection of VIPs developed over the past three decades, summarizing their characteristics, ClinGen calibrated scores, CAGI assessment results, publication details, access information, and citation patterns. We previously summarized 217 VIPs and their features in VIPdb in 2019. Building upon this foundation, we identified and categorized an additional 190 VIPs, resulting in a total of 407 VIPs in VIPdb version 2. The majority of the VIPs have the capacity to predict the impacts of single nucleotide variants and nonsynonymous variants. More VIPs tailored to predict the impacts of insertions and deletions have been developed since the 2010s. In contrast, relatively few VIPs are dedicated to the prediction of splicing, structural, synonymous, and regulatory variants. The increasing rate of citations to VIPs reflects the ongoing growth in their use, and the evolving trends in citations reveal development in the field and individual methods.

Conclusions: VIPdb version 2 summarizes 407 VIPs and their features, potentially facilitating VIP exploration for various variant interpretation applications. VIPdb is available at  https://genomeinterpretation.org/vipdb.

背景:变异解读对于从患者基因组中检测到的数百万个基因变异中识别出患者的致病基因变异至关重要。为此,人们开发了数百种变异影响预测器(VIP),也称为变异效应预测器(VEP),其方法和目标各不相同。为了便于探索可用的 VIP 选项,我们创建了变体影响预测因子数据库(VIPdb):变异影响预测因子数据库(VIPdb)第 2 版汇集了过去 30 年间开发的 VIP,总结了它们的特点、ClinGen 校准分数、CAGI 评估结果、出版详情、访问信息和引用模式。我们曾在 2019 年的 VIPdb 中总结了 217 项 VIP 及其特征。在此基础上,我们又识别并分类了 190 个要人,从而使 VIPdb 第 2 版中的要人总数达到 407 个。大多数 VIP 都能预测单核苷酸变异和非同义变异的影响。自 2010 年代以来,已开发出更多专门用于预测插入和缺失影响的 VIP。相比之下,专门预测剪接、结构、同义和调控变异的VIP相对较少。VIPs的引用率不断上升反映了其使用的持续增长,而引用率的变化趋势则揭示了该领域和个别方法的发展:VIPdb第2版总结了407个VIP及其特征,为各种变异解释应用中的VIP探索提供了潜在的便利。VIPdb可在https://genomeinterpretation.org/vipdb。
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引用次数: 0
Rapid discrimination between deleterious and benign missense mutations in the CAGI 6 experiment. 在 CAGI 6 实验中快速区分有害和良性错义突变。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-08-27 DOI: 10.1186/s40246-024-00655-z
Eshel Faraggi, Robert L Jernigan, Andrzej Kloczkowski

We describe the machine learning tool that we applied in the CAGI 6 experiment to predict whether single residue mutations in proteins are deleterious or benign. This tool was trained using only single sequences, i.e., without multiple sequence alignments or structural information. Instead, we used global characterizations of the protein sequence. Training and testing data for human gene mutations was obtained from ClinVar (ncbi.nlm.nih.gov/pub/ClinVar/), and for non-human gene mutations from Uniprot (www.uniprot.org). Testing was done on post-training data from ClinVar. This testing yielded high AUC and Matthews correlation coefficient (MCC) for well trained examples but low generalizability. For genes with either sparse or unbalanced training data, the prediction accuracy is poor. The resulting prediction server is available online at http://www.mamiris.com/Shoni.cagi6.

我们介绍了在 CAGI 6 实验中应用的机器学习工具,该工具用于预测蛋白质中的单残基突变是有害的还是良性的。该工具仅使用单序列进行训练,即不使用多序列比对或结构信息。相反,我们使用了蛋白质序列的全局特征。人类基因突变的训练和测试数据来自 ClinVar (ncbi.nlm.nih.gov/pub/ClinVar/),非人类基因突变的训练和测试数据来自 Uniprot (www.uniprot.org)。对来自 ClinVar 的训练后数据进行了测试。测试结果表明,训练有素的示例具有较高的 AUC 和马修斯相关系数 (MCC),但通用性较低。对于训练数据稀少或不平衡的基因,预测准确率较低。由此产生的预测服务器可在 http://www.mamiris.com/Shoni.cagi6 在线查阅。
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引用次数: 0
Shaping the future of kidney genetics in Australia: proceedings from the KidGen policy implementation workshop 2023. 塑造澳大利亚肾脏遗传学的未来:2023 年 KidGen 政策实施研讨会会议记录。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-08-17 DOI: 10.1186/s40246-024-00656-y
Amali Mallawaarachchi, Erik Biros, Trudie Harris, Bruce Bennetts, Tiffany Boughtwood, Justine Elliott, Lindsay Fowles, Robert Gardos, Denisse Garza, Ilias Goranitis, Matilda Haas, Vanessa Huntley, Julia Jefferis, Karin Kassahn, Anna Leaver, Ben Lundie, Sebastian Lunke, Caitlin O'Connor, Greg Pratt, Catherine Quinlan, Dianne Shearman, Jacqueline Soraru, Madhivanan Sundaram, Michel Tchan, Giulia Valente, Julie White, Ella Wilkins, Steve I Alexander, Noa Amir, Stephanie Best, Hossai Gul, Kushani Jayasinghe, Hugh McCarthy, Chirag Patel, Zornitza Stark, Andrew J Mallett

