{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T09:54:04Z","timestamp":1781690044634,"version":"3.54.5"},"reference-count":36,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T00:00:00Z","timestamp":1781654400000},"content-version":"vor","delay-in-days":167,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Human Mutation"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Colorectal cancer (CRC) is shaped by inherited genetic susceptibility, metabolic reprogramming, epigenetic regulation, and tumor microenvironment (TME) heterogeneity. Lactylation has recently emerged as an epigenetic mechanism that links lactate accumulation to chromatin remodeling and transcriptional regulation. However, the roles of lactylation\u2010related genes in CRC initiation and progression, particularly from the perspective of SNP\u2010based germline genetic variation, remain to be elucidated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We integrated GWAS analysis and single\u2010cell RNA sequencing to identify lactylation\u2010related pro\u2010oncogenic genes with potential genetic causal relevance and to further characterize their cellular localization and microenvironmental implications in CRC. GWAS uses inherited germline genetic variants, particularly SNPs associated with gene expression, as instrumental variables, thereby reducing confounding and reverse causation compared with conventional tumor expression\u2010based analyses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>GWAS analysis has identified germline variants in AXIN1, FASN, MLH1, and RAD50 that genetically predicted increased CRC risk. Single\u2010cell analysis was subsequently performed to evaluate the cell\u2010type\u2010specific distribution and functional relevance of these GWAS\u2010identified genes within CRC tissues. Among them, AXIN1 exhibited clearer differential expression and cell\u2010type\u2010specific distribution in CRC\u2010associated cell populations. AXIN1\u2010high cell populations were associated with metabolic adaptation, proliferative activity, lactylation\u2010related transcriptional programs, inflammatory responses, immune regulation, extracellular matrix remodeling, and TME adaptation. Besides, FASN was also confirmed as a genetically supported risk gene implicated in CRC metabolic reprogramming. MLH1 and RAD50 were retained as candidate risk genes at the germline causal level.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study integrates germline variant\u2010based causal inference with single\u2010cell microenvironmental interpretation, highlighting germline variant\u2010regulated lactylation in promoting colorectal cancer risk.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1155\/humu\/3085047","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T09:04:31Z","timestamp":1781687071000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Causal Effects and Single\u2010Cell Microenvironmental Implications of Germline Variant\u2010Regulated Lactylation\u2010Related Pro\u2010Oncogenic Genes in Colorectal Cancer"],"prefix":"10.1155","volume":"2026","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-6650-458X","authenticated-orcid":false,"given":"Biao","family":"Sheng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8129-6197","authenticated-orcid":false,"given":"Jianwei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,17]]},"reference":[{"key":"e_1_2_13_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(24)00360-X"},{"key":"e_1_2_13_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S2468-2667(23)00211-6"},{"key":"e_1_2_13_3_2","doi-asserted-by":"publisher","DOI":"10.1136\/bmj-2022-071707"},{"key":"e_1_2_13_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2024.102821"},{"key":"e_1_2_13_5_2","article-title":"Colorectal Cancer Treatment Commentary Review","volume":"213","author":"\u00d6nder A. H.","year":"2025","journal-title":"European Journal Of Cancer"},{"key":"e_1_2_13_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2024.115064"},{"key":"e_1_2_13_7_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1353787"},{"key":"e_1_2_13_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1678-1"},{"key":"e_1_2_13_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-024-02082-x"},{"key":"e_1_2_13_10_2","doi-asserted-by":"publisher","DOI":"10.1186\/s43556-025-00275-6"},{"key":"e_1_2_13_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2024.09.006"},{"key":"e_1_2_13_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.drup.2025.101248"},{"key":"e_1_2_13_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.drup.2024.101059"},{"key":"e_1_2_13_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-025-01410-7"},{"key":"e_1_2_13_15_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00281-021-00894-5"},{"key":"e_1_2_13_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tig.2025.05.009"},{"key":"e_1_2_13_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-019-0127-1"},{"key":"e_1_2_13_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2022.103895"},{"key":"e_1_2_13_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-024-00807-z"},{"key":"e_1_2_13_20_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12672-025-01775-1"},{"key":"e_1_2_13_21_2","doi-asserted-by":"publisher","DOI":"10.1186\/s10194-025-02075-3"},{"key":"e_1_2_13_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2024.104991"},{"key":"e_1_2_13_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41698-025-01236-6"},{"key":"e_1_2_13_24_2","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202408845"},{"key":"e_1_2_13_25_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-024-04955-9"},{"key":"e_1_2_13_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-025-07498-z"},{"key":"e_1_2_13_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcmgh.2022.10.017"},{"key":"e_1_2_13_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2020.11.004"},{"key":"e_1_2_13_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2020.11.006"},{"key":"e_1_2_13_30_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-019-1100-5"},{"key":"e_1_2_13_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2014.09.018"},{"key":"e_1_2_13_32_2","doi-asserted-by":"publisher","DOI":"10.1002\/bab.2229"},{"key":"e_1_2_13_33_2","doi-asserted-by":"publisher","DOI":"10.1515\/bc.2010.028"},{"key":"e_1_2_13_34_2","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201606773"},{"key":"e_1_2_13_35_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12964-024-01482-4"},{"key":"e_1_2_13_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2025.114501"}],"container-title":["Human Mutation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1155\/humu\/3085047","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1155\/humu\/3085047","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1155\/humu\/3085047","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T09:04:32Z","timestamp":1781687072000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1155\/humu\/3085047"}},"subtitle":[],"editor":[{"given":"Zhijia","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,1]]},"references-count":36,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1]]}},"alternative-id":["10.1155\/humu\/3085047"],"URL":"https:\/\/doi.org\/10.1155\/humu\/3085047","archive":["Portico"],"relation":{},"ISSN":["1059-7794","1098-1004"],"issn-type":[{"value":"1059-7794","type":"print"},{"value":"1098-1004","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1]]},"assertion":[{"value":"2026-05-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-27","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-17","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"3085047"}}