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Increased frequency of repeat expansion mutations across different populations. 重复扩增的人群频率表明不同人群的疾病流行率估计值增加。
Pub Date : 2024-07-08 DOI: 10.1101/2023.07.03.23292162
Kristina Ibañez, Bharati Jadhav, Matteo Zanovello, Delia Gagliardi, Christopher Clarkson, Stefano Facchini, Paras Garg, Alejandro Martin-Trujillo, Scott J Gies, Valentina Galassi Deforie, Anupriya Dalmia, Davina J Hensman Moss, Jana Vandrovcova, Clarissa Rocca, Loukas Moutsianas, Chiara Marini-Bettolo, Helen Walker, Chris Turner, Maryam Shoai, Jeffrey D Long, Pietro Fratta, Douglas R Langbehn, Sarah J Tabrizi, Mark J Caulfield, Andrea Cortese, Valentina Escott-Price, John Hardy, Henry Houlden, Andrew J Sharp, Arianna Tucci

Repeat expansion disorders (REDs) are a devastating group of predominantly neurological diseases. Together they are common, affecting 1 in 3,000 people worldwide with population-specific differences. However, prevalence estimates of REDs are hampered by heterogeneous clinical presentation, variable geographic distributions, and technological limitations leading to under-ascertainment. Here, leveraging whole genome sequencing data from 82,176 individuals from different populations, we found an overall disease allele frequency of REDs of 1 in 283 individuals. Modelling disease prevalence using genetic data, age at onset and survival, we show that the expected number of people with REDs would be two to three times higher than currently reported figures, indicating under-diagnosis and/or incomplete penetrance. While some REDs are population-specific, e.g. Huntington disease-like 2 in Africans, most REDs are represented in all broad genetic ancestries (i.e. Europeans, Africans, Americans, East Asians, and South Asians), challenging the notion that some REDs are found only in specific populations. These results have worldwide implications for local and global health communities in the diagnosis and counselling of REDs.

重复扩张障碍(REDs)是一组破坏性疾病,主要是神经系统疾病。它们加在一起很常见,影响到全世界每3000人中就有1人存在特定的人口差异。然而,REDs的患病率估计受到异质性临床表现、可变地理分布和技术限制的阻碍,导致确定不足。在这里,利用来自不同人群的82176个个体的全基因组测序数据,我们发现RED的总体携带者频率为1/340。利用基因数据、发病年龄和生存率对疾病流行率进行建模,我们发现RED的流行率是目前报道数字的3倍。虽然一些RED是特定于人群的,例如亨廷顿舞蹈症2型,但大多数RED在所有广泛的遗传祖先中都有代表性,包括非洲人和亚洲人,这挑战了一些RED只在欧洲人群中发现的观念。这些结果对地方和全球卫生界在地方和全球层面诊断和管理RED具有全球意义。
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引用次数: 0
GRPa-PRS: A risk stratification method to identify genetically-regulated pathways in polygenic diseases. 基因调控途径多基因风险评分(GRPa-PRS):一种识别多基因疾病中基因调控途径的风险分层方法。
Pub Date : 2024-07-05 DOI: 10.1101/2023.06.19.23291621
Xiaoyang Li, Brisa S Fernandes, Andi Liu, Jingchun Chen, Xiangning Chen, Zhongming Zhao, Yulin Dai

Background: Polygenic risk scores (PRS) are tools used to evaluate an individual's susceptibility to polygenic diseases based on their genetic profile. A considerable proportion of people carry a high genetic risk but evade the disease. On the other hand, some individuals with a low risk of eventually developing the disease. We hypothesized that unknown counterfactors might be involved in reversing the PRS prediction, which might provide new insights into the pathogenesis, prevention, and early intervention of diseases.

Methods: We built a novel computational framework to identify genetically-regulated pathways (GRPas) using PRS-based stratification for each cohort. We curated two AD cohorts with genotyping data; the discovery (disc) and the replication (rep) datasets include 2722 and 2854 individuals, respectively. First, we calculated the optimized PRS model based on the three recent AD GWAS summary statistics for each cohort. Then, we stratified the individuals by their PRS and clinical diagnosis into six biologically meaningful PRS strata, such as AD cases with low/high risk and cognitively normal (CN) with low/high risk. Lastly, we imputed individual genetically-regulated expression (GReX) and identified differential GReX and GRPas between risk strata using gene-set enrichment and variational analyses in two models, with and without APOE effects. An orthogonality test was further conducted to verify those GRPas are independent of PRS risk. To verify the generalizability of other polygenic diseases, we further applied a default model of GRPa-PRS for schizophrenia (SCZ).

Results: For each stratum, we conducted the same procedures in both the disc and rep datasets for comparison. In AD, we identified several well-known AD-related pathways, including amyloid-beta clearance, tau protein binding, and astrocyte response to oxidative stress. Additionally, we discovered resilience-related GRPs that are orthogonal to AD PRS, such as the calcium signaling pathway and divalent inorganic cation homeostasis. In SCZ, pathways related to mitochondrial function and muscle development were highlighted. Finally, our GRPa-PRS method identified more consistent differential pathways compared to another variant-based pathway PRS method.

Conclusions: We developed a framework, GRPa-PRS, to systematically explore the differential GReX and GRPas among individuals stratified by their estimated PRS. The GReX-level comparison among those strata unveiled new insights into the pathways associated with disease risk and resilience. Our framework is extendable to other polygenic complex diseases.

