BACKGROUND: Multiple sclerosis is a chronic immune-mediated disease of the brain and spinal cord resulting in physical and cognitive impairment in young adults. It is hypothesized that a disrupted bacterial and viral gut microbiota is a part of the pathogenesis mediating disease impact through an altered gut microbiota-brain axis. The aim of this study is to explore the characteristics of gut microbiota in multiple sclerosis and to associate it with disease variables, as the etiology of the disease remains only partially known. METHODS: Here, in a case-control setting involving 148 Danish cases with multiple sclerosis and 148 matched healthy control subjects, we performed shotgun sequencing of fecal microbial DNA and associated bacterial and viral microbiota findings with plasma cytokines, blood cell gene expression profiles, and disease activity. RESULTS: We found 61 bacterial species that were differentially abundant when comparing all multiple sclerosis cases with healthy controls, among which 31 species were enriched in cases. A cluster of inflammation markers composed of blood leukocytes, CRP, and blood cell gene expression of IL17A and IL6 was positively associated with a cluster of multiple sclerosis-related species. Bacterial species that were more abundant in cases with disease-active treatment-naïve multiple sclerosis were positively linked to a group of plasma cytokines including IL-22, IL-17A, IFN-β, IL-33, and TNF-α. The bacterial species richness of treatment-naïve multiple sclerosis cases was associated with number of relapses over a follow-up period of 2 years. However, in non-disease-active cases, we identified two bacterial species, Faecalibacterium prausnitzii and Gordonibacter urolithinfaciens, whose absolute abundance was enriched. These bacteria are known to produce anti-inflammatory metabolites including butyrate and urolithin. In addition, cases with multiple sclerosis had a higher viral species diversity and a higher abundance of Caudovirales bacteriophages. CONCLUSIONS: Considerable aberrations are present in the gut microbiota of patients with multiple sclerosis that are directly associated with blood biomarkers of inflammation, and in treatment-naïve cases bacterial richness is positively associated with disease activity. Yet, the finding of two symbiotic bacterial species in non-disease-active cases that produce favorable immune-modulating compounds provides a rationale for testing these bacteria as adjunct therapeutics in future clinical trials.

BACKGROUND: Rare diseases collectively impose a significant burden on healthcare systems, especially in underserved regions, like the Middle East, which lack access to genomic diagnostic services and the associated personalized management plans. METHODS: We established a clinical genomics and genetic counseling facility, within a multidisciplinary tertiary pediatric center, in the United Arab Emirates to locally diagnose and manage patients with rare diseases. Clinical genomic investigations included exome-based sequencing, chromosomal microarrays, and/or targeted testing. We assessed the diagnostic yield and implications for clinical management among this population. Variables were compared using the Fisher exact test. Tests were 2-tailed, and P < .05 was considered statistically significant. RESULTS: We present data on 1000 patients with rare diseases (46.2% females; average age, 4.6 years) representing 47 countries primarily from the Arabian Peninsula, the Levant, Africa, and Asia. The cumulative diagnostic yield was 32.5% (95% CI, 29.7-35.5%) and was higher for genomic sequencing-based testing than chromosomal microarrays (37.9% versus 17.2%, P = 0.0001) across all indications, consistent with the higher burden of single gene disorders. Of the 221 Mendelian disorders identified in this cohort, the majority (N = 184) were encountered only once, and those with recessive inheritance accounted for ~ 62% of sequencing diagnoses. Of patients with positive genetic findings (N = 325), 67.7% were less than 5 years of age, and 60% were offered modified management and/or intervention plans. Interestingly, 24% of patients with positive genetic findings received delayed diagnoses (average age, 12.4 years; range 7-37 years), most likely due to a lack of access to genomic investigations in this region. One such genetic finding ended a 15-year-long diagnostic odyssey, leading to a life-threatening diagnosis in one patient, who was then successfully treated using an experimental allogenic bone marrow transplant. Finally, we present cases with candidate genes within regions of homozygosity, likely underlying novel recessive disorders. CONCLUSIONS: Early access to genomic diagnostics for patients with suspected rare disorders in the Middle East is likely to improve clinical outcomes while driving gene discovery in this genetically underrepresented population.

