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Assessment of MYC Gene and WNT Pathway Alterations in Early-Onset Colorectal Cancer Among Hispanic/Latino Patients Using Integrated Multi-Omics Approaches.
Pub Date : 2025-02-22 DOI: 10.1101/2024.12.05.24318588
F G Carranza, B Waldrup, Y Jin, Y Amzaleg, M Postel, D W Craig, J D Carpten, B Salhia, D Hernandez, N Gutierrez, C N Ricker, J O Culver, C E Chavez, M C Stern, L Baezconde-Garbanati, H J Lenz, E Velazquez-Villarreal
<p><p>Colorectal cancer (CRC) has increased at an alarming rate amongst younger (< 50 years) individuals. Such early-onset colorectal cancer (EOCRC) has been particularly notable within the Hispanic/Latino population. Yet, this population has not been sufficiently profiled in terms of two critical elements of CRC -- the MYC proto-oncogene and WNT signaling pathway. Here, we performed a comprehensive multi-omics analysis on 30 early-onset and 37 late-onset CRC (≥ 50 years) samples from Hispanic/Latino patients. Our analysis included DNA exome sequencing for somatic mutations, somatic copy number alterations, and global and local genetic similarity. Using RNA sequencing, we also assessed differential gene expression, cellular pathways, and gene fusions. We then compared our findings from early-onset Hispanic/Latino patient samples with publicly available data from Non-Hispanic White cohorts. Across all early-onset patients, which had a median 1000 Genomes Project Peruvian-in-Lima-like (1KG-PEL-like) genetic similarity proportion of 60%, we identified 41 WNT pathway genes with significant mutations. Six important examples were APC, TCF7L2, DKK1, DKK2, FZD10, and LRP5. Notably, patients with mutations in DKK1 and DKK2 had the highest 1KG-PEL-like proportion (79%). When we compared the Hispanic/Latino cohort to the Non-Hispanic White cohorts, four of these key genes -- DKK1, DKK2, FZD10, and LRP5 -- were significant in both risk association analyses and differential gene expression. Interestingly, early-onset tumors (vs. late-onset) exhibited distinct somatic copy number alterations and gene expression profiles; the differences included MYC and drug-targetable WNT pathway genes. We also identified a novel WNT gene fusion, RSPO3, in early-onset tumors; it was associated with enhanced WNT signaling. This integrative analysis underscores the distinct molecular features of EOCRC cancer in the Hispanic/Latino population; reveals potential avenues for tailored precision medicine therapies; and emphasizes the importance of multi-omics approaches in studying colorectal carcinogenesis. We expect this data to help contribute towards reducing cancer health disparities.</p><p><strong>Significance: </strong>This study offers multi-omics profiling analysis of early-onset colorectal cancer (EOCRC) in an underserved community, explores the implications of <i>MYC</i> gene and WNT pathway alterations, and provides critical insights into cancer health disparities.</p><p><strong>Abstractshort version: </strong>Colorectal cancer (CRC) has risen at an alarming rate in early-onset (<50 yrs) cases. Both its increased incidence and higher rates of mortality are especially pronounced within the Hispanic/Latino population. Although the <i>MYC</i> gene and WNT signaling pathway are well-established in CRC, we lack sufficient data about what role these elements play in young Hispanic/Latino patients. Here, we assess how both the <i>MYC</i> gene and WNT pathway are altered in Hisp
{"title":"Assessment of MYC Gene and WNT Pathway Alterations in Early-Onset Colorectal Cancer Among Hispanic/Latino Patients Using Integrated Multi-Omics Approaches.","authors":"F G Carranza, B Waldrup, Y Jin, Y Amzaleg, M Postel, D W Craig, J D Carpten, B Salhia, D Hernandez, N Gutierrez, C N Ricker, J O Culver, C E Chavez, M C Stern, L Baezconde-Garbanati, H J Lenz, E Velazquez-Villarreal","doi":"10.1101/2024.12.05.24318588","DOIUrl":"https://doi.org/10.1101/2024.12.05.24318588","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Colorectal cancer (CRC) has increased at an alarming rate amongst younger (&lt; 50 years) individuals. Such early-onset colorectal cancer (EOCRC) has been particularly notable within the Hispanic/Latino population. Yet, this population has not been sufficiently profiled in terms of two critical elements of CRC -- the MYC proto-oncogene and WNT signaling pathway. Here, we performed a comprehensive multi-omics analysis on 30 early-onset and 37 late-onset CRC (≥ 50 years) samples from Hispanic/Latino patients. Our analysis included DNA exome sequencing for somatic mutations, somatic copy number alterations, and global and local genetic similarity. Using RNA sequencing, we also assessed differential gene expression, cellular pathways, and gene fusions. We then compared our findings from early-onset Hispanic/Latino patient samples with publicly available data from Non-Hispanic White cohorts. Across all early-onset patients, which had a median 1000 Genomes Project Peruvian-in-Lima-like (1KG-PEL-like) genetic similarity proportion of 60%, we identified 41 WNT pathway genes with significant mutations. Six important examples were APC, TCF7L2, DKK1, DKK2, FZD10, and LRP5. Notably, patients with mutations in DKK1 and DKK2 had the highest 1KG-PEL-like proportion (79%). When we compared the Hispanic/Latino cohort to the Non-Hispanic White cohorts, four of these key genes -- DKK1, DKK2, FZD10, and LRP5 -- were significant in both risk association analyses and differential gene expression. Interestingly, early-onset tumors (vs. late-onset) exhibited distinct somatic copy number alterations and gene expression profiles; the differences included MYC and drug-targetable WNT pathway genes. We also identified a novel WNT gene fusion, RSPO3, in early-onset tumors; it was associated with enhanced WNT signaling. This integrative analysis underscores the distinct molecular features of EOCRC cancer in the Hispanic/Latino population; reveals potential avenues for tailored precision medicine therapies; and emphasizes the importance of multi-omics approaches in studying colorectal carcinogenesis. We expect this data to help contribute towards reducing cancer health disparities.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Significance: &lt;/strong&gt;This study offers multi-omics profiling analysis of early-onset colorectal cancer (EOCRC) in an underserved community, explores the implications of &lt;i&gt;MYC&lt;/i&gt; gene and WNT pathway alterations, and provides critical insights into cancer health disparities.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Abstractshort version: &lt;/strong&gt;Colorectal cancer (CRC) has risen at an alarming rate in early-onset (&lt;50 yrs) cases. Both its increased incidence and higher rates of mortality are especially pronounced within the Hispanic/Latino population. Although the &lt;i&gt;MYC&lt;/i&gt; gene and WNT signaling pathway are well-established in CRC, we lack sufficient data about what role these elements play in young Hispanic/Latino patients. Here, we assess how both the &lt;i&gt;MYC&lt;/i&gt; gene and WNT pathway are altered in Hisp","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11875251/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143545539","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
VOYAGER: an international consortium investigating the role of human papilloma virus and genetics in oral and oropharyngeal cancer risk and survival.
Pub Date : 2025-02-22 DOI: 10.1101/2025.02.17.25322399
M Gormley, A Adhikari, T Dudding, M Pring, K Hurley, G J Macfarlane, P Lagiou, A Lagiou, J Polesel, A Agudo, L Alemany, W Ahrens, C M Healy, D I Conway, C Canova, I Holcatova, L Richiardi, A Znaor, A F Olshan, R J Hung, G Liu, S Bratman, X Zhao, J Holt, R Cortez, V Gaborieau, J D McKay, T Waterboer, P Brennan, N Hayes, B Diergaarde, S Virani

