{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T08:14:53Z","timestamp":1780647293044,"version":"3.54.1"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,10,7]],"date-time":"2024-10-07T00:00:00Z","timestamp":1728259200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Beta-2 microglobulin (\u03b22M) is acknowledged as a prognostic biomarker for B-cell malignancies. However, insights into the impact of \u03b22M on B-cell malignancy risk, and vice versa, are limited.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We conducted a genome-wide meta-analysis (GWMA), bidirectional two-sample Mendelian randomization (TSMR) analysis, and pathway enrichment analysis to explore the causal relationship between \u03b22M and B-cell malignancies and the underlying biological processes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The GWMA identified 55 lead SNPs across five genomic regions (three novel: WDR72, UMOD, and NLRC5) associated with \u03b22M. In the UKB, genetically predicted \u03b22M showed a positive association with diffuse large B-cell lymphoma (DLBCL; odds ratio [OR]: 1.742 per standard deviation increase in \u03b22M; 95% confidence interval [CI]: 1.215\u20132.498; <jats:italic>P<\/jats:italic> = 3.00 \u00d7 10<jats:sup>\u22123<\/jats:sup>; FDR = 7.50\u00d7 10<jats:sup>\u22123<\/jats:sup>) and Hodgkin lymphoma (HL; OR: 2.270; 95% CI: 1.525\u20133.380; <jats:italic>P<\/jats:italic> = 5.15 \u00d7 10<jats:sup>\u22125<\/jats:sup>; FDR =2.58 \u00d7 10<jats:sup>\u22124<\/jats:sup>). However, no associations were found with follicular lymphoma (FL), chronic lymphoid leukemia (CLL), or multiple myeloma (MM). Reverse TSMR analysis revealed no association between genetically predicted B-cell malignancies and \u03b22M. In FinnGen, \u03b22M was found to be associated with an increased risk of DLBCL (OR: 2.098; 95% CI: 1.358-3.242; <jats:italic>P<\/jats:italic> = 8.28 \u00d7 10<jats:sup>\u22124<\/jats:sup>; FDR = 4.14 \u00d7 10<jats:sup>\u22123<\/jats:sup>), HL (OR: 1.581; 95% CI: 1.167-2.142; <jats:italic>P<\/jats:italic> = 3.13 \u00d7 10<jats:sup>\u22123<\/jats:sup>; FDR = 5.22 \u00d7 10<jats:sup>\u22123<\/jats:sup>), and FL (OR: 2.113; 95% CI: 1.292-3.455; <jats:italic>P<\/jats:italic> = 2.90 \u00d7 10<jats:sup>\u22123<\/jats:sup>; FDR = 5.22 \u00d7 10<jats:sup>\u22123<\/jats:sup>). However, no association was found with CLL or MM. Reverse TSMR analysis indicated that genetically predicted DLBCL, FL, and MM may perturb \u03b22M levels. Pathway enrichment analysis suggested that the innate immune system represents a convergent biological process underlying \u03b22M, DLBCL, and HL.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our findings suggested that elevated levels of \u03b22M were associated with an increased risk of DLBCL and HL, which is potentially linked to dysfunction of the innate immune system.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2024.1448476","type":"journal-article","created":{"date-parts":[[2024,10,7]],"date-time":"2024-10-07T04:21:28Z","timestamp":1728274888000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Causal relationship between beta-2 microglobulin and B-cell malignancies: genome-wide meta-analysis and a bidirectional two-sample Mendelian randomization study"],"prefix":"10.3389","volume":"15","author":[{"given":"Jiuling","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueju","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,10,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.4143\/crt.2020.089","article-title":"Increasing incidence of B-cell non-hodgkin lymphoma and occurrence of second primary Malignancies in South Korea: 10-year follow-up using the Korean national health information database","volume":"52","author":"Kim","year":"2020","journal-title":"Cancer Res treatment: Off J Korean Cancer Assoc"},{"key":"B2","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1080\/10428194.2021.1975188","article-title":"Epidemiology of diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) in the United States and Western Europe: population-level projections for 2020-2025","volume":"63","author":"Kanas","year":"2022","journal-title":"Leukemia lymph"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1158\/1055-9965.EPI-08-1118","article-title":"Sex disparities in cancer incidence by period and age","volume":"18","author":"Cook","year":"2009","journal-title":"Cancer Epidemiol Biomarkers Prev"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2019.06.005","article-title":"Autoimmune diseases and hematological Malignancies: Exploring the underlying mechanisms from epidemiological evidence","volume":"64","author":"Hemminki","year":"2020","journal-title":"Semin Cancer Biol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1158\/1055-9965.EPI-11-0246","article-title":"Sex disparities in cancer mortality and survival","volume":"20","author":"Cook","year":"2011","journal-title":"Cancer Epidemiol Biomarkers Prev"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.32109","article-title":"Anthropometric characteristics, physical activity and risk of hematological Malignancies: A systematic review and meta-analysis of cohort studies","volume":"145","author":"Psaltopoulou","year":"2019","journal-title":"Int J cancer"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2012.333","article-title":"Alcohol