背景:阿尔茨海默病(AD)是老年人群中常见的神经退行性疾病,遗传因素在其中起着重要作用。相当一部分老年人具有高遗传性AD风险,但逃避AD。另一方面,一些AD风险较低的人最终发展为AD。我们假设未知的反作用因素可能参与逆转多基因风险评分(PRS)预测,这可能为AD的发病机制、预防和早期临床干预提供见解。方法:我们为每个队列建立了一个新的计算框架,使用基于PRS的分层来识别基因调控途径(GRPa)。我们用基因分型数据策划了两个AD队列;发现数据集和复制数据集分别包括2722个和2492个个体。首先,我们根据每个队列的三个最新AD GWAS汇总统计数据计算了优化的PRS模型。然后,我们根据PRS和临床诊断将个体分为认知正常(CN)和高PRS AD组(弹性组)、低PRS AD病例组(易感组)以及具有相似PRS背景的AD/CNs参与者。最后,我们估算了个体基因调控表达(GReX),并在有和没有APOE影响的两个模型中,通过基因集富集分析和基因集变分分析确定了亚组之间的差异GRPas。结果:对于每个亚组,我们在三个PRS模型的发现和复制数据集中进行了相同的程序,以进行比较。在具有APOE区域的模型1中,我们确定了众所周知的AD相关途径,包括淀粉样蛋白β清除、tau蛋白结合和星形胶质细胞对氧化应激的反应。在没有APOE区域的模型2中,突触功能、小胶质细胞功能、组氨酸代谢和硫酯酶活性显著,表明它们是独立于APOE影响的途径。最后,与另一种基于变体的路径PRS方法相比,我们的GRPa PRS方法降低了检测差异路径的错误发现率。结论:我们开发了一个名为GRPa-PRS的框架,以系统地探索根据估计的PRS分层的个体之间的差异GRPas。这些组之间的GReX水平比较揭示了对AD风险和恢复力相关途径的新见解。我们的框架可以扩展到其他多基因复杂疾病。
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引用次数: 0
The effect of combining antibiotics on resistance: A systematic review and meta-analysis. 抗生素联合用药对耐药性的影响:系统综述和荟萃分析。
Pub Date : 2024-06-28 DOI: 10.1101/2023.07.10.23292374
Berit Siedentop, Viacheslav N Kachalov, Christopher Witzany, Matthias Egger, Roger D Kouyos, Sebastian Bonhoeffer

When and under which conditions antibiotic combination therapy decelerates rather than accelerates resistance evolution is not well understood. We examined the effect of combining antibiotics on within-patient resistance development across various bacterial pathogens and antibiotics. We searched CENTRAL, EMBASE and PubMed for (quasi)-randomised controlled trials (RCTs) published from database inception to November 24th, 2022. Trials comparing antibiotic treatments with different numbers of antibiotics were included. A patient was considered to have acquired resistance if, at the follow-up culture, a resistant bacterium (as defined by the study authors) was detected that had not been present in the baseline culture. We combined results using a random effects model and performed meta-regression and stratified analyses. The trials' risk of bias was assessed with the Cochrane tool. 42 trials were eligible and 29, including 5054 patients, were qualified for statistical analysis. In most trials, resistance development was not the primary outcome and studies lacked power. The combined odds ratio (OR) for the acquisition of resistance comparing the group with the higher number of antibiotics with the comparison group was 1.23 (95% CI 0.68-2.25), with substantial between-study heterogeneity (I 2 =77%). We identified tentative evidence for potential beneficial or detrimental effects of antibiotic combination therapy for specific pathogens or medical conditions. The evidence for combining a higher number of antibiotics compared to fewer from RCTs is scarce and overall, is compatible with both benefit or harm. Trials powered to detect differences in resistance development or well-designed observational studies are required to clarify the impact of combination therapy on resistance.

抗生素联合治疗何时以及在何种条件下减缓而不是加速耐药性演变尚不清楚。我们研究了联合使用抗生素对患者体内各种细菌病原体和抗生素耐药性发展的影响。我们在CENTRAL、EMBASE和PubMed中搜索了从数据库创建到2022年11月24日发表的(准)随机对照试验(RCT)。将抗生素治疗与不同数量的抗生素进行比较的试验也包括在内。如果在后续培养中检测到基线培养中不存在的耐药细菌,则认为患者具有获得性耐药性。我们使用随机效应模型对结果进行了组合,并进行了元回归和分层分析。使用Cochrane工具评估试验的偏倚风险。42项试验符合条件,29项试验(包括5054名患者)符合统计分析条件。在大多数试验中,耐药性的发展不是主要结果,研究缺乏力量。与对照组相比,抗生素数量较高的组获得耐药性的综合优势比(OR)为1.23(95%CI 0.68-2.25),研究之间存在显著的异质性(I2=77%)。我们确定了抗生素联合治疗对特定病原体或医疗条件潜在有益或有害影响的初步证据。与随机对照试验中较少的抗生素相比,联合使用更高数量的抗生素的证据很少,总体而言,这与益处或危害都是一致的。需要进行旨在检测耐药性发展差异的试验或精心设计的观察性研究,以阐明联合治疗对耐药性的影响。
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引用次数: 0
Rare damaging CCR2 variants are associated with lower lifetime cardiovascular risk. 携带罕见破坏性CCR2基因变异的人患动脉粥样硬化疾病的风险较低。
Pub Date : 2024-06-26 DOI: 10.1101/2023.08.14.23294063
Marios K Georgakis, Rainer Malik, Omar El Bounkari, Natalie R Hasbani, Jiang Li, Jennifer E Huffman, Gabrielle Shakt, Reinier W P Tack, Tamara N Kimball, Yaw Asare, Alanna C Morrison, Noah L Tsao, Renae Judy, Braxton D Mitchell, Huichun Xu, May E Montasser, Ron Do, Eimear E Kenny, Ruth J F Loos, James G Terry, John Jeffrey Carr, Joshua C Bis, Bruce M Psaty, W T Longstreth, Kendra A Young, Sharon M Lutz, Michael H Cho, Jai Broome, Alyna T Khan, Fei Fei Wang, Nancy Heard-Costa, Sudha Seshadri, Ramachandran S Vasan, Nicholette D Palmer, Barry I Freedman, Donald W Bowden, Lisa R Yanek, Brian G Kral, Lewis C Becker, Patricia A Peyser, Lawrence F Bielak, Farah Ammous, April P Carson, Michael E Hall, Laura M Raffield, Stephen S Rich, Wendy S Post, Russel P Tracy, Kent D Taylor, Xiuqing Guo, Michael C Mahaney, Joanne E Curran, John Blangero, Shoa L Clarke, Jeffrey W Haessler, Yao Hu, Themistocles L Assimes, Charles Kooperberg, Jürgen Bernhagen, Christopher D Anderson, Scott M Damrauer, Ramin Zand, Jerome I Rotter, Paul S de Vries, Martin Dichgans

Background: Previous work has shown a role of CCL2, a key chemokine governing monocyte trafficking, in atherosclerosis. However, it remains unknown whether targeting CCR2, the cognate receptor of CCL2, provides protection against human atherosclerotic cardiovascular disease.