Head and neck cancer (HNC) is the sixth most common cancer globally. Incidence and survival rates vary significantly across geographic regions and tumor subsites. This is partly due to differences in risk factor exposure, which includes tobacco smoking, alcohol consumption and human papillomavirus (HPV) infection, alongside detection and treatment strategies. The VOYAGER (human papillomaVirus, Oral and oropharYngeal cAncer GEnomic Research) consortium is a collaboration between five large North American and European studies which generated data on 10,530 participants (7,233 cases and 3,297 controls). The primary goal of the collaboration was to improve understanding of the role of HPV and genetic factors in oral cavity and oropharyngeal cancer risk and outcome. Demographic and clinical data collected by the five studies were harmonized, and HPV status was determined for the majority of cases. In addition, 999 tumors were sequenced to define somatic mutations. These activities generated a comprehensive biomedical resource that can be utilized to answer critical outstanding research questions to help improve HNC prevention, early detection, treatment, and surveillance.

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引用次数: 0
Mendelian randomization analyses uncover causal relationships between brain structural connectome and risk of psychiatric disorders.
Pub Date : 2025-02-22 DOI: 10.1101/2025.02.20.25322606
Kanwei Xiao, Xinle Chang, Chenfei Ye, Zhiguo Zhang, Ting Ma, Jingyong Su

Growing evidence suggests abnormalities of brain structural connectome in psychiatric disorders, but the causal relationships remain underexplored. We conducted bidirectional two-sample Mendelian randomization (MR) analyses to investigate the causal links between 206 white-matter connectivity phenotypes (n = 26,333, UK Biobank) and 13 major psychiatric disorders (n = 14,307 to 1,222,882). Forward MR analyses identified causal effects of genetically predicted five white-matter structural connectivity phenotypes on six psychiatric disorders, with associations being significant or suggestive. For instance, structural connectivity between the left-hemisphere frontoparietal control network and right-hemisphere default mode network was significantly negatively associated with autism spectrum disorder risk, while increased structural connectivity between the right-hemisphere frontoparietal control network and hippocampus was significantly linked to decreased anorexia nervosa and cannabis use disorder risk. Reverse MR analyses revealed significantly or suggestively causal relationships between the risk of two psychiatric disorders and four different white-matter structural connectivity phenotypes. For example, the susceptibility of anorexia nervosa was found to be significantly negatively associated with structural connectivity between the left-hemisphere visual network and pallidum. These findings offer new insights into the etiology of psychiatric disorders and highlight potential biomarkers for early detection and prevention at the brain structural connectome level.