Alzheimer's disease (AD) is a genetically complex and heterogeneous disorder with multifaceted neuropathological features, including β-amyloid plaques, neurofibrillary tangles, and neuroinflammation. Over the past decade, emerging evidence has implicated both beneficial and pathological roles for innate immune genes and immune cells, including peripheral immune cells such as T cells, which can infiltrate the brain and either ameliorate or exacerbate AD neuropathogenesis. These findings support a neuroimmune axis of AD, in which the interplay of adaptive and innate immune systems inside and outside the brain critically impacts the etiology and pathogenesis of AD. In this review, we discuss the complexities of AD neuropathology at the levels of genetics and cellular physiology, highlighting immune signaling pathways and genes associated with AD risk and interactions among both innate and adaptive immune cells in the AD brain. We emphasize the role of peripheral immune cells in AD and the mechanisms by which immune cells, such as T cells and monocytes, influence AD neuropathology, including microglial clearance of amyloid-β peptide, the key component of β-amyloid plaque cores, pro-inflammatory and cytotoxic activity of microglia, astrogliosis, and their interactions with the brain vasculature. Finally, we review the challenges and outlook for establishing immune-based therapies for treating and preventing AD.

Author information: (1)Institute of Health Informatics, University College London, London, UK. (2)Division of Psychiatry, University College London, London, UK. (3)Biostatistics Unit, The Cyprus Institute of Neurology and Genetics, 2371, Nicosia, Cyprus. (4)Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, 2371, Nicosia, Cyprus. (5)Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK. (6)Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, 35254, Haifa, Israel. (7)Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20850, USA. (8)Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada. (9)Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada. (10)Department of Medicine, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, CA, 92617, USA. (11)N.N. Alexandrov Research Institute of Oncology and Medical Radiology, 223040, Minsk, Belarus. (12)Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany. (13)Department of Public Health Sciences, and Cancer Research Institute, Queen's University, Kingston, ON, K7L 3N6, Canada. (14)Department of Cancer Epidemiology, Clinical Sciences, Lund University, 222 42, Lund, Sweden. (15)Leuven Multidisciplinary Breast Center, Department of Oncology, Leuven Cancer Institute, University Hospitals Leuven, 3000, Louvain, Belgium. (16)Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg (FAU), 91054, Erlangen, Germany. (17)Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany. (18)Biomedical Network On Rare Diseases (CIBERER), 28029, Madrid, Spain. (19)Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), 28029, Madrid, Spain. (20)Institute of Biochemistry and Genetics, Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, 450054, Russia. (21)Department of Oncology, Helsinki University Hospital, University of Helsinki, 00290, Helsinki, Finland. (22)Department of Oncology, Örebro University Hospital, 70185, Örebro, Sweden. (23)Department of Radiation Oncology, Hannover Medical School, 30625, Hannover, Germany. (24)Gynaecology Research Unit, Hannover Medical School, 30625, Hannover, Germany. (25)Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, 2730, Herlev, Denmark. (26)Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, 2730, Herlev, Denmark. (27)Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark. (28)Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology IRCCS, 20141, Milan, Italy. (29)Division of Preventive Oncology, German Cancer Research Center (DKFZ), National Center for Tumor Diseases (NCT), 69120, Heidelberg, Germany. (30)German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany. (31)Department of Gynecology and Obstetrics, University of Tübingen, 72076, Tübingen, Germany. (32)Department of Medicine, Huntsman Cancer Institute, Salt Lake City, UT, 84112, USA. (33)Oncology and Genetics Unit, Instituto de Investigación Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, 36312, Vigo, Spain. (34)Hong Kong Hereditary Breast Cancer Family Registry, Hong Kong, China. (35)Department of Molecular Pathology, Hong Kong Sanatorium and Hospital, Hong Kong, China. (36)Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany. (37)Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, 03080, Korea. (38)Cancer Research Institute, Seoul National University, Seoul, 03080, Korea. (39)Institute of Health Policy and Management, Seoul National University Medical Research Center, Seoul, 03080, Korea. (40)Departments of Pediatrics and Medicine, Columbia