Methods: Computationally predicted damaging or loss-of-function (REVEL>0.5) variants within CCR2 were detected in whole-exome-sequencing data from 454,775 UK Biobank participants and tested for association with cardiovascular endpoints in gene-burden tests. Given the key role of CCR2 in monocyte mobilization, variants associated with lower monocyte count were prioritized for experimental validation. The response to CCL2 of human cells transfected with these variants was tested in migration and cAMP assays. Validated damaging variants were tested for association with cardiovascular endpoints, atherosclerosis burden, and vascular risk factors. Significant associations were replicated in six independent datasets (n=1,062,595).

Results: Carriers of 45 predicted damaging or loss-of-function CCR2 variants (n=787 individuals) were at lower risk of myocardial infarction and coronary artery disease. One of these variants (M249K, n=585, 0.15% of European ancestry individuals) was associated with lower monocyte count and with both decreased downstream signaling and chemoattraction in response to CCL2. While M249K showed no association with conventional vascular risk factors, it was consistently associated with a lower risk of myocardial infarction (Odds Ratio [OR]: 0.66 95% Confidence Interval [CI]: 0.54-0.81, p=6.1×10-5) and coronary artery disease (OR: 0.74 95%CI: 0.63-0.87, p=2.9×10-4) in the UK Biobank and in six replication cohorts. In a phenome-wide association study, there was no evidence of a higher risk of infections among M249K carriers.

Conclusions: Carriers of an experimentally confirmed damaging CCR2 variant are at a lower lifetime risk of myocardial infarction and coronary artery disease without carrying a higher risk of infections. Our findings provide genetic support for the translational potential of CCR2-targeting as an atheroprotective approach.

背景:CCL2/CCR2轴支配单核细胞向动脉粥样硬化病变的运输和募集。人类基因分析和基于人群的研究支持循环CCL2水平与动脉粥样硬化之间的联系。尽管如此,对CCL2(主要的CCL2受体)的药理学靶向是否能提供对人类动脉粥样硬化疾病的保护仍然未知。方法:在来自454775名英国生物银行参与者(40-69岁)的全外显子组测序数据中,我们确定了CCR2基因中的预测功能丧失(LoF)或损伤性错义(REVEL评分>0.5)变体。我们优先考虑与低单核细胞计数相关的变异(p结果:在CCR2基因中共鉴定出45种预测的LoF或破坏性错义变体,其中4种也与较低的单核细胞计数显著相关,但与其他白细胞计数无关。这些变体的杂合携带者出现综合动脉粥样硬化结果的风险较低,在四个血管床上显示出较低的动脉粥样硬化负担冠状动脉疾病和心肌梗死的终生风险较低。没有证据表明与低密度脂蛋白胆固醇、血压、血糖状况或C反应蛋白等血管风险因素有关。使用cAMP测定,我们发现用最常见的CCR2损伤变体(3:46358273:T:a,M249K,547个载体,频率:0.14%)转染的细胞显示出对CCL2的信号传导减少。M249K变异株与心肌梗死的相关性在各队列中是一致的(ORUKB:0.62 95%CI:0.39-0.96;ORexternal:0.64 95%CI:0.34-1.19;ORpooled:0.64 95%CI:0.450.90)。在一项现象广泛的相关性研究中,我们没有发现破坏性CCR2变异株携带者常见感染或死亡风险更高的证据。结论:破坏性CCR2变异体的杂合携带者动脉粥样硬化负担较低,心肌梗死的终生风险较低。结合先前实验和流行病学研究的证据,我们的发现强调了CCR2靶向作为动脉粥样硬化保护方法的转化潜力。
{"title":"Rare damaging <i>CCR2</i> variants are associated with lower lifetime cardiovascular risk.","authors":"Marios K Georgakis, Rainer Malik, Omar El Bounkari, Natalie R Hasbani, Jiang Li, Jennifer E Huffman, Gabrielle Shakt, Reinier W P Tack, Tamara N Kimball, Yaw Asare, Alanna C Morrison, Noah L Tsao, Renae Judy, Braxton D Mitchell, Huichun Xu, May E Montasser, Ron Do, Eimear E Kenny, Ruth J F Loos, James G Terry, John Jeffrey Carr, Joshua C Bis, Bruce M Psaty, W T Longstreth, Kendra A Young, Sharon M Lutz, Michael H Cho, Jai Broome, Alyna T Khan, Fei Fei Wang, Nancy Heard-Costa, Sudha Seshadri, Ramachandran S Vasan, Nicholette D Palmer, Barry I Freedman, Donald W Bowden, Lisa R Yanek, Brian G Kral, Lewis C Becker, Patricia A Peyser, Lawrence F Bielak, Farah Ammous, April P Carson, Michael E Hall, Laura M Raffield, Stephen S Rich, Wendy S Post, Russel P Tracy, Kent D Taylor, Xiuqing Guo, Michael C Mahaney, Joanne E Curran, John Blangero, Shoa L Clarke, Jeffrey W Haessler, Yao Hu, Themistocles L Assimes, Charles Kooperberg, Jürgen Bernhagen, Christopher D Anderson, Scott M Damrauer, Ramin Zand, Jerome I Rotter, Paul S de Vries, Martin Dichgans","doi":"10.1101/2023.08.14.23294063","DOIUrl":"10.1101/2023.08.14.23294063","url":null,"abstract":"<p><strong>Background: </strong>Previous work has shown a role of CCL2, a key chemokine governing monocyte trafficking, in atherosclerosis. However, it remains unknown whether targeting CCR2, the cognate receptor of CCL2, provides protection against human atherosclerotic cardiovascular disease.</p><p><strong>Methods: </strong>Computationally predicted damaging or loss-of-function (REVEL>0.5) variants within <i>CCR2</i> were detected in whole-exome-sequencing data from 454,775 UK Biobank participants and tested for association with cardiovascular endpoints in gene-burden tests. Given the key role of CCR2 in monocyte mobilization, variants associated with lower monocyte count were prioritized for experimental validation. The response to CCL2 of human cells transfected with these variants was tested in migration and cAMP assays. Validated damaging variants were tested for association with cardiovascular endpoints, atherosclerosis burden, and vascular risk factors. Significant associations were replicated in six independent datasets (n=1,062,595).</p><p><strong>Results: </strong>Carriers of 45 predicted damaging or loss-of-function <i>CCR2</i> variants (n=787 individuals) were at lower risk of myocardial infarction and coronary artery disease. One of these variants (M249K, n=585, 0.15% of European ancestry individuals) was associated with lower monocyte count and with both decreased downstream signaling and chemoattraction in response to CCL2. While M249K showed no association with conventional vascular risk factors, it was consistently associated with a lower risk of myocardial infarction (Odds Ratio [OR]: 0.66 95% Confidence Interval [CI]: 0.54-0.81, p=6.1×10<sup>-5</sup>) and coronary artery disease (OR: 0.74 95%CI: 0.63-0.87, p=2.9×10<sup>-4</sup>) in the UK Biobank and in six replication cohorts. In a phenome-wide association study, there was no evidence of a higher risk of infections among M249K carriers.</p><p><strong>Conclusions: </strong>Carriers of an experimentally confirmed damaging <i>CCR2</i> variant are at a lower lifetime risk of myocardial infarction and coronary artery disease without carrying a higher risk of infections. Our findings provide genetic support for the translational potential of CCR2-targeting as an atheroprotective approach.</p>","PeriodicalId":18659,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10462211/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10260864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Long-term exposure to wildland fire smoke PM2.5 and mortality in the contiguous United States. 美国周边地区的野火烟雾PM2.5和死亡率。
Pub Date : 2024-06-11 DOI: 10.1101/2023.01.31.23285059
Yiqun Ma, Emma Zang, Yang Liu, Jing Wei, Yuan Lu, Harlan M Krumholz, Michelle L Bell, Kai Chen