The KidGen Collaborative's Policy Implementation Workshop 2023 celebrated the 10th anniversary of Australia's first kidney genetics clinic in Brisbane. This event marked the establishment of a national network now comprising 19 kidney genetics clinics across Australia, all dedicated to providing equitable access to genomic testing for families affected by genetic kidney diseases. The workshop reflected on past progress and outlined future objectives for kidney genetics in Australia, recognising the collaborative efforts of clinical teams, researchers, and patients. Key insights from the workshop are documented in the proceedings.

KidGen 协作组织 2023 年政策实施研讨会庆祝了澳大利亚首家肾脏遗传诊所在布里斯班成立十周年。此次活动标志着一个全国性网络的建立,该网络目前由澳大利亚各地的 19 家肾脏遗传学诊所组成,所有诊所都致力于为受遗传性肾脏疾病影响的家庭提供公平的基因组检测机会。研讨会回顾了过去的进展,概述了澳大利亚肾脏遗传学的未来目标,肯定了临床团队、研究人员和患者的共同努力。研讨会的主要观点记录在会议记录中。
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引用次数: 0
Assessing the contribution of genes involved in monogenic bone disorders to the etiology of atypical femoral fractures. 评估涉及单基因骨病的基因对非典型股骨骨折病因的影响。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-08-15 DOI: 10.1186/s40246-024-00652-2
Natalia Garcia-Giralt, Diana Ovejero, Daniel Grinberg, Xavier Nogues, Santos Castañeda, Susanna Balcells, Raquel Rabionet

Background: Recent studies suggested that genetic variants associated with monogenic bone disorders were involved in the pathogenesis of atypical femoral fractures (AFF). Here, we aim to identify rare genetic variants by whole exome sequencing in genes involved in monogenic rare skeletal diseases in 12 women with AFF and 4 controls without any fracture.

Results: Out of 33 genetic variants identified in women with AFF, eleven (33.3%) were found in genes belonging to the Wnt pathway (LRP5, LRP6, DAAM2, WNT1, and WNT3A). One of them was rated as pathogenic (p.Pro582His in DAAM2), while all others were rated as variants of uncertain significance according to ClinVar and ACMG criteria.

Conclusions: Osteoporosis, rare bone diseases, and AFFs may share the same genes, thus making it even more difficult to identify unique risk factors.

背景:最近的研究表明,与单基因骨骼疾病相关的基因变异参与了非典型股骨骨折(AFF)的发病机制。在此,我们旨在通过全外显子组测序鉴定 12 名股骨非典型骨折女性患者和 4 名未发生任何骨折的对照者中涉及单基因罕见骨骼疾病的基因的罕见遗传变异:在 AFF 女性患者中发现的 33 个基因变异中,有 11 个(33.3%)是在 Wnt 通路(LRP5、LRP6、DAAM2、WNT1 和 WNT3A)的基因中发现的。根据 ClinVar 和 ACMG 标准,其中一个变异被评为致病变异(DAAM2 中的 p.Pro582His),其他所有变异均被评为意义不确定的变异:结论:骨质疏松症、罕见骨病和 AFF 可能具有相同的基因,因此更难确定独特的风险因素。
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引用次数: 0
Public perceptions of international genetic information sharing for biomedical research in China: a case study of the social media debate on the article "A Pangenome Reference of 36 Chinese Populations" published in Nature. 中国公众对生物医学研究中国际遗传信息共享的看法:关于《自然》杂志上发表的《36 个中国种群的庞基因组参考》一文的社交媒体辩论的案例研究。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-08-07 DOI: 10.1186/s40246-024-00650-4
Zhangyu Wang, Meng Wang, Li Du

Background: The international disclosure of Chinese human genetic data continues to be a contentious issue in China, generating public debates in both traditional and social media channels. Concerns have intensified after Chinese scientists' research on pangenome data was published in the prestigious journal Nature.