University, New York, NY, 10032, USA. (41)Division of Molecular Pathology, The Netherlands Cancer Institute - Antoni Van Leeuwenhoek Hospital, Amsterdam, 1066 CX, The Netherlands. (42)Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA. (43)Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 65, Stockholm, Sweden. (44)Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA. (45)Department of Pathology, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands. (46)Department of Human Genetics, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands. (47)Nutrition and Metabolism Section, International Agency for Research On Cancer (IARC-WHO), 69372, Lyon, France. (48)School of Life Sciences, University of Westminster, London, W1W 6UW, UK. (49)Faculty of Medicine, University of Southampton, Southampton, SO17 1BJ, UK. (50)Institute of Human Genetics, Comprehensive Cancer Center Erlangen-EMN, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg (FAU), 91054, Erlangen, Germany. (51)Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA. (52)Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA. (53)Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA. (54)Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, 04107, Leipzig, Germany. (55)LIFE - Leipzig Research Centre for Civilization Diseases, University of Leipzig, 04103, Leipzig, Germany. (56)Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, M13 9WL, UK. (57)North West Genomics Laboratory Hub, Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, M13 9WL, UK. (58)David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, CA, 90095, USA. (59)The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, SW7 3RP, UK. (60)Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, 2730, Herlev, Denmark. (61)Genomic Medicine Group, International Cancer Genetics and Epidemiology Group, Fundación Pœblica Galega de Medicina Xenómica, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, 15706, Santiago de Compostela, Spain. (62)Moores Cancer Center, University of California San Diego, La Jolla, CA, 92037, USA. (63)Department of Epidemiology, Shanghai Cancer Institute, Shanghai, 20032, China. (64)Medical Oncology Department, Centro Investigación Biomédica en Red de Cáncer (CIBERONC), Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), 28040, Madrid, Spain. (65)Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, 10032, USA. (66)Institute of Clinical Trials and Methodology, University College London, London, WC1V 6LJ, UK. (67)Health and Medical University, 14471, Potsdam, Germany. (68)Center for Research in Epidemiology and Population Health (CESP), Team Exposome and Heredity, INSERM, University Paris-Saclay, 94805, Villejuif, France. (69)Molecular Epidemiology Group, German Cancer Research Center (DKFZ), C08069120, Heidelberg, Germany. (70)Molecular Biology of Breast Cancer, University Womens Clinic Heidelberg, University of Heidelberg, 69120, Heidelberg, Germany. (71)Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764, Neuherberg, Germany. (72)Center for Familial Breast and Ovarian Cancer, Faculty of Medicine, University Hospital Cologne, University of Cologne, 50937, Cologne, Germany. (73)Center for Integrated Oncology (CIO), Faculty of Medicine, University Hospital Cologne, University of Cologne, 50937, Cologne, Germany. (74)Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA. (75)Institute of Environmental Medicine, Karolinska Institutet, 171 77, Stockholm, Sweden. (76)Department of Oncology, 118 83, Sšdersjukhuset, Stockholm, Sweden. (77)Division of Informatics, Imaging and Data Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, M13 9PT, UK. (78)Nightingale and Genesis Prevention Centre, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, M23 9LT, UK. (79)NIHR Manchester Biomedical Research Unit, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, M13 9WL, UK. (80)Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, CB1 8RN, UK. (81)Translational Cancer Research Area, University of Eastern Finland, 70210, Kuopio, Finland. (82)Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, 70210, Kuopio, Finland. (83)Saw Swee Hock School of Public Health, National University of Singapore, National University Health System, Singapore, 119077, Singapore. (84)Department of Surgery, National University Health System, Singapore, 119228, Singapore. (85)Department of Mathematical Sciences, Faculty of Science and Engineering, University of Nottingham Malaysia Campus, 43500, Semenyih, Selangor, Malaysia. (86)Breast Cancer Research Programme, Cancer Research Malaysia, Subang Jaya, 47500, Selangor, Malaysia. (87)Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, 3015 GD, The Netherlands. (88)Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, 70376, Stuttgart, Germany. (89)University of Tübingen, 72074, Tübingen, Germany. (90)Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, 