越来越多的证据表明,大脑结构连接组异常与精神疾病有关,但其中的因果关系仍未得到充分探讨。我们进行了双向双样本孟德尔随机化(MR)分析,研究了206种白色物质连接表型(n = 26,333,英国生物库)与13种主要精神疾病(n = 14,307至1,222,882)之间的因果关系。前向磁共振分析确定了基因预测的五种白色物质结构连通性表型对六种精神疾病的因果效应,相关性显著或具有暗示性。例如,左半球额顶控制网络和右半球默认模式网络之间的结构连通性与自闭症谱系障碍风险呈显著负相关,而右半球额顶控制网络和海马体之间结构连通性的增加与神经性厌食症和大麻使用障碍风险的降低呈显著相关。反向磁共振分析显示,两种精神疾病的风险与四种不同的白质结构连接表型之间存在明显或提示性的因果关系。例如,研究发现神经性厌食症的易感性与左半球视觉网络和苍白球之间的结构连通性呈显著负相关。这些发现为精神疾病的病因学提供了新的见解,并强调了在大脑结构连接组水平进行早期检测和预防的潜在生物标记物。
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引用次数: 0
Genome-wide transcriptome analysis reveals sex-specific biological differences in the early phase of an acute myocardial infarction.
Pub Date : 2025-02-21 DOI: 10.1101/2025.02.19.25322579
Aaron Shulkin, Perman Pandal, Eliseo Vazquez, Elizabeth Jasmin Cortez-Toledo, Kwame Atsina, Tesfaye Mersha, Javier E Lopez

Background: Clinical outcomes of acute myocardial infarction (AMI) are known to vary between females and males; however, the nature of this sex dimorphism remains controversial. Most AMI transcriptomic studies have not considered differences between females and males, and combined sexes in their analysis to increase sample size and gain power (canonical approach). Our objective was to (1) use a sex-specific differentially expressed gene meta-analysis (ss-DEGma) in blood and (2) identify sex-specific pathways related to the early phase of AMI.

Methods: Gene expression data (7 sets) for sex-combined (canonical) and sex-specific analysis (ss-DEGma) were obtained from the publicly-available GEO database. Datasets from whole blood and peripheral blood cells sampled within 3 days post-AMI were analyzed using GEO2R. The massiR tool identified sex in 72% of samples. The top-ranking DEGs were used to identify significant sex-specific biological pathways in the KEGG database (FDR <0.05).

Results: We performed this meta-analysis in 291 women and 452 men and > 20,000 genes (see Table for identified DEGs). Sex-combined DEGs yielded 100 significant KEGG pathways. Sex-specific DEGs yielded 8/61 (13%) additional new pathways not identified by the sex-combined analysis. Sex-combined pathways were predominantly immunological (35%), while male- and female-specific pathways were 43% and 18% immunological, respectively. Proliferative and metabolic pathways were the next most represented pathways in females, which were not present in males at all.

Conclusion: We present 8 new sex-specific AMI-related transcriptional pathways not identified in the canonical sex-combined analysis. Furthermore, we find that 53% of pathways identified in the canonical sex-combined analysis are not shared between sexes. This data underscores an urgent need for prospective sex-specific transcriptomic analysis to define the sex-specific biological difference post-AMI.

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引用次数: 0
A Trypanosoma cruzi Trans-Sialidase Peptide Demonstrates High Serological Prevalence Among Infected Populations Across Endemic Regions of Latin America.
Pub Date : 2025-02-21 DOI: 10.1101/2025.01.22.25320967
Hannah M Kortbawi, Ryan J Marczak, Jayant V Rajan, Nash L Bulaong, John E Pak, Wesley Wu, Grace Wang, Anthea Mitchell, Aditi Saxena, Aditi Maheshwari, Charles J Fleischmann, Emily A Kelly, Evan Teal, Rebecca L Townsend, Susan L Stramer, Emi E Okamoto, Jacqueline E Sherbuk, Eva H Clark, Robert H Gilman, Rony Colanzi, Efstathios D Gennatas, Caryn Bern, Joseph L DeRisi, Jeffrey D Whitman

Infection by Trypanosoma cruzi, the agent of Chagas disease, can irreparably damage the cardiac and gastrointestinal systems during decades of parasite persistence and related inflammation in these tissues. Diagnosis of chronic disease requires confirmation by multiple serological assays due to the imperfect performance of existing clinical tests. Current serology tests utilize antigens discovered over three decades ago with small specimen sets predominantly from South America, and lower test performance has been observed in patients who acquired T. cruzi infection in Central America and Mexico. Here, we attempt to address this gap by evaluating antibody responses against the entire T. cruzi proteome with phage display immunoprecipitation sequencing comprised of 228,127 47-amino acid peptides. We utilized diverse specimen sets from Mexico, Central America and South America, as well as different stages of cardiac disease severity, from 185 cases and 143 controls. We identified over 1,300 antigenic T. cruzi peptides derived from 961 proteins between specimen sets. A total of 67 peptides were reactive in 70% of samples across all regions, and 3 peptide epitopes were enriched in ≥90% of seropositive samples. Of these three, only one antigen, belonging to the trans-sialidase family, has not previously been described as a diagnostic target. Orthogonal validation of this peptide demonstrated increased antibody reactivity for infections originating from Central America. Overall, this study provides proteome-wide identification of seroreactive T. cruzi peptides across a large cohort spanning multiple endemic areas and identified a novel trans-sialidase peptide antigen (TS-2.23) with significant potential for translation into diagnostic serological assays.

