medRxiv : the preprint server for health sciences最新文献

{"title":"Measuring changes in <i>Plasmodium falciparum</i> census population size in response to sequential malaria control interventions.","authors":"Kathryn E Tiedje, Qi Zhan, Shazia Ruybal-Pesantez, Gerry Tonkin-Hill, Qixin He, Mun Hua Tan, Dionne C Argyropoulos, Samantha L Deed, Anita Ghansah, Oscar Bangre, Abraham R Oduro, Kwadwo A Koram, Mercedes Pascual, Karen P Day","doi":"10.1101/2023.05.18.23290210","DOIUrl":"10.1101/2023.05.18.23290210","url":null,"abstract":"<p><p>Here we introduce a new endpoint ″census population size″ to evaluate the epidemiology and control of <i>Plasmodium falciparum</i> infections, where the parasite, rather than the infected human host, is the unit of measurement. To calculate census population size, we rely on a definition of parasite variation known as multiplicity of infection (MOI _<i>var</i> ), based on the hyper-diversity of the <i>var</i> multigene family. We present a Bayesian approach to estimate MOI _<i>var</i> from sequencing and counting the number of unique DBLα tags (or DBLα types) of <i>var</i> genes, and derive from it census population size by summation of MOI _<i>var</i> in the human population. We track changes in this parasite population size and structure through sequential malaria interventions by indoor residual spraying (IRS) and seasonal malaria chemoprevention (SMC) from 2012 to 2017 in an area of high-seasonal malaria transmission in northern Ghana. Following IRS, which reduced transmission intensity by > 90% and decreased parasite prevalence by ~40-50%, significant reductions in <i>var</i> diversity, MOI _<i>var</i> , and population size were observed in ~2,000 humans across all ages. These changes, consistent with the loss of diverse parasite genomes, were short lived and 32-months after IRS was discontinued and SMC was introduced, <i>var</i> diversity and population size rebounded in all age groups except for the younger children (1-5 years) targeted by SMC. Despite major perturbations from IRS and SMC interventions, the parasite population remained very large and retained the <i>var</i> population genetic characteristics of a high-transmission system (high <i>var</i> diversity; low <i>var</i> repertoire similarity) demonstrating the resilience of <i>P. falciparum</i> to short-term interventions in high-burden countries of sub-Saharan Africa.</p>","PeriodicalId":18659,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/2d/26/nihpp-2023.05.18.23290210v2.PMC10246142.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10371859","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}

{"title":"Pan-cancer mutational signature analysis of 111,711 targeted sequenced tumors using SATS.","authors":"Donghyuk Lee, Min Hua, Difei Wang, Lei Song, Tongwu Zhang, Xing Hua, Kai Yu, Xiaohong R Yang, Stephen J Chanock, Jianxin Shi, Maria Teresa Landi, Bin Zhu","doi":"10.1101/2023.05.18.23290188","DOIUrl":"10.1101/2023.05.18.23290188","url":null,"abstract":"<p><p>Tumor mutational signatures are informative for cancer diagnosis and treatment. However, targeted sequencing, commonly used in clinical settings, lacks specialized analytical tools and a dedicated catalogue of mutational signatures. Here, we introduce SATS, a scalable mutational signature analyzer for targeted sequencing data. SATS leverages tumor mutational burdens to identify and quantify signatures in individual tumors, overcoming the challenges of sparse mutations and variable gene panels. Validations across simulated data, pseudo-targeted sequencing data, and matched whole-genome and targeted sequencing samples show that SATS can accurately detect common mutational signatures and estimate their burdens. Applying SATS to 111,711 tumors from the AACR Project GENIE, we created a pan-cancer mutational signature catalogue specific to targeted sequencing. We further validated signatures in lung, breast and colorectal cancers using an additional 16,774 independent samples. This signature catalogue is a valuable resource for estimating signature burdens in individual targeted sequenced tumors, facilitating the integration of mutational signatures with clinical data.</p>","PeriodicalId":18659,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10327246/pdf/nihpp-2023.05.18.23290188v1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9807255","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}

