{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T16:32:19Z","timestamp":1791304339218,"version":"4.3.1"},"reference-count":23,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"50","license":[{"start":{"date-parts":[[2024,12,13]],"date-time":"2024-12-13T00:00:00Z","timestamp":1734048000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2024,12,13]]},"abstract":"<jats:p>This study explores the hidden connection between HLA DR on CD14\u2010 CD16+ monocytes and ankylosing spondylitis (AS), with a particular emphasis on investigating and measuring the impact of 1091 blood metabolites as potential mediators. We harnessed the power of summary-level data extracted from a comprehensive genome-wide association study to delve into the intricate relationship between genetically predicted HLA DR on CD14\u2010 CD16+ monocytes (3621 cases) and AS (1193 cases and 374,621 controls). Furthermore, we employed a two-step Mendelian randomization (MR) methodology to elucidate the extent to which blood metabolites contribute to the effects observed in CD14\u2010 CD16+ monocytes, ultimately influencing the development of AS. This methodological approach provides a comprehensive and rigorous exploration of the interplay between blood metabolites and AS, shedding light on the underlying mechanisms governing this intricate association. Through MR analysis, our investigation revealed an increase in HLA DR on CD14\u2010 CD16+ monocytes within plasma, which correspondingly led to a reduction in the incidence of AS. The primary MR analysis yielded an odds ratio of 0.64 with a 95% confidence interval spanning from 0.53 to 0.78, underscoring the protective effect of elevated HLA DR on CD14\u2010 CD16+ monocytes against the development of AS. Furthermore, our study found no compelling evidence to suggest that AS exerts any discernible influence on HLA DR on CD14\u2010 CD16+ monocytes. Instead, our investigation identified N6, N6, N6-trimethyllysine levels (TML), a blood metabolite, as the sole mediator in the relationship between HLA DR on CD14\u2010 CD16+ monocytes and AS. Notably, the genetic prediction of AS mediated by TML accounted for a substantial \u20102.98% proportion of the observed variance. Our investigation has delineated a causal association between HLA DR on CD14\u2010 CD16+ monocytes and AS. Specifically, HLA DR on CD14\u2010 CD16+ monocytes exhibited a protective effect against the development of AS. Conversely, AS mediated by TML emerged as a risk factor, though the precise impact of HLA DR on CD14\u2010 CD16+ monocytes on AS pathogenesis remains enigmatic. It is imperative to embark on further investigations into potential mediators. In a clinical setting, it is imperative to carefully monitor the patient\u2019s HLA DR on CD14\u2010 CD16+ monocytes levels.<\/jats:p>","DOI":"10.1097\/md.0000000000040892","type":"journal-article","created":{"date-parts":[[2024,12,16]],"date-time":"2024-12-16T19:02:35Z","timestamp":1734375755000},"page":"e40892","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":2,"title":["The mediating role of the genetically predicted N6, N6, N6-trimethyllysine levels in the association between HLA DR on CD14\u2010 CD16+ monocytes and ankylosing spondylitis"],"prefix":"10.1097","volume":"103","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-4362-3251","authenticated-orcid":false,"given":"Danyun","family":"Hua","sequence":"first","affiliation":[{"name":"Fenghua Hospital of Traditional Chinese Medicine, Ningbo, Zhejiang Province, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Wang","sequence":"additional","affiliation":[{"name":"Fenghua Hospital of Traditional Chinese Medicine, Ningbo, Zhejiang Province, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Li","sequence":"additional","affiliation":[{"name":"Fenghua Hospital of Traditional Chinese Medicine, Ningbo, Zhejiang Province, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Xu","sequence":"additional","affiliation":[{"name":"Fenghua Hospital of Traditional Chinese Medicine, Ningbo, Zhejiang Province, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohu","family":"Yin","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"R1-20250503","doi-asserted-by":"crossref","first-page":"822582","DOI":"10.3389\/fimmu.2021.822582","article-title":"Editorial: advances in pathogenesis, etiology, and therapies for ankylosing spondylitis.","volume":"12","author":"Chen","year":"2021","journal-title":"Front Immunol"},{"key":"R2-20250503","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1111\/1756-185X.14080","article-title":"Epigenetics of ankylosing spondylitis: recent developments.","volume":"24","author":"Yang","year":"2021","journal-title":"Int J Rheum Dis"},{"key":"R3-20250503","doi-asserted-by":"crossref","first-page":"1163258","DOI":"10.3389\/fimmu.2023.1163258","article-title":"Investigating the causal relationship between ankylosing spondylitis and osteoporosis in the European population: a bidirectional Mendelian randomization study.","volume":"14","author":"Mei","year":"2023","journal-title":"Front Immunol"},{"key":"R4-20250503","doi-asserted-by":"crossref","first-page":"1379","DOI":"10.1016\/S0140-6736(07)60635-7","article-title":"Ankylosing spondylitis.","volume":"369","author":"Braun","year":"2007","journal-title":"Lancet"},{"key":"R5-20250503","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1038\/ng.873","article-title":"Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility [published correction appears in Nat Genet. 2011 Sep;43(9):919. 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