南美锥虫病的病原体--南美锥虫的感染会对心脏和胃肠系统造成不可挽回的损害,寄生虫会在这些组织中持续存在数十年并引发相关炎症。由于现有的临床检测方法性能不完善,慢性疾病的诊断需要通过多种血清学检测方法进行确认。目前的血清学检测使用的是三十多年前发现的抗原,样本量较小,主要来自南美洲,而且在中美洲和墨西哥感染了克鲁兹绦虫的患者身上观察到的检测性能较低。在这里,我们试图通过噬菌体展示免疫沉淀测序来评估针对整个克鲁兹绦虫蛋白质组的抗体反应,其中包括 228,127 个 47 氨基酸肽,从而填补这一空白。我们利用了来自墨西哥、中美洲和南美洲的不同标本集,以及 185 例病例和 143 例对照的不同阶段的心脏疾病严重程度。我们从标本集之间的 961 种蛋白质中鉴定出 1300 多种抗原性 T. cruzi 肽。共有 67 种肽在所有地区 70% 的样本中具有反应性,3 种肽表位在血清阳性样本中的富集率≥90%。在这 3 个肽表位中,只有一个属于反式硅烷基酶家族的抗原以前未被描述为诊断靶标。对该肽的正交验证表明,来自中美洲的感染会增加抗体反应性。总之,这项研究对跨越多个流行地区的大量人群中的血清反应性 T. cruzi 多肽进行了蛋白质组鉴定,并发现了一种新型的反硅烷化酶多肽抗原(TS-2.23),该抗原具有转化为血清学诊断测定的巨大潜力。一句话总结:用克鲁兹绦虫全蛋白质组文库设计的噬菌体展示免疫沉淀测序(PhIP-seq)揭示了在拉丁美洲流行地区高度流行的具有抗体反应的反式半乳淀粉酶肽抗原(TS-2.23)。
{"title":"A <i>Trypanosoma cruzi</i> Trans-Sialidase Peptide Demonstrates High Serological Prevalence Among Infected Populations Across Endemic Regions of Latin America.","authors":"Hannah M Kortbawi, Ryan J Marczak, Jayant V Rajan, Nash L Bulaong, John E Pak, Wesley Wu, Grace Wang, Anthea Mitchell, Aditi Saxena, Aditi Maheshwari, Charles J Fleischmann, Emily A Kelly, Evan Teal, Rebecca L Townsend, Susan L Stramer, Emi E Okamoto, Jacqueline E Sherbuk, Eva H Clark, Robert H Gilman, Rony Colanzi, Efstathios D Gennatas, Caryn Bern, Joseph L DeRisi, Jeffrey D Whitman","doi":"10.1101/2025.01.22.25320967","DOIUrl":"10.1101/2025.01.22.25320967","url":null,"abstract":"<p><p>Infection by <i>Trypanosoma cruzi</i>, the agent of Chagas disease, can irreparably damage the cardiac and gastrointestinal systems during decades of parasite persistence and related inflammation in these tissues. Diagnosis of chronic disease requires confirmation by multiple serological assays due to the imperfect performance of existing clinical tests. Current serology tests utilize antigens discovered over three decades ago with small specimen sets predominantly from South America, and lower test performance has been observed in patients who acquired <i>T. cruzi</i> infection in Central America and Mexico. Here, we attempt to address this gap by evaluating antibody responses against the entire <i>T. cruzi</i> proteome with phage display immunoprecipitation sequencing comprised of 228,127 47-amino acid peptides. We utilized diverse specimen sets from Mexico, Central America and South America, as well as different stages of cardiac disease severity, from 185 cases and 143 controls. We identified over 1,300 antigenic <i>T. cruzi</i> peptides derived from 961 proteins between specimen sets. A total of 67 peptides were reactive in 70% of samples across all regions, and 3 peptide epitopes were enriched in ≥90% of seropositive samples. Of these three, only one antigen, belonging to the trans-sialidase family, has not previously been described as a diagnostic target. Orthogonal validation of this peptide demonstrated increased antibody reactivity for infections originating from Central America. Overall, this study provides proteome-wide identification of seroreactive <i>T. cruzi</i> peptides across a large cohort spanning multiple endemic areas and identified a novel trans-sialidase peptide antigen (TS-2.23) with significant potential for translation into diagnostic serological assays.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11838992/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143461313","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
Genetics of cardiovascular outcomes in individuals with chronic kidney disease: the Chronic Renal Insufficiency Cohort (CRIC) study.
Pub Date : 2025-02-21 DOI: 10.1101/2025.02.19.25322572
Jia Wen, Bridget M Lin, Quan Sun, Min-Zhi Jiang, Greg Linchangco, Gang Li, Ruochen Chen, Alan S Go, Tyne W Miller-Fleming, Megan M Shuey, Debbie L Cohen, Panduranga S Rao, Mahboob Rahman, Nancy J Cox, James P Lash, Wyliena Guan, Daniel C Posner, Qin Hui, Serena C Houghton, Adriana M Hung, Kelly Cho, Peter W F Wilson, Haibo Zhou, Yan V Sun, Yun Li, Nora Franceschini