{"title":"Associations of longitudinal BMI percentile classification patterns in early childhood with neighborhood-level social determinants of health.","authors":"Mehak Gupta, Thao-Ly T Phan, Félice Lê-Scherban, Daniel Eckrich, H Timothy Bunnell, Rahmatollah Beheshti","doi":"10.1101/2023.06.08.23291145","DOIUrl":"10.1101/2023.06.08.23291145","url":null,"abstract":"<p><strong>Background: </strong>Understanding social determinants of health (SDOH) that may be risk factors for childhood obesity is important to developing targeted interventions to prevent obesity. Prior studies have examined these risk factors, mostly examining obesity as a static outcome variable.</p><p><strong>Methods: </strong>We extracted EHR data from 2012-2019 for a children's health system that includes 2 hospitals and wide network of outpatient clinics spanning 5 East Coast states in the US. Using data-driven and algorithmic clustering, we have identified distinct BMI-percentile classification groups in children from 0 to 7 years of age. We used two separate algorithmic clustering methods to confirm the robustness of the identified clusters. We used multinomial logistic regression to examine the associations between clusters and 27 neighborhood SDOHs and compared positive and negative SDOH characteristics separately.</p><p><strong>Results: </strong>From the cohort of 36,910 children, five BMI-percentile classification groups emerged: always having obesity (n=429; 1.16%), overweight most of the time (n=15,006; 40.65%), increasing BMI-percentile (n=9,060; 24.54%), decreasing BMI-percentile (n=5,058; 13.70%), and always normal weight (n=7,357; 19.89%). Compared to children in the decreasing BMI-percentile and always normal weight groups, children in the other three groups were more likely to live in neighborhoods with higher poverty, unemployment, crowded households, single-parent households, and lower preschool enrollment.</p><p><strong>Conclusions: </strong>Neighborhood-level SDOH factors have significant associations with children's BMI-percentile classification and changes in classification. This highlights the need to develop tailored obesity interventions for different groups to address the barriers faced by communities that can impact the weight and health of children living within them.</p><p><strong>Impact statement: </strong>This study demonstrates the association between longitudinal BMI-percentile patterns and SDOH in early childhood. Five distinct clusters with different BMI-percentile trajectories are found and a strong association between these clusters and SDOH is observed. Our findings highlight the importance of targeted prevention and treatment interventions based on children's SDOH.</p>","PeriodicalId":18659,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/cb/85/nihpp-2023.06.08.23291145v1.PMC10312866.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10122268","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}

{"title":"A Large-Scale Proteomics Resource of Circulating Extracellular Vesicles for Biomarker Discovery in Pancreatic Cancer.","authors":"Bruno Bockorny, Lakshmi Muthuswamy, Ling Huang, Marco Hadisurya, Christine Maria Lim, Leo L Tsai, Ritu R Gill, Jesse L Wei, Andrea J Bullock, Joseph E Grossman, Robert J Besaw, Supraja Narasimhan, W Andy Tao, Sofia Perea, Mandeep S Sawhney, Steven D Freedman, Manuel Hidalgo, Anton Iliuk, Senthil K Muthuswamy","doi":"10.1101/2023.03.13.23287216","DOIUrl":"10.1101/2023.03.13.23287216","url":null,"abstract":"<p><p>Pancreatic cancer has the worst prognosis of all common tumors. Earlier cancer diagnosis could increase survival rates and better assessment of metastatic disease could improve patient care. As such, there is an urgent need to develop biomarkers to diagnose this deadly malignancy. Analyzing circulating extracellular vesicles (cEVs) using 'liquid biopsies' offers an attractive approach to diagnose and monitor disease status. However, it is important to differentiate EV-associated proteins enriched in patients with pancreatic ductal adenocarcinoma (PDAC) from those with benign pancreatic diseases such as chronic pancreatitis and intraductal papillary mucinous neoplasm (IPMN). To meet this need, we combined the novel EVtrap method for highly efficient isolation of EVs from plasma and conducted proteomics analysis of samples from 124 individuals, including patients with PDAC, benign pancreatic diseases and controls. On average, 912 EV proteins were identified per 100µL of plasma. EVs containing high levels of PDCD6IP, SERPINA12 and RUVBL2 were associated with PDAC compared to the benign diseases in both discovery and validation cohorts. EVs with PSMB4, RUVBL2 and ANKAR were associated with metastasis, and those with CRP, RALB and CD55 correlated with poor clinical prognosis. Finally, we validated a 7-EV protein PDAC signature against a background of benign pancreatic diseases that yielded an 89% prediction accuracy for the diagnosis of PDAC. To our knowledge, our study represents the largest proteomics profiling of circulating EVs ever conducted in pancreatic cancer and provides a valuable open-source atlas to the scientific community with a comprehensive catalogue of novel cEVs that may assist in the development of biomarkers and improve the outcomes of patients with PDAC.</p>","PeriodicalId":18659,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10055460/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9274949","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}