Methods: This study scrutinized microblogs posted on Weibo, a popular Chinese social media site, in the two months immediately following the publication (June 14, 2023-August 21, 2023). Content analysis was conducted to assess the nature of public responses, justifications for positive or negative attitudes, and the users' overall knowledge of how Chinese human genetic information is regulated and managed in China.

Results: Weibo users displayed contrasting attitudes towards the article's public disclose of pangenome research data, with 18% positive, 64% negative, and 18% neutral. Positive attitudes came primarily from verified government and media accounts, which praised the publication. In contrast, negative attitudes originated from individual users who were concerned about national security and health risks and often believed that the researchers have betrayed China. The benefits of data sharing highlighted in the commentaries included advancements in disease research and scientific progress. Approximately 16% of the microblogs indicated that Weibo users had misunderstood existing regulations and laws governing data sharing and stewardship.

Conclusions: Based on the predominantly negative public attitudes toward scientific data sharing established by our study, we recommend enhanced outreach by scientists and scientific institutions to increase the public understanding of developments in genetic research, international data sharing, and associated regulations. Additionally, governmental agencies can alleviate public fears and concerns by being more transparent about their security reviews of international collaborative research involving Chinese human genetic data and its cross-border transfer.

背景:在中国,中国人类基因数据的国际公开仍然是一个有争议的问题,在传统和社交媒体渠道上都引发了公众辩论。在中国科学家关于庞基因组数据的研究发表在著名期刊《自然》(Nature)上后,人们的担忧加剧了:本研究仔细研究了紧随论文发表后两个月内(2023 年 6 月 14 日至 2023 年 8 月 21 日)在中国流行的社交媒体网站微博上发布的微博。研究对微博内容进行了分析,以评估公众反应的性质、持积极或消极态度的理由,以及用户对中国如何规范和管理中国人类遗传信息的总体认识:结果:微博用户对文章公开披露庞基因组研究数据的态度截然不同,18%持肯定态度,64%持否定态度,18%持中立态度。积极态度主要来自经核实的政府和媒体账户,他们对该出版物表示赞赏。与此相反,负面态度主要来自个人用户,他们担心国家安全和健康风险,通常认为研究人员背叛了中国。评论中强调的数据共享的好处包括疾病研究的进步和科学进步。约 16% 的微博指出,微博用户误解了有关数据共享和管理的现行法规和法律:根据我们的研究,公众对科学数据共享的态度主要是负面的,因此我们建议科学家和科研机构加强宣传,提高公众对基因研究的发展、国际数据共享和相关法规的了解。此外,政府机构可以通过对涉及中国人类基因数据的国际合作研究及其跨境转移进行更透明的安全审查,减轻公众的恐惧和担忧。
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引用次数: 0
Genome-wide association study and meta-analysis of phytosterols identifies a novel locus for serum levels of campesterol. 植物甾醇的全基因组关联研究和荟萃分析确定了一个新的血清坎培酯醇水平基因座。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-08-01 DOI: 10.1186/s40246-024-00649-x
Jamil Alenbawi, Yasser A Al-Sarraj, Umm-Kulthum I Umlai, Ayat Kadhi, Nagham N Hendi, Georges Nemer, Omar M E Albagha

Sitosterolemia is a rare inherited disorder caused by mutations in the ABCG5/ABCG8 genes. These genes encode proteins involved in the transport of plant sterols. Mutations in these genes lead to decreased excretion of phytosterols, which can accumulate in the body and lead to a variety of health problems, including premature coronary artery disease. We conducted the first genome-wide association study (GWAS) in the Middle East/North Africa population to identify genetic determinants of plant sterol levels in Qatari people. GWAS was performed on serum levels of β-sitosterol and campesterol using the Metabolon platform from Qatar Biobank (QBB) and genome sequence data provided by Qatar Genome Program. A trans-ancestry meta-analysis of data from our Qatari cohort with summary statistics from a previously published large cohort (9758 subjects) of European ancestry was conducted. Using conditional analysis, we identified two independent single nucleotide polymorphisms associated with β-sitosterol (rs145164937 and rs4299376), and two others with campesterol (rs7598542 and rs75901165) in the Qatari population in addition to previously reported variants. All of them map to the ABCG5/8 locus except rs75901165 which is located within the Intraflagellar Transport 43 (IFT43) gene. The meta-analysis replicated most of the reported variants, and our study provided significant support for the association of variants in SCARB1 and ABO with sitosterolemia. Evaluation of a polygenic risk score devised from European GWAS data showed moderate performance when applied to QBB (adjusted-R2 = 0.082). These findings provide new insights into the genetic architecture of phytosterol metabolism while showing the importance including under-represented populations in future GWAS studies.