Genome-wide association studies (GWAS) identified multiple loci for cardiovascular disease, but their relevance to individuals with chronic kidney disease (CKD), who are at higher risk of cardiovascular disease, is unknown. In this study, we performed GWAS analyses of coronary heart disease (CHD) or all-cause stroke in African (AFR) and European (EUR) American participants with CKD of the Chronic Renal Insufficiency Cohort (CRIC). Mixed- effect logistic regression models were race-stratified and adjusted for age, sex, site of recruitment, estimated glomerular filtration rate (eGFR), and principal components, followed by meta-analysis. We attempted replication in participants from two biobanks with biomarker or ICD-10 (International Classification of Diseases, 10th Revision) diagnostic codes for CKD. We assessed the association of single nucleotide variants (SNVs) at known CHD and stroke loci in CRIC and tested the genetic correlation among CRIC, a biobank-based cohort and published GWAS of cardiovascular disease. Among 3,588 CRIC participants, 1,203 had CHD and 535 had all-cause stroke. We identified six SNVs across three loci ( LINC02744 , AZIN1- AS1 , and ATP6V0A4 ) associated with all-cause stroke, and two intronic SNVs at the PPARG locus associated with CHD. However, SNV associations were not significant in replication studies. Published SNVs for CHD or stroke were not associated with cardiovascular outcomes in CRIC. When testing the genetic correlations between published GWAS and CRIC GWAS, they were significant for CHD (genetic correlations (rg) range of 0.39 to 0.51, p-value< 0.007). These findings suggest some differences in the genetic architecture of CHD and stroke among individuals with CKD compared to those from the general population, although large numbers of CKD participants are needed to assess if findings are related to participant selection and CKD severity, or non-traditional risk factors in people with CKD.

{"title":"Genetics of cardiovascular outcomes in individuals with chronic kidney disease: the Chronic Renal Insufficiency Cohort (CRIC) study.","authors":"Jia Wen, Bridget M Lin, Quan Sun, Min-Zhi Jiang, Greg Linchangco, Gang Li, Ruochen Chen, Alan S Go, Tyne W Miller-Fleming, Megan M Shuey, Debbie L Cohen, Panduranga S Rao, Mahboob Rahman, Nancy J Cox, James P Lash, Wyliena Guan, Daniel C Posner, Qin Hui, Serena C Houghton, Adriana M Hung, Kelly Cho, Peter W F Wilson, Haibo Zhou, Yan V Sun, Yun Li, Nora Franceschini","doi":"10.1101/2025.02.19.25322572","DOIUrl":"10.1101/2025.02.19.25322572","url":null,"abstract":"<p><p>Genome-wide association studies (GWAS) identified multiple loci for cardiovascular disease, but their relevance to individuals with chronic kidney disease (CKD), who are at higher risk of cardiovascular disease, is unknown. In this study, we performed GWAS analyses of coronary heart disease (CHD) or all-cause stroke in African (AFR) and European (EUR) American participants with CKD of the Chronic Renal Insufficiency Cohort (CRIC). Mixed- effect logistic regression models were race-stratified and adjusted for age, sex, site of recruitment, estimated glomerular filtration rate (eGFR), and principal components, followed by meta-analysis. We attempted replication in participants from two biobanks with biomarker or ICD-10 (International Classification of Diseases, 10th Revision) diagnostic codes for CKD. We assessed the association of single nucleotide variants (SNVs) at known CHD and stroke loci in CRIC and tested the genetic correlation among CRIC, a biobank-based cohort and published GWAS of cardiovascular disease. Among 3,588 CRIC participants, 1,203 had CHD and 535 had all-cause stroke. We identified six SNVs across three loci ( <i>LINC02744</i> , <i>AZIN1- AS1</i> , and <i>ATP6V0A4</i> ) associated with all-cause stroke, and two intronic SNVs at the <i>PPARG</i> locus associated with CHD. However, SNV associations were not significant in replication studies. Published SNVs for CHD or stroke were not associated with cardiovascular outcomes in CRIC. When testing the genetic correlations between published GWAS and CRIC GWAS, they were significant for CHD (genetic correlations (rg) range of 0.39 to 0.51, <i>p-value<</i> 0.007). These findings suggest some differences in the genetic architecture of CHD and stroke among individuals with CKD compared to those from the general population, although large numbers of CKD participants are needed to assess if findings are related to participant selection and CKD severity, or non-traditional risk factors in people with CKD.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11875325/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143545486","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
A Streamlined Point-of-Care CRISPR Test for Tuberculosis Detection Directly from Sputum.
Pub Date : 2025-02-21 DOI: 10.1101/2025.02.19.25322517
Owen R S Dunkley, Alexandra G Bell, Nisha H Modi, Yujia Huang, Soleil Tseng, Robert Reiss, Naranjargal Daivaa, J Lucian Davis, Deninson Alejandro Vargas, Padmapriya Banada, Yingda L Xie, Cameron Myhrvold