Despite the substantial evidence on the health effects of short-term exposure to ambient fine particles (PM2.5), including increasing studies focusing on those from wildland fire smoke, the impacts of long-term wildland fire smoke PM2.5 exposure remain unclear. We investigated the association between long-term exposure to wildland fire smoke PM2.5 and non-accidental mortality and mortality from a wide range of specific causes in all 3,108 counties in the contiguous U.S., 2007-2020. Controlling for non-smoke PM2.5, air temperature, and unmeasured spatial and temporal confounders, we found a non-linear association between 12-month moving average concentration of smoke PM2.5 and monthly non-accidental mortality rate. Relative to a month with the long-term smoke PM2.5 exposure below 0.1 μg/m3, non-accidental mortality increased by 0.16-0.63 and 2.11 deaths per 100,000 people per month when the 12-month moving average of PM2.5 concentration was of 0.1-5 and 5+ μg/m3, respectively. Cardiovascular, ischemic heart disease, digestive, endocrine, diabetes, mental, and chronic kidney disease mortality were all found to be associated with long-term wildland fire smoke PM2.5 exposure. Smoke PM2.5 contributed to approximately 11,415 non-accidental deaths/year (95% CI: 6,754, 16,075) in the contiguous U.S. Higher smoke PM2.5-related increases in mortality rates were found for people aged 65 above. Positive interaction effects with extreme heat (monthly number of days with daily mean air temperature higher than the county's 90th percentile warm season air temperature) were also observed. Our study identified the detrimental effects of long-term exposure to wildland fire smoke PM2.5 on a wide range of mortality outcomes, underscoring the need for public health actions and communications that span the health risks of both short- and long-term exposure.

尽管越来越多的证据表明美国西部野火烟雾对健康的影响,但全国范围内野火烟雾细颗粒物(PM2.5)造成的死亡风险和负担仍不清楚。本研究旨在调查野火烟雾PM2.5与各种原因导致的死亡率、心血管疾病、呼吸系统疾病和精神障碍之间的关系,并计算2006-2016年美国所有3108个县的相应可归因死亡率负担。国家卫生统计中心每月收集县级死亡率统计数据。野火烟雾PM2.5浓度来源于分辨率为10×10km2的时空模型。在控制非烟雾PM2.5、空气温度以及未测量的空间和时间混杂因素的情况下,我们发现烟雾PM2.5增加1微克/立方米与全因死亡率增加0.14%(95%置信区间[CI]:0.11%,0.17%)、心血管死亡率增加0.13%(95%CI:0.08%,0.18%)、呼吸系统死亡率增加0.16%(95%CI:0.07%,0.25%)显著相关,精神障碍死亡率为1.08%(95%CI:0.93%、1.23%)。在毗邻的美国,烟雾PM2.5每年导致约1141人全因死亡(95%置信区间:8931388),其中超过四分之三的人死于心血管、呼吸和精神原因。我们发现,男性比女性更容易受到伤害,0至64岁的人比≥65岁的人更容易受到感染,少数种族/族裔比非西班牙裔白人更容易受到攻击。研究发现,轻度干旱会增强烟雾PM2.5与死亡率之间的联系。我们的研究结果表明,野火烟雾PM2.5危害身心健康,这表明美国需要更有效的野火缓解策略和公共卫生对策。
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引用次数: 0
The Genetic Architecture of Biological Age in Nine Human Organ Systems. 九个人体器官系统中生物年龄的遗传结构。
Pub Date : 2024-06-11 DOI: 10.1101/2023.06.08.23291168
Junhao Wen, Ye Ella Tian, Ioanna Skampardoni, Zhijian Yang, Yuhan Cui, Filippos Anagnostakis, Elizabeth Mamourian, Bingxin Zhao, Arthur W Toga, Andrew Zaleskey, Christos Davatzikos