3010, Australia. (91)Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SM2 5NG, UK. (92)Division of Cancer Sciences, University of Manchester, Manchester, M13 9PL, UK. (93)Nuffield Department of Population Health, University of Oxford, Oxford, OX3 7LF, UK. (94)Center for Clinical Cancer Genetics, The University of Chicago, Chicago, IL, 60637, USA. (95)Division of Cancer Information and Control, Aichi Cancer Center Research Institute, Nagoya, 464-8681, Japan. (96)Division of Cancer Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan. (97)Division of Epidemiology, Center for Public Health Sciences, National Cancer Center Institute for Cancer Control, Tokyo, 104-0045, Japan. (98)Department of Genetics and Pathology, Pomeranian Medical University, 71-252, Szczecin, Poland. (99)Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, 71-252, Szczecin, Poland. (100)Department of Gynaecology and Obstetrics, University Hospital Ulm, 89075, Ulm, Germany. (101)Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA, 94305, USA. (102)Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, 94304, USA. (103)Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, 03080, Korea. (104)Department of Genetics and Fundamental Medicine, Bashkir State University, Ufa, 450000, Russia. (105)Department of Surgery, Daerim Saint Mary's Hospital, Seoul, 07442, Korea. (106)Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, 20892, USA. (107)Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA. (108)Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0450, Oslo, Norway. (109)Department of Medical Genetics, Oslo University Hospital and University of Oslo, 0379, Oslo, Norway. (110)Department of Histopathology and Cytology, Clinical Hospital Acibadem Sistina, Skopje, 1000, Republic of North Macedonia. (111)Department of Surgery, The University of Hong Kong, Hong Kong, China. (112)Department of Surgery and Cancer Genetics Center, Hong Kong Sanatorium and Hospital, Hong Kong, China. (113)Department of Computational and Quantitative Medicine, City of Hope, Duarte, CA, 91010, USA. (114)City of Hope Comprehensive Cancer Center, City of Hope, Duarte, CA, 91010, USA. (115)VIB Center for Cancer Biology, 3001, Louvain, Belgium. (116)Laboratory for Translational Genetics, Department of Human Genetics, University of Leuven, 3000, Louvain, Belgium. (117)Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, 96813, USA. (118)Human Genetics Division, Genome Institute of Singapore, Singapore, 138672, Singapore. (119)Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA. (120)Division of Population Health, Health Services Research and Primary Care, School of Health Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, M13 9PL, UK. (121)Biobank of Eastern Finland, Kuopio University Hospital, Kuopio, Finland. (122)Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany. (123)Department of Clinical Science and Education, Sšdersjukhuset, Karolinska Institutet, 118 83, Stockholm, Sweden. (124)Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, 464-8681, Japan. (125)Department of Medical Oncology, University Hospital of Heraklion, 711 10, Heraklion, Greece. (126)School of Population and Public Health, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada. (127)Cancer Control Research, BC Cancer, Vancouver, BC, V5Z 1L3, Canada. (128)Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, 00290, Helsinki, Finland. (129)Department of Gynecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, 40225, Düsseldorf, Germany. (130)Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, 27709, USA. (131)Institute for Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany. (132)Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. (133)Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. (134)Department of Epidemiology, Gillings School of Global Public Health and UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. (135)Integrated Major in Innovative Medical Science, Seoul National University College of Medicine, Seoul, 03080, South Korea. (136)Department of Population Science, American Cancer Society, Atlanta, GA, 30303, USA. (137)Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. (138)Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK. (139)Research Centre for Genetic Engineering and Biotechnology "Georgi D. Efremov", MASA, Skopje, 1000, Republic of North Macedonia. (140)Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale Dei Tumori (INT), 20133, Milan, Italy. (141)Department of Basic Sciences, Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH & RC), Lahore, 54000, Pakistan. (142)Medical Oncology Department, Hospital Universitario Puerta de Hierro, 28222, Madrid, Spain. (143)Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA. (144)Department of Oncology, University Hospital of Larissa, 411 