Mycobacterium tuberculosis (Mtb) is a major threat to global health and is responsible for over one million deaths each year. To stem the tide of cases and maximize opportunities for early interventions, there is an urgent need for affordable and simple means of tuberculosis diagnosis in under-resourced areas. We sought to develop a CRISPR-based isothermal assay coupled with a compatible, straightforward sample processing technique for point-of-care use. Here, we combine Recombinase Polymerase Amplification (RPA) with Cas13a and Cas12a, to create two parallelised one-pot assays that detect two conserved elements of Mtb (IS6110 and IS1081) and an internal control targeting human DNA. These assays were shown to be compatible with lateral flow and can be readily lyophilized. Our finalized assay exhibited sensitivity over a wide range of bacterial loads (105 to 102 CFU/mL) in sputum. The limit of detection (LoD) of the assay was determined to be 69.0 (51.0 - 86.9) CFU/mL for Mtb strain H37Rv spiked in sputum and 80.5 (59.4 - 101.6) CFU/mL for M. bovis BCG. Our assay showed no cross reactivity against a wide range of bacterial/fungal isolates. Clinical tests on 13 blinded sputum samples revealed 100% (6/6) sensitivity and 100% (7/7) specificity compared to culture. Our assay exhibited comparable sensitivity in clinical samples to the microbiological gold standard, TB culture, and to the nucleic acid state-of-the-art, GeneXpert MTB/RIF Ultra. This technology streamlines TB diagnosis from sample extraction to assay readout in a rapid and robust format, making it the first test to combine amplification and detection while being compatible with both lateral flow and lyophilization.

{"title":"A Streamlined Point-of-Care CRISPR Test for Tuberculosis Detection Directly from Sputum.","authors":"Owen R S Dunkley, Alexandra G Bell, Nisha H Modi, Yujia Huang, Soleil Tseng, Robert Reiss, Naranjargal Daivaa, J Lucian Davis, Deninson Alejandro Vargas, Padmapriya Banada, Yingda L Xie, Cameron Myhrvold","doi":"10.1101/2025.02.19.25322517","DOIUrl":"10.1101/2025.02.19.25322517","url":null,"abstract":"<p><p><i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) is a major threat to global health and is responsible for over one million deaths each year. To stem the tide of cases and maximize opportunities for early interventions, there is an urgent need for affordable and simple means of tuberculosis diagnosis in under-resourced areas. We sought to develop a CRISPR-based isothermal assay coupled with a compatible, straightforward sample processing technique for point-of-care use. Here, we combine Recombinase Polymerase Amplification (RPA) with Cas13a and Cas12a, to create two parallelised one-pot assays that detect two conserved elements of <i>Mtb</i> (<i>IS6110</i> and <i>IS1081</i>) and an internal control targeting human DNA. These assays were shown to be compatible with lateral flow and can be readily lyophilized. Our finalized assay exhibited sensitivity over a wide range of bacterial loads (10<sup>5</sup> to 10<sup>2</sup> CFU/mL) in sputum. The limit of detection (LoD) of the assay was determined to be 69.0 (51.0 - 86.9) CFU/mL for <i>Mtb</i> strain H37Rv spiked in sputum and 80.5 (59.4 - 101.6) CFU/mL for <i>M. bovis</i> BCG. Our assay showed no cross reactivity against a wide range of bacterial/fungal isolates. Clinical tests on 13 blinded sputum samples revealed 100% (6/6) sensitivity and 100% (7/7) specificity compared to culture. Our assay exhibited comparable sensitivity in clinical samples to the microbiological gold standard, TB culture, and to the nucleic acid state-of-the-art, GeneXpert MTB/RIF Ultra. This technology streamlines TB diagnosis from sample extraction to assay readout in a rapid and robust format, making it the first test to combine amplification and detection while being compatible with both lateral flow and lyophilization.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11875272/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143545523","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
A technology-based randomized controlled trial of self-affirmation and gain-framed health messaging to reduce sedentary behavior in older adults.
Pub Date : 2025-02-21 DOI: 10.1101/2025.02.18.25322482
Meishan Ai, Nagashree Thovinakere, Caitlin S Walker, Cora Ordway, Elizabeth Quinoñez, Emily Melsky, Frank D'Agostino, Calvin Tobias, Susan Whitfield-Gabrieli, Siobhan M Phillips, Dominika M Pindus, Charles Hilman, Timothy P Morris, Arthur F Kramer, Maiya R Geddes

Objective: Sedentary behavior significantly increases the risk for chronic diseases and cognitive decline in aging, underscoring the need for effective interventions. Older adults exhibit a 'positivity effect', whereby processing of positive information is prioritized over negative information. In addition, self-affirmation was shown to reduce sedentary behavior in younger adults, but its effects in older adults remain unknown. This study tested a novel, technology-based intervention combining daily self-affirmation and gain-framed health messages to reduce sedentary behavior in older adults.