Understanding the genetic basis of biological aging in multi-organ systems is vital for elucidating age-related disease mechanisms and identifying therapeutic interventions. This study characterized the genetic architecture of the biological age gap (BAG) across nine human organ systems in 377,028 individuals of European ancestry from the UK Biobank. We discovered 393 genomic loci-BAG pairs (P-value<5×10-8) linked to the brain, eye, cardiovascular, hepatic, immune, metabolic, musculoskeletal, pulmonary, and renal systems. We observed BAG-organ specificity and inter-organ connections. Genetic variants associated with the nine BAGs are predominantly specific to the respective organ system while exerting pleiotropic effects on traits linked to multiple organ systems. A gene-drug-disease network confirmed the involvement of the metabolic BAG-associated genes in drugs targeting various metabolic disorders. Genetic correlation analyses supported Cheverud's Conjecture1 - the genetic correlation between BAGs mirrors their phenotypic correlation. A causal network revealed potential causal effects linking chronic diseases (e.g., Alzheimer's disease), body weight, and sleep duration to the BAG of multiple organ systems. Our findings shed light on promising therapeutic interventions to enhance human organ health within a complex multi-organ network, including lifestyle modifications and potential drug repositioning strategies for treating chronic diseases. All results are publicly available at https://labs-laboratory.com/medicine.

了解多器官系统中生物衰老的遗传基础对于阐明与年龄相关的疾病机制和确定治疗干预措施至关重要。这项研究描述了英国生物库377028名欧洲血统个体的九个人体器官系统的生物年龄差距(BAG)的遗传结构。我们发现了393个基因组基因座,包括143个新的基因座,与大脑、眼睛、心血管、肝脏、免疫、代谢、肌肉骨骼、肺和肾系统的BAG相关。我们还观察了BAG器官特异性和器官间串扰。与九种BAG相关的遗传变异主要针对各自的器官系统,同时对与多个器官系统相关的性状产生多效性影响。一个基因-药物-疾病网络证实了代谢BAG相关基因参与靶向各种代谢紊乱的药物。遗传相关性分析支持Cheverud的推测1——BAG之间的遗传相关性反映了它们的表型相关性。因果网络揭示了慢性疾病(如阿尔茨海默病)、体重和睡眠时间与多器官系统BAG之间的潜在因果关系。我们的研究结果揭示了在复杂的多器官网络中增强人体器官健康的有前景的治疗干预措施,包括改变生活方式和治疗慢性病的潜在药物重新定位策略。所有结果可在以下网站公开获取:https://labs.loni.usc.edu/medicine.
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引用次数: 0
International Multi-Specialty Expert Physician Preoperative Identification of Extranodal Extension n Oropharyngeal Cancer Patients using Computed Tomography: Prospective Blinded Human Inter-Observer Performance Evaluation. 口咽癌症患者计算机断层扫描中结外延伸的多专业专家医师鉴定:前瞻性盲法人类观察者间性能评估。
Pub Date : 2024-06-08 DOI: 10.1101/2023.02.25.23286432
Onur Sahin, Serageldin Kamel, Kareem A Wahid, Cem Dede, Nicolette Taku, Renjie He, Mohamed A Naser, Setareh Sharafi, Antti Mäkitie, Benjamin H Kann, Kimmo Kaski, Jaakko Sahlsten, Joel Jaskari, Moran Amit, Gregory M Chronowski, Eduardo M Diaz, Adam S Garden, Ryan P Goepfert, Jeffrey P Guenette, G Brandon Gunn, Jussi Hirvonen, Frank Hoebers, Katherine A Hutcheson, Nandita Guha-Thakurta, Jason Johnson, Diana Kaya, Shekhar D Khanpara, Kristofer Nyman, Stephen Y Lai, Miriam Lango, Kim O Learned, Anna Lee, Carol M Lewis, Anastasios Maniakas, Amy C Moreno, Jeffery N Myers, Jack Phan, Kristen B Pytynia, David I Rosenthal, Vlad C Sandulache, Dawid Schellingerhout, Shalin J Shah, Andrew G Sikora, Abdallah S R Mohamed, Melissa M Chen, Clifton D Fuller

Importance: Extranodal extension (pENE) is a critical prognostic factor in oropharyngeal cancer (OPC) that drives therapeutic disposition. Determination of pENE from radiological imaging has been associated with high inter-observer variability. However, the impact of clinician specialty on human observer performance of imaging-detected extranodal extension (iENE) remains poorly understood.

Objective: To characterize the impact of clinician specialty on the accuracy of pre-operative iENE in human papillomavirus-positive (HPV+) OPC using computed tomography (CT) images.

Design setting and participants: This prospective observational human performance study analyzed pre-therapy CT images from 24 HPV+ OPC patients, with duplication of 6 scans (n=30) of which 21 were pathologically confirmed pENE. Thirty-four expert observers, including 11 radiologists, 12 surgeons, and 11 radiation oncologists, independently assessed these scans for iENE and reported human-detected radiologic criteria and observer confidence.

Main outcomes and measures: The primary outcomes included accuracy, sensitivity, specificity, area under the receiver operating characteristic curve (AUC), and Brier score for each physician, compared to ground-truth pENE. The significance of radiographic signs for prediction of pENE were determined through logistic regression analysis. Fleiss' kappa measured interobserver agreement, and Hanley-MacNeil AUC discrimination testing.

Results: Median accuracy across all specialties was 0.57 (95%CI 0.39 to 0.73), with no specialty showing discriminate performance greater than random estimation (median AUC 0.64, 95%CI 0.44 to 0.83). Significant differences between radiologists and surgeons in Brier scores (0.33 vs. 0.26, p < 0.01), radiation oncologists and surgeons in sensitivity (0.48 vs. 0.69, p > 0.1), and radiation oncologists and radiologists/surgeons in specificity (0.89 vs. 0.56, p > 0.1). Indistinct capsular contour and nodal necrosis were significant predictors of correct pENE status among all specialties. Interobserver agreement was weak for all the radiographic criteria, regardless of specialty (κ<0.6).