drinking, tobacco smoking and subtypes of haematological Malignancy in the UK Million Women Study","volume":"107","author":"Kroll","year":"2012","journal-title":"Br J cancer"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1159\/000354194","article-title":"Impact of interleukin-6 in hematological Malignancies","volume":"40","author":"Burger","year":"2013","journal-title":"Transfusion Med hemother: offizielles Organ der Deutschen Gesellschaft fur Transfusionsmedizin und Immunhamatol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1186\/s12916-022-02506-x","article-title":"C-reactive protein and cancer risk: a pan-cancer study of prospective cohort and Mendelian randomization analysis","volume":"20","author":"Zhu","year":"2022","journal-title":"BMC Med"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1002\/hon.2312","article-title":"Beta-2 microglobulin as a significant prognostic factor and a new risk model for patients with diffuse large B-cell lymphoma","volume":"35","author":"Kanemasa","year":"2017","journal-title":"Hematol Oncol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.14237","article-title":"Prognostic significance of baseline peripheral absolute neutrophil, monocyte and serum \u03b22-microglobulin level in patients with diffuse large b-cell lymphoma: a new prognostic model","volume":"175","author":"Chen","year":"2016","journal-title":"Br J haematol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.10998","article-title":"An elevated serum beta-2-microglobulin level is an adverse prognostic factor for overall survival in patients with early-stage Hodgkin disease","volume":"95","author":"Chronowski","year":"2002","journal-title":"Cancer"},{"key":"B13","article-title":"The prognostic significance of beta(2)-microglobulin in patients with Hodgkin\u2019s lymphoma","volume":"87","author":"Vassilakopoulos","year":"2002","journal-title":"Haematologica"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.11502","article-title":"Prognostic relevance of serum beta2 microglobulin in patients with follicular lymphoma treated with anthracycline-containing regimens","volume":"92","author":"Federico","year":"2007","journal-title":"A GISL study Haematol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2009.005561","article-title":"Predictive value of beta2-microglobulin (beta2-m) levels in chronic lymphocytic leukemia since Binet A stages","volume":"94","author":"Gentile","year":"2009","journal-title":"Haematologica"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.13032","article-title":"Italian external and multicentric validation of the MD Anderson Cancer Center nomogram and prognostic index for chronic lymphocytic leukaemia patients: analysis of 1502 cases","volume":"167","author":"Gentile","year":"2014","journal-title":"Br J haematol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1182\/blood-2014-02-556399","article-title":"Development of a comprehensive prognostic index for patients with chronic lymphocytic leukemia","volume":"124","author":"Pflug","year":"2014","journal-title":"Blood"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2005.04.242","article-title":"International staging system for multiple myeloma","volume":"23","author":"Greipp","year":"2005","journal-title":"J Clin Oncol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2017.17219","article-title":"Mendelian randomization","volume":"318","author":"Emdin","year":"2017","journal-title":"Jama"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddu328","article-title":"Mendelian randomization: genetic anchors for causal inference in epidemiological studies","volume":"23","author":"Davey Smith","year":"2014","journal-title":"Hum Mol Genet"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/ije\/dyg070","article-title":"[amp]]lsquo;Mendelian randomization\u2019: can genetic epidemiology contribute to understanding environmental determinants of disease","volume":"32","author":"Smith","year":"2003","journal-title":"Int J Epidemiol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1158\/1055-9965.Epi-19-0803","article-title":"Lipid trait variants and the risk of non-hodgkin lymphoma subtypes: A Mendelian randomization study","volume":"29","author":"Kleinstern","year":"2020","journal-title":"Cancer epidemiol Biomarkers Prev"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.34214","article-title":"Causal relationships between inflammatory factors and multiple myeloma: A bidirectional Mendelian randomization study","volume":"151","author":"Wang","year":"2022","journal-title":"Int J cancer"},{"key":"B24","doi-asserted-by":"publisher","first-page":"480","DOI":"10.1038\/s41467-021-27850-z","article-title":"A genome-wide association study of serum proteins reveals shared loci with common diseases","volume":"13","author":"Gudjonsson","year":"2022","journal-title":"Nat Commun"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00978-w","article-title":"Large-scale integration of the plasma proteome with genetics and disease","volume":"53","author":"Ferkingstad","year":"2021","journal-title":"Nat Genet"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btq340","article-title":"METAL: fast and efficient meta-analysis of genomewide association scans","volume":"26","author":"Willer","year":"2010","journal-title":"Bioinf (Oxford England)"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1826","DOI":"10.1038\/s41467-017-01261-5","article-title":"Functional mapping and annotation of genetic associations with FUMA","volume":"8","author":"Watanabe","year":"2017","journal-title":"Nat Commun"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1002\/gepi.21758","article-title":"Mendelian randomization analysis with multiple genetic variants using summarized data","volume":"37","author":"Burgess","year":"2013","journal-title":"Genet Epidemiol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1007\/s10654-017-0255-x","article-title":"Interpreting findings from Mendelian randomization using the MR-Egger method","volume":"32","author":"Burgess","year":"2017","journal-title":"Eur J Epidemiol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1002\/gepi.21965","article-title":"Consistent estimation in mendelian randomization with some invalid instruments using a weighted median estimator","volume":"40","author":"Bowden","year":"2016","journal-title":"Genet Epidemiol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0099-7","article-title":"Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases","volume":"50","author":"Verbanck","year":"2018","journal-title":"Nat Genet"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.cgh.2022.01.045","article-title":"Mendelian randomization analysis reveals no causal relationship between nonalcoholic fatty liver disease and severe COVID-19","volume":"20","author":"Li","year":"2022","journal-title":"Clin Gastroenterol Hepatol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa407","article-title":"TIMER2.0 for analysis of tumor-infiltrating immune cells","volume":"48","author":"Li","year":"2020","journal-title":"Nucleic Acids Res"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-013-1274-7","article-title":"Genome-wide association study identified the human leukocyte antigen region as a novel locus for plasma beta-2 microglobulin","volume":"132","author":"Tin","year":"2013","journal-title":"Hum Genet"},{"key":"B35","first-page":"27","article-title":"beta 2-Microglobulin in clinical medicine. Scandinavian journal of clinical and laboratory investigation","volume":"154","author":"Karlsson","year":"1980","journal-title":"Supplementum"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms10023","article-title":"Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function","volume":"7","author":"Pattaro","year":"2016","journal-title":"Nat Commun"},{"key":"B37","doi-asserted-by":"publisher","first-page":"4350","DOI":"10.1038\/s41467-021-24491-0","article-title":"Discovery and prioritization of variants and genes for kidney function in >1.2 million individuals","volume":"12","author":"Stanzick","year":"2021","journal-title":"Nat Commun"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.micinf.2011.12.007","article-title":"NLRC5: a newly discovered MHC class I transactivator (CITA)","volume":"14","author":"Meissner","year":"2012","journal-title":"Microbes infect"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1008684107","article-title":"NLR family member NLRC5 is a transcriptional regulator of MHC class I genes","volume":"107","author":"Meissner","year":"2010","journal-title":"Proc Natl Acad Sci United States America"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.xgen.2024.100506","article-title":"Genetic associations with ratios between protein levels detect new pQTLs and reveal protein-protein interactions","volume":"4","author":"Suhre","year":"2024","journal-title":"Cell Genomics"},{"key":"B41","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1016\/j.canlet.2021.06.008","article-title":"Beta2-microglobulin(B2M) in cancer immunotherapies: Biological function, resistance and remedy","volume":"517","author":"Wang","year":"2021","journal-title":"Cancer letters"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2011.11.006","article-title":"Combined genetic inactivation of \u03b22-Microglobulin and CD58 reveals frequent escape from immune recognition in diffuse large B cell lymphoma","volume":"20","author":"Challa-Malladi","year":"2011","journal-title":"Cancer Cell"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1038\/s41379-019-0322-9","article-title":"The inhibitory receptor CD94\/NKG2A on CD8(+) tumor-infiltrating lymphocytes in colorectal cancer: a promising new druggable immune checkpoint in the context of HLAE\/\u03b22m overexpression","volume":"33","author":"Eug\u00e8ne","year":"2020","journal-title":"Modern Pathol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1161\/circresaha.120.317119","article-title":"[amp]]beta;2M signals monocytes through non-canonical TGF\u03b2 Receptor signal transduction","volume":"128","author":"Hilt","year":"2021","journal-title":"Circ Res"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1448476\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,7]],"date-time":"2024-10-07T04:21:30Z","timestamp":1728274890000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1448476\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,7]]},"references-count":44,"alternative-id":["10.3389\/fimmu.2024.1448476"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2024.1448476","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,7]]},"article-number":"1448476"}}