Sitosterolemia 是一种罕见的遗传性疾病,由 ABCG5/ABCG8 基因突变引起。这些基因编码参与植物固醇转运的蛋白质。这些基因的突变会导致植物固醇的排泄减少,而植物固醇会在体内积聚并导致各种健康问题,包括过早的冠状动脉疾病。我们首次在中东/北非人群中开展了全基因组关联研究(GWAS),以确定卡塔尔人体内植物固醇水平的遗传决定因素。我们利用卡塔尔生物库(Qatar Biobank,QBB)的 Metabolon 平台和卡塔尔基因组计划提供的基因组序列数据,对血清中的β-谷甾醇和坎培酯醇水平进行了 GWAS 研究。我们对来自卡塔尔队列的数据和之前发表的欧洲血统大型队列(9758 名受试者)的汇总统计数据进行了跨祖先荟萃分析。通过条件分析,我们在卡塔尔人群中发现了两个与β-谷甾醇相关的独立单核苷酸多态性(rs145164937 和 rs4299376),以及两个与坎培酯醇相关的独立单核苷酸多态性(rs7598542 和 rs75901165)。除 rs75901165 位于鞘内转运 43(IFT43)基因外,其他所有变异都映射到 ABCG5/8 位点。荟萃分析复制了大多数已报道的变异,我们的研究为 SCARB1 和 ABO 变异与 sitosterolemia 的关联提供了重要支持。根据欧洲 GWAS 数据设计的多基因风险评分在应用于 QBB 时表现一般(调整后 R2 = 0.082)。这些发现为植物甾醇代谢的遗传结构提供了新的见解,同时也表明了在未来的 GWAS 研究中纳入代表性不足的人群的重要性。
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引用次数: 0
Clinical outcomes of patients with mut-type methylmalonic acidemia identified through expanded newborn screening in China. 中国通过扩大新生儿筛查发现的突变型甲基丙二酸血症患者的临床疗效。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-07-29 DOI: 10.1186/s40246-024-00646-0
Shiying Ling, Shengnan Wu, Ruixue Shuai, Yue Yu, Wenjuan Qiu, Haiyan Wei, Chiju Yang, Peng Xu, Hui Zou, Jizhen Feng, Tingting Niu, Haili Hu, Huiwen Zhang, Lili Liang, Yu Wang, Ting Chen, Feng Xu, Xuefan Gu, Lianshu Han

Background: Isolated methylmalonic acidemia, an autosomal recessive disorder of propionate metabolism, is usually caused by mutations in the methylmalonyl-CoA mutase gene (mut-type). Because no universal consensus was made on whether mut-type methylmalonic acidemia should be included in newborn screening (NBS), we aimed to compare the outcome of this disorder detected by NBS with that detected clinically and investigate the influence of NBS on the disease course.

Design & methods: In this study, 168 patients with mut-type methylmalonic acidemia diagnosed by NBS were compared to 210 patients diagnosed after disease onset while NBS was not performed. Clinical data of these patients from 7 metabolic centers in China were analyzed retrospectively, including initial manifestations, biochemical metabolites, the responsiveness of vitamin B12 therapy, and gene variation, to explore different factors on the long-term outcome.

Results: By comparison of the clinically-diagnosed patients, NBS-detected patients showed younger age at diagnosis, less incidence of disease onset, better responsiveness of vitamin B12, younger age at start of treatment, lower levels of biochemical features before and after treatment, and better long-term prognosis (P < 0.01). Onset of disease, blood C3/C2 ratio and unresponsiveness of vitamin B12 were more positively associated with poor outcomes of patients whether identified by NBS. Moreover, the factors above as well as older age at start of treatment were positively associated with mortality.

Conclusions: This research highly demonstrated NBS could prevent major disease-related events and allow an earlier treatment initiation. As a key prognostic factor, NBS is beneficial for improving the overall survival of infants with mut-type methylmalonic acidemia.