10, Larissa, Greece. (145)School of Cancer and Pharmaceutical Sciences, Comprehensive Cancer Centre, Guy's Campus, King's College London, London, SE1 9RT, UK. (146)Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute - Antoni Van Leeuwenhoek Hospital, Amsterdam, 1066 CX, The Netherlands. (147)Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany. (148)Department of Health Sciences Research, Mayo Clinic, Rochester, MN, 55905, USA. (149)Department of Internal Medicine, Division of Medical Oncology, University of Kansas Medical Center, Westwood, KS, 66205, USA. (150)Institute of Biomedical Sciences, Academia Sinica, Taipei, 115, Taiwan. (151)School of Public Health, China Medical University, Taichung, Taiwan. (152)Genomics Center, Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Québec City, QC, G1V 4G2, Canada. (153)Department of Population Health Sciences, Weill Cornell Medicine, New York, NY, 10065, USA. (154)Epigenetic and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, 27709, USA. (155)Department of Surgery, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia. (156)Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, 43210, USA. (157)Department of Surgery, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands. (158)Institute of Human Genetics, Pontificia Universidad Javeriana, 110231, Bogota, Colombia. (159)Center for Population Health Research, National Institute of Public Health, 62100, Cuernavaca, Morelos, Mexico. (160)Department of Quantitative Health Sciences, Division of Epidemiology, Mayo Clinic, Rochester, MN, 55905, USA. (161)Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, 27709, USA. (162)Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, 90570, Oulu, Finland. (163)Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre Oulu, 90570, Oulu, Finland. (164)Department of Surgical Sciences, Uppsala University, 751 05, Uppsala, Sweden. (165)Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, 114, Taiwan. (166)Department of Medicine, Diller Family Comprehensive Cancer Center, Institute for Human Genetics, UCSF Helen, University of California San Francisco, San Francisco, CA, 94115, USA. (167)Health Data Research UK, University College London, London, UK. (168)University College London Hospitals Biomedical Research Centre (UCLH BRC), London, UK. (169)The Alan Turing Institute, London, UK. (170)Division of Psychiatry, University College London, London, UK. k.kuchenbaecker@ucl.ac.uk. (171)UCL Genetics Institute, University College London, London, UK. k.kuchenbaecker@ucl.ac.uk. (#)Contributed equally

BACKGROUND: The genetic architectures of colorectal cancer are distinct across different populations. To date, the majority of polygenic risk scores (PRSs) are derived from European (EUR) populations, which limits their accurate extrapolation to other populations. Here, we aimed to generate a PRS by incorporating East Asian (EAS) and EUR ancestry groups and validate its utility for colorectal cancer risk assessment among different populations. METHODS: A large-scale colorectal cancer genome-wide association study (GWAS), harboring 35,145 cases and 288,934 controls from EAS and EUR populations, was used for the EAS-EUR GWAS meta-analysis and the construction of candidate EAS-EUR PRSs via different approaches. The performance of each PRS was then validated in external GWAS datasets of EAS (727 cases and 1452 controls) and EUR (1289 cases and 1284 controls) ancestries, respectively. The optimal PRS was further tested using the UK Biobank longitudinal cohort of 355,543 individuals and ultimately applied to stratify individual risk attached by healthy lifestyle. RESULTS: In the meta-analysis across EAS and EUR populations, we identified 48 independent variants beyond genome-wide significance (P < 5 × 10-8) at previously reported loci. Among 26 candidate EAS-EUR PRSs, the PRS-CSx approach-derived PRS (defined as PRSCSx) that harbored genome-wide variants achieved the optimal discriminatory ability in both validation datasets, as well as better performance in the EAS population compared to the PRS derived from known variants. Using the UK Biobank cohort, we further validated a significant dose-response effect of PRSCSx on incident colorectal cancer, in which the risk was 2.11- and 3.88-fold higher in individuals with intermediate and high PRSCSx than in the low score subgroup (Ptrend = 8.15 × 10-53). Notably, the detrimental effect of being at a high genetic risk could be largely attenuated by adherence to a favorable lifestyle, with a 0.53% reduction in 5-year absolute risk. CONCLUSIONS: In summary, we systemically constructed an EAS-EUR PRS to effectively stratify colorectal cancer risk, which highlighted its clinical implication among diverse ancestries. Importantly, these findings also supported that a healthy lifestyle could reduce the genetic impact on incident colorectal cancer.