Methods: In a 6-week randomized controlled trial (NCT0431536), 48 cognitively unimpaired, sedentary older adults were randomized into two groups: The intervention group (mean age=70.0±5.4years) completed daily self-affirmation based on their highest-ranked value, followed by gain-framed health messages. The active control group (mean age=68.4±5.0years) performed self-affirmation on their lowest-ranked value, followed by loss-framed messages. This was a single-blinded clinical trial that incorporated a hybrid efficacy and implementation design. Thus, information about intervention feasibility was examined. In addition, baseline motivational traits, including reward sensitivity, were assessed as moderators of behavior change. The neural basis of self-affirmation and gain-framed health messaging was examined at baseline using a task-based, event-related fMRI paradigm across groups, after randomization at the outset of the intervention.

Results: The intervention showed high adherence (0.92±0.08) and positive ease-of-use ratings. While the intervention did not significantly reduce sedentary behavior compared to the active control condition, increased reward sensitivity predicted reduced sedentary behavior across all participants. FMRI results showed increased ventral striatal activation in the intervention group, compared to the active control group during reading of gain-framed compared to neutral messages.

Conclusions: This study supports the feasibility of technology-based sedentary beahvior reduction interventions for older adults. While self-affirmation combined with gain-framed messaging did not significantly reduce sedentary behavior, gain-framed messages engaged the reward network, and reward sensitivity predicted future reduction in sedentary behavior.

目的:久坐不动会大大增加老年人患慢性病和认知能力下降的风险,因此需要采取有效的干预措施。老年人表现出一种 "积极效应",即在处理积极信息时优先考虑消极信息。此外,自我肯定被证明可以减少年轻人的久坐行为,但其对老年人的影响仍然未知。本研究测试了一种新颖的、基于技术的干预方法,该方法结合了每日自我肯定和收益框架健康信息,以减少老年人的久坐行为:在一项为期 6 周的随机对照试验(NCT0431536)中,48 名认知能力未受损、久坐不动的老年人被随机分为两组:干预组(平均年龄为(70.0±5.4)岁)每天根据自己的最高价值进行自我肯定,然后接受以收益为框架的健康信息。积极对照组(平均年龄=68.4±5.0岁)根据自己的最低价值进行自我肯定,然后是以损失为框架的信息。这是一项单盲临床试验,采用了疗效和实施的混合设计。因此,对干预可行性的信息进行了研究。此外,还对基线动机特征(包括奖励敏感性)进行了评估,作为行为改变的调节因素。在干预开始时进行随机分组后,使用基于任务、与事件相关的 fMRI 范式对各组的基线自我肯定和收益框架健康信息的神经基础进行了检查:干预的依从性很高(0.92±0.08),易用性评价也很好。虽然与主动对照组相比,干预并没有明显减少久坐行为,但奖励敏感性的提高预示着所有参与者的久坐行为都会减少。核磁共振成像(FMRI)结果显示,与主动对照组相比,干预组在阅读有增益框架的信息时,腹侧纹状体激活增加:本研究支持对老年人进行基于技术的减少久坐行为干预的可行性。虽然自我肯定与收益框架信息相结合并不能显著减少久坐行为,但收益框架信息能吸引奖励网络,而奖励敏感性能预测未来久坐行为的减少。
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引用次数: 0
Development of a questionnaire library for rapid health data acquisition during wildfire events.
Pub Date : 2025-02-21 DOI: 10.1101/2025.02.10.25321891
Lilian Liu, Christine Loftus, Diana Rohlman, Edmund Seto, Elena Austin

Rapid health outcome data acquisition using existing questionnaires can greatly facilitate time-sensitive research during or after a wildfire event. We aimed to develop a readily available library of questionnaires for self-reported health outcomes to serve as a centralized platform for wildfire researchers seeking to quickly design instruments tailored to their research aims. In this paper, we describe the methodology used to identify relevant health questionnaires and compile them into a structured library. We first followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 checklist and performed a systematic literature review of prior research on wildfire exposure and health and used this to 1) identify health outcome categories associated with wildfire and smoke exposure and 2) extract questionnaires used for self-report of health outcomes related to wildfire exposure. We also performed a secondary search of existing questionnaire repositories to identify additional instruments relevant to health impacts of wildfire exposure. All questionnaires (n=100) were organized by eight health outcome categories (mental health = 60, respiratory health = 19, overall health = 17, sleep = 10, cardiovascular health = 4, allergy = 1, irritation (eye, throat, skin) = 2, and metabolic health = 1). The library (see supplementary information) will be accompanied by a decision-tree framework in development, which will assist future users in building new questionnaires that best fit their study population and research aims. Both the questionnaire library and the forthcoming decision-support framework will be publicly accessible to researchers, public health agencies, and other groups interested in rapid response data collection to characterize the impacts of wildfires. Additionally, this method of creating a wildfire exposure health questionnaire library may serve as a template for rapid collection of questionnaire-based data following other disasters.