Conclusions and relevance: Multiobserver testing shows physician discrimination of HPV+OPC pENE on pre-operative CT remains non-different than blind guessing, with high interrater variability and low diagnostic accuracy, regardless of clinician specialty. While minor differences in diagnostic performance among specialties are noted, they do not significantly affect the overall poor agreement and discrimination rates observed. The findings underscore the need for further research into automated detection systems or enhanced imaging techniques to improve the accuracy and reliability of iENE assessments in clinical practice.

背景:结外延伸(ENE)是口咽癌症(OPC)的一个重要的不良预后因素,常被用于治疗决策。临床医生根据放射学成像确定ENE是一项困难的任务,具有较高的观察者间变异性。然而,临床专业在ENE测定中的作用尚未得到探索。方法:选择24例人乳头瘤病毒阳性(HPV+)OPC患者的治疗前CT图像进行分析;随机选择6次扫描进行重复,共30次扫描,其中21次经病理证实为ENE。34名专家临床医生注释员,包括11名放射科医生、12名外科医生和11名放射肿瘤学家,分别评估了30次ENE CT扫描,并注意到是否存在特定的放射学标准和对其预测的信心。使用每位医生的准确度、灵敏度、特异性、受试者工作特征曲线下面积(AUC)和Brier评分来测量判别性能。使用Mann-Whitney U检验计算判别性能的统计比较。通过逻辑回归分析确定了正确辨别ENE状态的重要放射学因素。使用Fleiss’kappa测量观察者之间的一致性。结果:所有专业ENE判别的中位准确度为0.57。放射科医生和外科医生的Brier评分(0.33 vs.0.26)、放射肿瘤学家和外科医生的敏感性(0.48 vs.0.69)、放射肿瘤医生和放射科医生/外科医生的特异性(0.89 vs.0.56)存在显著差异。不同专业在准确性或AUC方面没有显著差异。在回归分析中,包膜轮廓不清、淋巴结坏死和淋巴结脱落是重要因素。Fleiss’kappa在所有射线照相标准中均小于0.6,与专业无关。结论:无论临床医生的专业如何,在HPV+OPC患者的CT成像中检测ENE仍然是一项具有高变异性的艰巨任务。尽管专家之间确实存在一些差异,但它们往往是最小的。可能需要进一步研究从射线图像中自动分析ENE。
{"title":"International Multi-Specialty Expert Physician Preoperative Identification of Extranodal Extension n Oropharyngeal Cancer Patients using Computed Tomography: Prospective Blinded Human Inter-Observer Performance Evaluation.","authors":"Onur Sahin, Serageldin Kamel, Kareem A Wahid, Cem Dede, Nicolette Taku, Renjie He, Mohamed A Naser, Setareh Sharafi, Antti Mäkitie, Benjamin H Kann, Kimmo Kaski, Jaakko Sahlsten, Joel Jaskari, Moran Amit, Gregory M Chronowski, Eduardo M Diaz, Adam S Garden, Ryan P Goepfert, Jeffrey P Guenette, G Brandon Gunn, Jussi Hirvonen, Frank Hoebers, Katherine A Hutcheson, Nandita Guha-Thakurta, Jason Johnson, Diana Kaya, Shekhar D Khanpara, Kristofer Nyman, Stephen Y Lai, Miriam Lango, Kim O Learned, Anna Lee, Carol M Lewis, Anastasios Maniakas, Amy C Moreno, Jeffery N Myers, Jack Phan, Kristen B Pytynia, David I Rosenthal, Vlad C Sandulache, Dawid Schellingerhout, Shalin J Shah, Andrew G Sikora, Abdallah S R Mohamed, Melissa M Chen, Clifton D Fuller","doi":"10.1101/2023.02.25.23286432","DOIUrl":"10.1101/2023.02.25.23286432","url":null,"abstract":"<p><strong>Importance: </strong>Extranodal extension (pENE) is a critical prognostic factor in oropharyngeal cancer (OPC) that drives therapeutic disposition. Determination of pENE from radiological imaging has been associated with high inter-observer variability. However, the impact of clinician specialty on human observer performance of imaging-detected extranodal extension (iENE) remains poorly understood.</p><p><strong>Objective: </strong>To characterize the impact of clinician specialty on the accuracy of pre-operative iENE in human papillomavirus-positive (HPV+) OPC using computed tomography (CT) images.</p><p><strong>Design setting and participants: </strong>This prospective observational human performance study analyzed pre-therapy CT images from 24 HPV+ OPC patients, with duplication of 6 scans (n=30) of which 21 were pathologically confirmed pENE. Thirty-four expert observers, including 11 radiologists, 12 surgeons, and 11 radiation oncologists, independently assessed these scans for iENE and reported human-detected radiologic criteria and observer confidence.</p><p><strong>Main outcomes and measures: </strong>The primary outcomes included accuracy, sensitivity, specificity, area under the receiver operating characteristic curve (AUC), and Brier score for each physician, compared to ground-truth pENE. The significance of radiographic signs for prediction of pENE were determined through logistic regression analysis. Fleiss' kappa measured interobserver agreement, and Hanley-MacNeil AUC discrimination testing.</p><p><strong>Results: </strong>Median accuracy across all specialties was 0.57 (95%CI 0.39 to 0.73), with no specialty showing discriminate performance greater than random estimation (median AUC 0.64, 95%CI 0.44 to 0.83). Significant differences between radiologists and surgeons in Brier scores (0.33 vs. 0.26, p < 0.01), radiation oncologists and surgeons in sensitivity (0.48 vs. 0.69, p > 0.1), and radiation oncologists and radiologists/surgeons in specificity (0.89 vs. 0.56, p > 0.1). Indistinct capsular contour and nodal necrosis were significant predictors of correct pENE status among all specialties. Interobserver agreement was weak for all the radiographic criteria, regardless of specialty (<i>κ</i><0.6).</p><p><strong>Conclusions and relevance: </strong>Multiobserver testing shows physician discrimination of HPV+OPC pENE on pre-operative CT remains non-different than blind guessing, with high interrater variability and low diagnostic accuracy, regardless of clinician specialty. While minor differences in diagnostic performance among specialties are noted, they do not significantly affect the overall poor agreement and discrimination rates observed. The findings underscore the need for further research into automated detection systems or enhanced imaging techniques to improve the accuracy and reliability of iENE assessments in clinical practice.</p>","PeriodicalId":18659,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9980252/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9115355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
HIV-1 latency reversal agent boosting is not limited by opioid use. 阿片类药物的使用并不限制有效的低剂量HIV-1潜伏逆转剂的增强。
Pub Date : 2024-06-04 DOI: 10.1101/2023.05.26.23290576
Tyler Lilie, Jennifer Bouzy, Archana Asundi, Jessica Taylor, Samantha Roche, Alex Olson, Kendyll Coxen, Heather Corry, Hannah Jordan, Kiera Clayton, Nina Lin, Athe Tsibris