BACKGROUND: Klebsiella pneumoniae (Kp) Gram-negative bacteria cause nosocomial infections and rapidly acquire antimicrobial resistance (AMR), which makes it a global threat to human health. It also has a comparatively rare hypervirulent phenotype that can lead to severe disease in otherwise healthy individuals. Unlike classic Kp, canonical hypervirulent strains usually have limited AMR. However, after initial case reports in 2015, carbapenem-resistant hypervirulent Kp has increased in prevalence, including in China, but there is limited understanding of its burden  in other geographical regions. METHODS: Here, we examined the largest collection of publicly available sequenced Kp isolates (n=13,178), containing 1603 different sequence types (e.g. ST11 15.0%, ST258 9.5%), and 2174 (16.5%) hypervirulent strains. We analysed the plasmid replicons and carbapenemase and siderophore encoding genes to understand the movement of hypervirulence and AMR genes located on plasmids, and their convergence in carbapenem-resistant hypervirulent Kp. RESULTS: We identified and analysed 3034 unique plasmid replicons to inform the epidemiology and transmission dynamics of carbapenem-resistant hypervirulent Kp (n=1028, 7.8%). We found several outbreaks globally, including one involving ST11 strains in China and another of ST231 in Asia centred on India, Thailand, and Pakistan. There was evidence of global flow of Kp, including across multiple continents. In most cases, clusters of Kp isolates are the result of hypervirulence genes entering classic strains, instead of carbapenem resistance genes entering canonical hypervirulent ones. CONCLUSIONS: Our analysis demonstrates the importance of plasmid analysis in the monitoring of carbapenem-resistant and hypervirulent strains of Kp. With the growing adoption of omics-based technologies for clinical and surveillance applications, including in geographical regions with gaps in data and knowledge (e.g. sub-Saharan Africa), the identification of the spread of AMR will inform infection control globally.

BACKGROUND: Diabetic nephropathy (DN) is the leading cause of end-stage renal disease, and histopathologic glomerular lesions are among the earliest structural alterations of DN. However, the signaling pathways that initiate these glomerular alterations are incompletely understood. METHODS: To delineate the cellular and molecular basis for DN initiation, we performed single-cell and bulk RNA sequencing of renal cells from type 2 diabetes mice (BTBR ob/ob) at the early stage of DN. RESULTS: Analysis of differentially expressed genes revealed glucose-independent responses in glomerular cell types. The gene regulatory network upstream of glomerular cell programs suggested the activation of mechanosensitive transcriptional pathway MRTF-SRF predominantly taking place in mesangial cells. Importantly, activation of MRTF-SRF transcriptional pathway was also identified in DN glomeruli in independent patient cohort datasets. Furthermore, ex vivo kidney perfusion suggested that the regulation of MRTF-SRF is a common mechanism in response to glomerular hyperfiltration. CONCLUSIONS: Overall, our study presents a comprehensive single-cell transcriptomic landscape of early DN, highlighting mechanosensitive signaling pathways as novel targets of diabetic glomerulopathy.