{"title":"United States' qualifying conditions compared to evidence of the 2017 National Academy of Sciences Report.","authors":"Elena L Stains, Amy L Kennalley, Maria Tian, Kevin F Boehnke, Chadd K Kraus, Brian J Piper","doi":"10.1101/2023.05.01.23289286","DOIUrl":"10.1101/2023.05.01.23289286","url":null,"abstract":"<p><strong>Objective: </strong>To compare the 2017 National Academies of Sciences, Engineering, and Medicine (NAS) report to state medical cannabis (MC) laws defining approved qualifying conditions (QC) from 2017 to 2024 and to determine if there exist gaps in evidence-based decision making.</p><p><strong>Methods: </strong>The 2017 NAS report assessed therapeutic evidence for over twenty medical conditions treated with MC. We identified the QCs of 38 states (including Washington, D.C.) where MC was legal in 2024. We also identified the QCs that these states used in 2017. QCs were then categorized based on NAS-established level of evidence: substantial/conclusive evidence of effectiveness, moderate evidence of effectiveness, limited evidence of effectiveness, limited evidence of ineffectiveness, and no/insufficient evidence to support or refute effectiveness. This study was completed between January 31, 2023 through May 20, 2024.</p><p><strong>Results: </strong>Most states listed at least one QC with substantial evidence-80.0% of states in 2017 and 97.0% in 2024. However, in 2024 only 8.3% of the QCs on states' QC lists met the standard of substantial evidence. Of the 20 most popular QCs in the country in 2017 and 2024, one only (chronic pain) was categorized by the NAS as having substantial evidence for effectiveness. However, seven (ALS, Alzheimer's disease, epilepsy, glaucoma, Huntington's disease, Parkinson's disease, spastic spinal cord damage) were rated as either ineffective or insufficient evidence.</p><p><strong>Conclusion: </strong>Most QCs lack evidence for use based on the 2017 NAS report. Many states recommend QCs with little evidence, such as amyotrophic lateral sclerosis (ALS), or even those for which MC is ineffective, like depression. There have been insufficient updates to QCs since the NAS report. These findings highlight a disparity between state-level MC recommendations and the evidence to support them.</p>","PeriodicalId":18659,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10197720/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9858876","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}

{"title":"Increased frequency of repeat expansion mutations across different populations.","authors":"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","doi":"10.1101/2023.07.03.23292162","DOIUrl":"10.1101/2023.07.03.23292162","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":18659,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/49/9d/nihpp-2023.07.03.23292162v1.PMC10350132.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10214583","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}

{"title":"GRPa-PRS: A risk stratification method to identify genetically-regulated pathways in polygenic diseases.","authors":"Xiaoyang Li, Brisa S Fernandes, Andi Liu, Jingchun Chen, Xiangning Chen, Zhongming Zhao, Yulin Dai","doi":"10.1101/2023.06.19.23291621","DOIUrl":"10.1101/2023.06.19.23291621","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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 <i>APOE</i> 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).</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":18659,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/fb/59/nihpp-2023.06.19.23291621v1.PMC10327215.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9811433","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}

{"title":"The effect of combining antibiotics on resistance: A systematic review and meta-analysis.","authors":"Berit Siedentop, Viacheslav N Kachalov, Christopher Witzany, Matthias Egger, Roger D Kouyos, Sebastian Bonhoeffer","doi":"10.1101/2023.07.10.23292374","DOIUrl":"10.1101/2023.07.10.23292374","url":null,"abstract":"<p><p>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 24^th, 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>I</i> ^<i>2</i> =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.</p>","PeriodicalId":18659,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/1f/7b/nihpp-2023.07.10.23292374v1.PMC10370225.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9932673","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}

{"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^-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.</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}

{"title":"Long-term exposure to wildland fire smoke PM_2.5 and mortality in the contiguous United States.","authors":"Yiqun Ma, Emma Zang, Yang Liu, Jing Wei, Yuan Lu, Harlan M Krumholz, Michelle L Bell, Kai Chen","doi":"10.1101/2023.01.31.23285059","DOIUrl":"10.1101/2023.01.31.23285059","url":null,"abstract":"<p><p>Despite the substantial evidence on the health effects of short-term exposure to ambient fine particles (PM_2.5), including increasing studies focusing on those from wildland fire smoke, the impacts of long-term wildland fire smoke PM_2.5 exposure remain unclear. We investigated the association between long-term exposure to wildland fire smoke PM_2.5 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 PM_2.5, air temperature, and unmeasured spatial and temporal confounders, we found a non-linear association between 12-month moving average concentration of smoke PM_2.5 and monthly non-accidental mortality rate. Relative to a month with the long-term smoke PM_2.5 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 PM_2.5 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 PM_2.5 exposure. Smoke PM_2.5 contributed to approximately 11,415 non-accidental deaths/year (95% CI: 6,754, 16,075) in the contiguous U.S. Higher smoke PM_2.5-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 90^th percentile warm season air temperature) were also observed. Our study identified the detrimental effects of long-term exposure to wildland fire smoke PM_2.5 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.</p>","PeriodicalId":18659,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/c6/37/nihpp-2023.01.31.23285059v1.PMC9915814.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10802212","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}