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引用次数: 0
Trajectories of blood-based protein biomarkers in chronic traumatic brain injury.
Pub Date : 2025-02-21 DOI: 10.1101/2025.02.16.25322303
Amelia J Hicks, Jay Plourde, Enna Selmanovic, Nicola L de Souza, Kaj Blennow, Henrik Zetterberg, Kristen Dams-O'Connor

Blood-based protein biomarkers may provide important insights into the long-term neuropathology of traumatic brain injury (TBI). This is urgently required to identify mechanistic processes underlying post-traumatic neurodegeneration (PTND); a progressive post-recovery clinical decline experienced by a portion of TBI survivors. The aim of this study was to examine change over time in protein levels in a chronic TBI cohort. We selected six markers (Aβ 42 /Aβ 40 , GFAP, NfL, BD-tau, p-tau231, and p-tau181) with known importance in acute TBI and/or other neurodegenerative conditions. We used a longitudinal design with two time points approximately 3.5 years apart on average (SD 1.34). Proteins were measured in plasma using the ultrasensitive Single molecule array technology for 63 participants with mild to severe chronic TBI (sustained ≥ 1 year ago; M 28 years; SD 16.3 since their first blow to the head) from the Late Effects of TBI study (48% female; current age M 52 years; SD 13.4). Multivariate linear mixed effect models with adjustments for multiple comparisons were performed to examine trajectories in proteins over time with age and age squared as covariates. A series of sensitivity analyses were conducted to account for outliers and to explore effects of key covariates: sex, APOE ε4 carrier status, medical comorbidities, age at first blow to the head, time since first blow to the head, and injury severity. Over an average of 3.5 years, there were significant reductions in plasma Aβ 42 /Aβ 40 (β = -0.004, SE = 0.001, t = -3.75, q = .001) and significant increases in plasma GFAP (β = 12.96, SE = 4.41, t = 2.94, q = .01). There were no significant changes in NFL, BD-tau, p-tau231, or p-tau181. Both plasma Aβ 42 /Aβ 40 and GFAP have been associated with brain amyloidosis, suggesting a role for Aβ mis-metabolism and aggregation in the long-term neuropathological consequences of TBI. These findings are hypothesis generating for future studies exploring the diverse biological mechanisms of PTND.

{"title":"Trajectories of blood-based protein biomarkers in chronic traumatic brain injury.","authors":"Amelia J Hicks, Jay Plourde, Enna Selmanovic, Nicola L de Souza, Kaj Blennow, Henrik Zetterberg, Kristen Dams-O'Connor","doi":"10.1101/2025.02.16.25322303","DOIUrl":"https://doi.org/10.1101/2025.02.16.25322303","url":null,"abstract":"<p><p>Blood-based protein biomarkers may provide important insights into the long-term neuropathology of traumatic brain injury (TBI). This is urgently required to identify mechanistic processes underlying post-traumatic neurodegeneration (PTND); a progressive post-recovery clinical decline experienced by a portion of TBI survivors. The aim of this study was to examine change over time in protein levels in a chronic TBI cohort. We selected six markers (Aβ <sub>42</sub> /Aβ <sub>40</sub> , GFAP, NfL, BD-tau, p-tau231, and p-tau181) with known importance in acute TBI and/or other neurodegenerative conditions. We used a longitudinal design with two time points approximately 3.5 years apart on average (SD 1.34). Proteins were measured in plasma using the ultrasensitive Single molecule array technology for 63 participants with mild to severe chronic TBI (sustained ≥ 1 year ago; M 28 years; SD 16.3 since their first blow to the head) from the Late Effects of TBI study (48% female; current age M 52 years; SD 13.4). Multivariate linear mixed effect models with adjustments for multiple comparisons were performed to examine trajectories in proteins over time with age and age squared as covariates. A series of sensitivity analyses were conducted to account for outliers and to explore effects of key covariates: sex, <i>APOE</i> ε4 carrier status, medical comorbidities, age at first blow to the head, time since first blow to the head, and injury severity. Over an average of 3.5 years, there were significant reductions in plasma Aβ <sub>42</sub> /Aβ <sub>40</sub> (β = -0.004, SE = 0.001, t = -3.75, q = .001) and significant increases in plasma GFAP (β = 12.96, SE = 4.41, t = 2.94, q = .01). There were no significant changes in NFL, BD-tau, p-tau231, or p-tau181. Both plasma Aβ <sub>42</sub> /Aβ <sub>40</sub> and GFAP have been associated with brain amyloidosis, suggesting a role for Aβ mis-metabolism and aggregation in the long-term neuropathological consequences of TBI. These findings are hypothesis generating for future studies exploring the diverse biological mechanisms of PTND.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11875239/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143545590","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
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medRxiv : the preprint server for health sciences
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