The opioid epidemic may impact the HIV-1 reservoir and its reversal from latency in virally suppressed people with HIV (PWH). We studied forty-seven PWH and observed that lowering the concentration of HIV-1 latency reversal agents (LRA), used in combination with small molecules that do not reverse latency, synergistically increases the magnitude of HIV-1 re-activation ex vivo, regardless of opioid use. This LRA boosting, which combines a Smac mimetic or low-dose protein kinase C agonist with histone deacetylase inhibitors, can generate significantly more unspliced HIV-1 transcription than phorbol 12-myristate 13-acetate (PMA) with ionomycin (PMAi), the maximal known HIV-1 reactivator. LRA boosting associated with greater histone acetylation in CD4+ T cells and modulated T cell activation-induced markers and intracellular cytokine production; Smac mimetic-based boosting was less likely to induce immune activation. We found that HIV-1 reservoirs in PWH contain unspliced and polyadenylated (polyA) virus mRNA, the ratios of which are greater in resting than total CD4+ T cells and can correct to 1:1 with PMAi exposure. Latency reversal results in greater fold-change increases to HIV-1 poly(A) mRNA than unspliced message. Multiply spliced HIV-1 transcripts and virion production did not consistently increase with LRA boosting, suggesting the presence of a persistent post-transcriptional block. LRA boosting can be leveraged to probe the mechanisms of an effective cellular HIV-1 latency reversal program.

HIV-1和阿片类药物流行对病毒库动态的综合影响尚不清楚。为了评估阿片类药物的使用对HIV-1潜伏逆转的影响,我们研究了47名受抑制的HIV-1参与者,并观察到较低浓度的联合潜伏逆转剂(LRA)会导致协同病毒在体外重新激活,而与阿片类药的使用无关。Smac模拟物或低剂量蛋白激酶C激动剂,即单独不能逆转潜伏期的化合物,与低剂量组蛋白脱乙酰酶抑制剂联合使用,产生的HIV-1转录显著多于佛波醇12-肉豆蔻酸13-乙酸酯(PMA)和离子霉素(已知的最大HIV-1再激活剂)。这种LRA增强没有性别或种族差异,并且与CD4+T细胞中更大的组蛋白乙酰化和T细胞表型的调节有关。病毒产生和多重剪接HIV-1转录物的频率没有增加,这表明转录后阻断仍然限制了HIV-1 LRA的有效增强。
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引用次数: 0
Genetic Associations with Placental Proteins in Maternal Serum Identify Biomarkers for Hypertension in Pregnancy. 母体血清中胎盘蛋白的基因关联确定了妊娠期高血压的生物标记。
Pub Date : 2024-05-30 DOI: 10.1101/2023.05.25.23290460
Qi Yan, Nathan R Blue, Buu Truong, Yu Zhang, Rafael F Guerrero, Nianjun Liu, Michael C Honigberg, Samuel Parry, Rebecca B McNeil, Hyagriv N Simhan, Judith Chung, Brian M Mercer, William A Grobman, Robert Silver, Philip Greenland, George R Saade, Uma M Reddy, Ronald J Wapner, David M Haas

Background: Preeclampsia is a complex syndrome that accounts for considerable maternal and perinatal morbidity and mortality. Despite its prevalence, no effective disease-modifying therapies are available. Maternal serum placenta-derived proteins have been in longstanding use as markers of risk for aneuploidy and placental dysfunction, but whether they have a causal contribution to preeclampsia is unknown.

Objective: We aimed to investigate the genetic regulation of serum placental proteins in early pregnancy and their potential causal links with preeclampsia and gestational hypertension.

Study design: This study used a nested case-control design with nulliparous women enrolled in the nuMoM2b study from eight clinical sites across the United States between 2010 and 2013. The first- and second-trimester serum samples were collected, and nine proteins were measured, including vascular endothelial growth factor (VEGF), placental growth factor, endoglin, soluble fms-like tyrosine kinase-1 (sFlt-1), a disintegrin and metalloproteinase domain-containing protein 12 (ADAM-12), pregnancy-associated plasma protein A, free beta-human chorionic gonadotropin, inhibin A, and alpha-fetoprotein. This study used genome-wide association studies to discern genetic influences on these protein levels, treating proteins as outcomes. Furthermore, Mendelian randomization was used to evaluate the causal effects of these proteins on preeclampsia and gestational hypertension, and their further causal relationship with long-term hypertension, treating proteins as exposures.

Results: A total of 2,352 participants were analyzed. We discovered significant associations between the pregnancy zone protein locus and concentrations of ADAM-12 (rs6487735, P= 3.03×10 -22 ), as well as between the vascular endothelial growth factor A locus and concentrations of both VEGF (rs6921438, P= 7.94×10 -30 ) and sFlt-1 (rs4349809, P= 2.89×10 -12 ). Our Mendelian randomization analyses suggested a potential causal association between first-trimester ADAM-12 levels and gestational hypertension (odds ratio=0.78, P= 8.6×10 -4 ). We also found evidence for a potential causal effect of preeclampsia (odds ratio=1.75, P =8.3×10 -3 ) and gestational hypertension (odds ratio=1.84, P =4.7×10 -3 ) during the index pregnancy on the onset of hypertension 2-7 years later. The additional mediation analysis indicated that the impact of ADAM-12 on postpartum hypertension could be explained in part by its indirect effect through gestational hypertension (mediated effect=-0.15, P= 0.03).