背景:孤立型甲基丙二酸血症是一种常染色体隐性遗传的丙酸代谢紊乱,通常由甲基丙二酰-CoA突变酶基因(突变型)突变引起。由于对突变型甲基丙二酸血症是否应纳入新生儿筛查(NBS)尚未达成普遍共识,我们旨在比较NBS与临床发现的该疾病的结果,并研究NBS对病程的影响:在这项研究中,168 名通过 NBS 诊断的突变型甲基丙二酸血症患者与 210 名在发病后未进行 NBS 诊断的患者进行了比较。对这些患者来自中国 7 个代谢中心的临床数据进行回顾性分析,包括初始表现、生化代谢物、维生素 B12 治疗反应性和基因变异,以探讨影响长期预后的不同因素:结果:与临床诊断的患者相比,NBS检测出的患者诊断年龄更小、发病率更低、对维生素B12的反应性更好、开始治疗的年龄更小、治疗前后的生化特征水平更低、远期预后更好(P 结论:该研究高度证明了NBS可预防和治疗慢性乙型肝炎:这项研究高度证明了 NBS 可以预防重大疾病相关事件的发生,并能更早地开始治疗。作为一个关键的预后因素,NBS 有利于提高突变型甲基丙二酸血症婴儿的总体生存率。
{"title":"Clinical outcomes of patients with mut-type methylmalonic acidemia identified through expanded newborn screening in China.","authors":"Shiying Ling, Shengnan Wu, Ruixue Shuai, Yue Yu, Wenjuan Qiu, Haiyan Wei, Chiju Yang, Peng Xu, Hui Zou, Jizhen Feng, Tingting Niu, Haili Hu, Huiwen Zhang, Lili Liang, Yu Wang, Ting Chen, Feng Xu, Xuefan Gu, Lianshu Han","doi":"10.1186/s40246-024-00646-0","DOIUrl":"10.1186/s40246-024-00646-0","url":null,"abstract":"<p><strong>Background: </strong>Isolated methylmalonic acidemia, an autosomal recessive disorder of propionate metabolism, is usually caused by mutations in the methylmalonyl-CoA mutase gene (mut-type). Because no universal consensus was made on whether mut-type methylmalonic acidemia should be included in newborn screening (NBS), we aimed to compare the outcome of this disorder detected by NBS with that detected clinically and investigate the influence of NBS on the disease course.</p><p><strong>Design & methods: </strong>In this study, 168 patients with mut-type methylmalonic acidemia diagnosed by NBS were compared to 210 patients diagnosed after disease onset while NBS was not performed. Clinical data of these patients from 7 metabolic centers in China were analyzed retrospectively, including initial manifestations, biochemical metabolites, the responsiveness of vitamin B12 therapy, and gene variation, to explore different factors on the long-term outcome.</p><p><strong>Results: </strong>By comparison of the clinically-diagnosed patients, NBS-detected patients showed younger age at diagnosis, less incidence of disease onset, better responsiveness of vitamin B12, younger age at start of treatment, lower levels of biochemical features before and after treatment, and better long-term prognosis (P < 0.01). Onset of disease, blood C3/C2 ratio and unresponsiveness of vitamin B12 were more positively associated with poor outcomes of patients whether identified by NBS. Moreover, the factors above as well as older age at start of treatment were positively associated with mortality.</p><p><strong>Conclusions: </strong>This research highly demonstrated NBS could prevent major disease-related events and allow an earlier treatment initiation. As a key prognostic factor, NBS is beneficial for improving the overall survival of infants with mut-type methylmalonic acidemia.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"18 1","pages":"84"},"PeriodicalIF":3.8,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11288086/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141792352","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
A qualitative approach to assess the opinion of physicians about the challenges and prospects of pharmacogenomic testing implementation in clinical practice in Greece. 采用定性方法评估医生对希腊临床实践中实施药物基因组测试的挑战和前景的看法。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-07-19 DOI: 10.1186/s40246-024-00648-y
Margarita-Ioanna Koufaki, George P Patrinos, Konstantinos Z Vasileiou

Background: Pharmacogenomics (PGx) constitutes an important part of personalized medicine and has several clinical applications. PGx role in clinical practice is known, however, it has not been widely adopted yet. In this study, we aim to investigate the perspectives of Greek physicians regarding the implementation of PGx testing in clinical practice and the key issues associated with it.

