{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T15:26:16Z","timestamp":1763997976637,"version":"3.45.0"},"reference-count":36,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T00:00:00Z","timestamp":1763942400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: Vitamin D is increasingly recognized as a key immunomodulatory nutrient, influencing innate and adaptive immune responses. While 25-hydroxyvitamin D [25(OH)D] is widely used to assess vitamin D status, the active form, 1,25-dihydroxyvitamin D [1,25(OH)2D], may exert distinct effects on immune function. This study investigates the concentration-dependent and sex-specific relationships of both vitamin D metabolites with systemic inflammatory markers in a large clinical cohort. Objectives: To characterize the associations of 25(OH)D and 1,25(OH)2D with total white blood cell (WBC) count and leukocyte subtypes, including neutrophils, lymphocytes, monocytes, eosinophils, and basophils. Methods: We conducted a retrospective cross-sectional analysis of 125,537 adults (37.9% male; age 18\u201389 years) from routine laboratory diagnostics collected between 2014 and 2020 in Germany. Serum 25(OH)D and 1,25(OH)2D were measured using standardized chemiluminescent immunoassays. Inflammatory markers were assessed via automated hematology. Multivariable-adjusted linear and non-linear regression models were used to assess associations, adjusting for age, sex, and season. Results: Neutrophils and Monocytes: Displayed U-shaped associations with both 25(OH)D and 1,25(OH)2D. Neutrophil counts were lowest at 25(OH)D levels of ~40\u201360 nmol\/L and increased significantly at both lower and higher extremes (p &lt; 0.001). Lymphocytes: Inverse relationship with 25(OH)D (p &lt; 0.001), and an inverse U-shaped relationship with 1,25(OH)2D, peaking at ~90 pmol\/L, with counts decreasing at both lower and higher levels (p &lt; 0.001). Sex-specific analysis revealed that the relationship between 1,25(OH)2D and lymphocyte count remained independent only in men, Eosinophils and Basophils: Demonstrated consistently negative correlations with both forms of vitamin D across all concentration ranges (p &lt; 0.001). Conclusions: Our findings reveal distinct, concentration-dependent associations between vitamin D metabolites and leukocyte profiles, with evidence for nonlinear and sex-specific immunological effects. Both low and high levels of 25(OH)D and 1,25(OH)2D were linked to increased neutrophil and monocyte counts, suggesting that vitamin D excess, like deficiency, may be linked to low-grade inflammation. These data are hypothesis-generating and suggest that personalized monitoring of vitamin D status may be relevant for future research on immune health, particularly in populations at risk for inflammatory or metabolic disease, but they do not provide a basis for clinical decision-making.<\/jats:p>","DOI":"10.3390\/nu17233670","type":"journal-article","created":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T14:59:04Z","timestamp":1763996344000},"page":"3670","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Nonlinear and Sex-Specific Associations of Vitamin D Metabolites with Inflammatory Blood Markers in 125,537 Adults"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-3060-282X","authenticated-orcid":false,"given":"Xitong","family":"Li","sequence":"first","affiliation":[{"name":"Fifth Department of Medicine (Nephrology\/Endocrinology\/Rheumatology\/Pneumology), University Medical Center Mannheim, University of Heidelberg, 69120 Mannheim, Germany"},{"name":"Department of Nephrology, Charit\u00e9 Universit\u00e4tsmedizin Berlin, 10117 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4997-1257","authenticated-orcid":false,"given":"Xin","family":"Chen","sequence":"additional","affiliation":[{"name":"Fifth Department of Medicine (Nephrology\/Endocrinology\/Rheumatology\/Pneumology), University Medical Center Mannheim, University of Heidelberg, 69120 Mannheim, Germany"},{"name":"Institute for Clinical Research and Systems Medicine, Health and Medical University, 14467 Potsdam, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5688-2108","authenticated-orcid":false,"given":"Yvonne","family":"Liu","sequence":"additional","affiliation":[{"name":"Fifth Department of Medicine (Nephrology\/Endocrinology\/Rheumatology\/Pneumology), University Medical Center Mannheim, University of Heidelberg, 69120 Mannheim, Germany"},{"name":"Department of Nephrology, Charit\u00e9 Universit\u00e4tsmedizin Berlin, 10117 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingyun","family":"Wang","sequence":"additional","affiliation":[{"name":"Fifth Department of Medicine (Nephrology\/Endocrinology\/Rheumatology\/Pneumology), University Medical Center Mannheim, University of Heidelberg, 69120 Mannheim, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carl-Friedrich","family":"Hocher","sequence":"additional","affiliation":[{"name":"Fifth Department of Medicine (Nephrology\/Endocrinology\/Rheumatology\/Pneumology), University Medical Center Mannheim, University of Heidelberg, 69120 Mannheim, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christoph","family":"Reichetzeder","sequence":"additional","affiliation":[{"name":"Institute for Clinical Research and Systems Medicine, Health and Medical University, 14467 Potsdam, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saban","family":"Elitok","sequence":"additional","affiliation":[{"name":"Institute for Clinical Research and Systems Medicine, Health and Medical University, 14467 Potsdam, Germany"},{"name":"Department of Nephrology and Endocrinology, Klinikum Ernst von Bergmann, 14467 Potsdam, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1718-2918","authenticated-orcid":false,"given":"Bernhard K.","family":"Kr\u00e4mer","sequence":"additional","affiliation":[{"name":"Fifth Department of Medicine (Nephrology\/Endocrinology\/Rheumatology\/Pneumology), University Medical Center Mannheim, University of Heidelberg, 69120 Mannheim, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne","family":"Sch\u00f6nbunn","sequence":"additional","affiliation":[{"name":"Institute of Medical Diagnostics (IMD), 12247 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cornelia","family":"Doebis","sequence":"additional","affiliation":[{"name":"Institute of Medical Diagnostics (IMD), 12247 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katrin","family":"Huesker","sequence":"additional","affiliation":[{"name":"Institute of Medical Diagnostics (IMD), 12247 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Volker","family":"von Baehr","sequence":"additional","affiliation":[{"name":"Institute of Medical Diagnostics (IMD), 12247 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8143-0579","authenticated-orcid":false,"given":"Berthold","family":"Hocher","sequence":"additional","affiliation":[{"name":"Fifth Department of Medicine (Nephrology\/Endocrinology\/Rheumatology\/Pneumology), University Medical Center Mannheim, University of Heidelberg, 69120 Mannheim, Germany"},{"name":"Institute of Medical Diagnostics (IMD), 12247 Berlin, Germany"},{"name":"Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha 410008, China"},{"name":"School of Medicine, Central South University, Changsha 410078, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1016\/j.earlhumdev.2015.08.007","article-title":"Calcium, phosphorus, and bone metabolism in the fetus and newborn","volume":"91","author":"Kovacs","year":"2015","journal-title":"Early Hum. 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