Conclusions: Our study discovered significant genetic associations with placental proteins ADAM-12, VEGF, and sFlt-1, offering insights into their regulation during pregnancy. Mendelian randomization analys

背景:子痫前期是一种复杂的综合征,是孕产妇和围产期发病率和死亡率相当高的原因。尽管其发病率很高,但目前还没有有效的疾病调节疗法。长期以来,母体血清胎盘衍生蛋白一直被用作非整倍体和胎盘功能障碍风险的标志物,但它们是否与子痫前期有因果关系尚不清楚:我们旨在研究妊娠早期血清胎盘蛋白的遗传调控及其与子痫前期和妊娠高血压的潜在因果关系:本研究采用巢式病例对照设计,研究对象为 2010 年至 2013 年间参加 nuMoM2b 研究的美国 8 个临床研究机构的无胎盘妇女。研究人员采集了第一胎和第二胎的血清样本,并测定了九种蛋白质,包括血管内皮生长因子(VEGF)、胎盘生长因子、内皮素、可溶性瘤样酪氨酸激酶-1(sFlt-1)、含崩解蛋白和金属蛋白酶结构域的蛋白12(ADAM-12)、妊娠相关血浆蛋白A、游离β-人绒毛膜促性腺激素、抑制素A和甲胎蛋白。本研究采用全基因组关联研究,将蛋白质作为结果来处理,以确定遗传对这些蛋白质水平的影响。此外,研究还采用孟德尔随机法评估了这些蛋白质对先兆子痫和妊娠高血压的因果影响,以及它们与长期高血压的进一步因果关系:共对 2,352 名参与者进行了分析。我们发现妊娠区蛋白位点与 ADAM-12 的浓度(rs6487735,P= 3.03×10 -22)之间存在明显关联,血管内皮生长因子 A 位点与血管内皮生长因子(VEGF)(rs6921438,P= 7.94×10 -30)和 sFlt-1 (rs4349809,P= 2.89×10 -12)的浓度之间也存在明显关联。我们的孟德尔随机分析表明,首胎 ADAM-12 水平与妊娠高血压之间存在潜在的因果关系(几率比=0.78,P= 8.6×10 -4)。我们还发现了子痫前期(几率比=1.75,P=8.3×10 -3)和妊娠高血压(几率比=1.84,P=4.7×10 -3)对 2-7 年后高血压发病的潜在因果关系。额外的中介分析表明,ADAM-12对产后高血压的影响可通过其对妊娠高血压的间接影响得到部分解释(中介效应=-0.15,P= 0.03):我们的研究发现了胎盘蛋白ADAM-12、血管内皮生长因子和sFlt-1的重要遗传关联,为了解它们在孕期的调控提供了见解。孟德尔随机分析表明,胎盘蛋白(尤其是ADAM-12)的血清水平与妊娠高血压之间存在潜在的因果关系,可能为未来的预防和治疗研究提供参考。
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引用次数: 0
The pivotal role of the X-chromosome in the genetic architecture of the human brain. X染色体在人类大脑遗传结构中的关键作用。
Pub Date : 2024-05-19 DOI: 10.1101/2023.08.30.23294848
Zhiwen Jiang, Patrick F Sullivan, Tengfei Li, Bingxin Zhao, Xifeng Wang, Tianyou Luo, Shuai Huang, Peter Y Guan, Jie Chen, Yue Yang, Jason L Stein, Yun Li, Dajiang Liu, Lei Sun, Hongtu Zhu

Genes on the X-chromosome are extensively expressed in the human brain. However, little is known for the X-chromosome's impact on the brain anatomy, microstructure, and functional network. We examined 1,045 complex brain imaging traits from 38,529 participants in the UK Biobank. We unveiled potential autosome-X-chromosome interactions, while proposing an atlas outlining dosage compensation (DC) for brain imaging traits. Through extensive association studies, we identified 72 genome-wide significant trait-locus pairs (including 29 new associations) that share genetic architectures with brain-related disorders, notably schizophrenia. Furthermore, we discovered unique sex-specific associations and assessed variations in genetic effects between sexes. Our research offers critical insights into the X-chromosome's role in the human brain, underscoring its contribution to the differences observed in brain structure and functionality between sexes.

X染色体上的基因在人脑中广泛表达,对大脑发育、智力残疾和其他大脑相关疾病产生重大影响。为了全面研究X染色体对大脑皮层、白质束微观结构以及内在和外在大脑功能的影响,我们检查了英国生物库中从34000名受试者中获得的2822个复杂的大脑成像特征。我们揭示了潜在的自体X染色体相互作用,同时提出了每组性状的剂量补偿(DC)图谱。我们观察到X染色体对皮质脊髓束以及视觉网络的功能幅度和连接性的显著影响。在关联研究中,我们鉴定了50个富含Xq28的全基因组显著性状基因座对,其中22个在独立数据集中复制(n=4900)。值得注意的是,13对新鉴定的染色体位于X染色体的非拟常染色体区(NPR)。右腹侧间脑的体积与rs2361468(位于PJA1上游约3kb,PJA1是一种保守且普遍表达的基因,与多种精神疾病有关)索引的基因座中的精神分裂症和教育程度具有共同的遗传结构。在假染色体区(标准杆数)或Y染色体中未发现显著关联。最后,我们探索了X染色体上的性别特异性关联,并比较了性别之间不同的遗传效应。我们发现,在相似的样本量下,男性(33对9)可以发现更多的关联。总之,我们的研究为X染色体在人脑中的作用提供了宝贵的见解,有助于观察到大脑结构和功能的性别差异。
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medRxiv : the preprint server for health sciences
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