Methods: Fourteen interviews were conducted with physicians of various specialties for which PGx applications are available. A semi-structured interview guide was utilized based on the Consolidated Framework for Implementation Research (CFIR) context and the Diffusion of Innovation model. Transcripts were coded independently and compared by two members of the research team. Descriptive statistics were generated using Microsoft Excel.

Results: Six main themes emerged: awareness and use of PGx testing; source of information; key stakeholders of the PGx supply chain, their interactions and change agents; clinical benefit and significance of PGx testing; barriers and lack of reimbursement; and recommendations to boost the PGx adoption rate. Most respondents were aware of PGx applications, but only three had already recommended PGx testing. Peer-reviewed journals along with clinical guidelines were regarded as the most used source of information while stakeholders of the PGx supply chain were discussed. PGx was considered that promote patient-centered care, enhance medication clinical effectiveness, decrease the risk of side effects, and reduce healthcare costs. Lack of reimbursement, scarcity of resources, and high PGx cost were the foremost barriers affecting PGx adoption.

Conclusions: It was concluded that if case PGx testing is reimbursed and physicians' training is reinforced, PGx implementation will be boosted and improved shortly.

背景:药物基因组学(PGx)是个性化医疗的重要组成部分,在临床上有多种应用。PGx 在临床实践中的作用众所周知,但尚未被广泛采用。在本研究中,我们旨在调查希腊医生对在临床实践中实施 PGx 检测的看法以及与之相关的关键问题:方法:我们对可应用 PGx 的各专科医师进行了 14 次访谈。根据实施研究综合框架 (CFIR) 和创新扩散模型,采用了半结构化访谈指南。研究小组的两名成员对访谈记录进行了独立编码和比较。使用 Microsoft Excel 生成描述性统计:出现了六大主题:对 PGx 检验的认识和使用;信息来源;PGx 供应链的主要利益相关者、他们之间的互动和变革推动者;PGx 检验的临床益处和意义;障碍和缺乏报销;以及提高 PGx 采用率的建议。大多数受访者都知道 PGx 的应用,但只有三个受访者已经推荐了 PGx 检测。同行评议期刊和临床指南被认为是最常用的信息来源,而 PGx 供应链的利益相关者也参与了讨论。PGx 被认为能促进以患者为中心的护理、提高药物临床疗效、降低副作用风险并降低医疗成本。缺乏补偿、资源稀缺和 PGx 成本高昂是影响 PGx 应用的主要障碍:结论:如果病例 PGx 检测能获得报销并加强对医生的培训,PGx 的实施将很快得到推动和改善。
{"title":"A qualitative approach to assess the opinion of physicians about the challenges and prospects of pharmacogenomic testing implementation in clinical practice in Greece.","authors":"Margarita-Ioanna Koufaki, George P Patrinos, Konstantinos Z Vasileiou","doi":"10.1186/s40246-024-00648-y","DOIUrl":"10.1186/s40246-024-00648-y","url":null,"abstract":"<p><strong>Background: </strong>Pharmacogenomics (PGx) constitutes an important part of personalized medicine and has several clinical applications. PGx role in clinical practice is known, however, it has not been widely adopted yet. In this study, we aim to investigate the perspectives of Greek physicians regarding the implementation of PGx testing in clinical practice and the key issues associated with it.</p><p><strong>Methods: </strong>Fourteen interviews were conducted with physicians of various specialties for which PGx applications are available. A semi-structured interview guide was utilized based on the Consolidated Framework for Implementation Research (CFIR) context and the Diffusion of Innovation model. Transcripts were coded independently and compared by two members of the research team. Descriptive statistics were generated using Microsoft Excel.</p><p><strong>Results: </strong>Six main themes emerged: awareness and use of PGx testing; source of information; key stakeholders of the PGx supply chain, their interactions and change agents; clinical benefit and significance of PGx testing; barriers and lack of reimbursement; and recommendations to boost the PGx adoption rate. Most respondents were aware of PGx applications, but only three had already recommended PGx testing. Peer-reviewed journals along with clinical guidelines were regarded as the most used source of information while stakeholders of the PGx supply chain were discussed. PGx was considered that promote patient-centered care, enhance medication clinical effectiveness, decrease the risk of side effects, and reduce healthcare costs. Lack of reimbursement, scarcity of resources, and high PGx cost were the foremost barriers affecting PGx adoption.</p><p><strong>Conclusions: </strong>It was concluded that if case PGx testing is reimbursed and physicians' training is reinforced, PGx implementation will be boosted and improved shortly.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"18 1","pages":"82"},"PeriodicalIF":3.8,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11264745/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141727112","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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