{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,26]],"date-time":"2026-07-26T05:40:43Z","timestamp":1785044443690,"version":"3.55.0"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,8,25]],"date-time":"2025-08-25T00:00:00Z","timestamp":1756080000000},"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. Nutr."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Emerging evidence suggests vitamin D plays a dual role in immune regulation, yet its interplay with genetic susceptibility in early-life allergy development remains poorly understood. This prospective cohort study investigated whether cord blood 25-hydroxyvitamin D [25(OH)D] levels interact with immunoregulatory gene variants to influence childhood food allergy risk.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A total of 1,049 mother-infant pairs from the Shanghai Allergy Cohort were stratified by cord blood 25(OH)D concentrations (&amp;lt;15, 15\u201325, &amp;gt;25\u202fng\/mL). Food allergy diagnoses at 6, 12, and 24\u202fmonths followed standardized clinical criteria. Five single-nucleotide polymorphisms (SNPs) (IL4, IL4R, IL13, MS4A2) were genotyped using MALDI-TOF MS. Multivariable logistic regression evaluated associations between vitamin D, genetic polymorphisms, and allergy outcomes, adjusting for birth season, maternal allergy history, and environmental confounders. Gene-vitamin D interactions were tested via stratified analyses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A U-shaped relationship was observed between cord blood serum25(OH)D levels and the risk of developing childhood food allergies. Both deficient (&amp;lt;15\u202fng\/mL) and elevated (&amp;gt;25\u202fng\/mL) 25(OH)D levels at birth independently increased 6-month food allergy risk (adjusted OR\u202f=\u202f2.55 and 2.38, respectively). By 24\u202fmonths, only deficient levels showed attenuated effects (OR\u202f=\u202f1.14, <jats:italic>p<\/jats:italic>\u202f=\u202f0.779). IL4R rs1801275 AA, IL13 rs20541 GG, and IL-4 rs2243250 CC genotypes synergistically amplified allergy risk under vitamin D deficiency (adjusted OR\u202f=\u202f26.14, <jats:italic>p<\/jats:italic>\u202f=\u202f0.019; OR\u202f=\u202f6.51, <jats:italic>p<\/jats:italic>\u202f=\u202f0.025; OR\u202f=\u202f4.13, <jats:italic>p<\/jats:italic>\u202f=\u202f0.007). Notably, the protective effect of MS4A2 rs569108 GG genotype observed at reference vitamin D levels (adjusted OR\u202f=\u202f0.55, <jats:italic>p<\/jats:italic>\u202f=\u202f0.016) was attenuated at high levels (OR\u202f=\u202f0.68, <jats:italic>p<\/jats:italic>\u202f=\u202f0.149).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Genetic susceptibility in Th2 pathway genes (IL4R, IL-4, IL13) dramatically amplified food allergy risk under vitamin D deficiency, with AA\/GG\/CC genotypes conferring 4- to 26-fold increased susceptibility. Conversely, the protective effect of MS4A2 rs569108 GG genotype was compromised at high vitamin D levels (&amp;gt;25\u202fng\/mL). Our findings underscore that personalized vitamin D thresholds during pregnancy must account for fetal genetic background to mitigate allergy risk.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnut.2025.1652487","type":"journal-article","created":{"date-parts":[[2025,8,25]],"date-time":"2025-08-25T04:10:35Z","timestamp":1756095035000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Association of cord blood vitamin D and genetic polymorphisms with childhood food allergy in Shanghai, China: a prospective 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D and allergic diseases","volume":"15","author":"Zhang","year":"2024","journal-title":"Front Immunol"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"177","DOI":"10.3390\/nu13010177","article-title":"Vitamin D and immunological patterns of allergic diseases in children","volume":"13","author":"Lipi\u0144ska-Opa\u0142ka","year":"2021","journal-title":"Nutrients"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"1533","DOI":"10.1007\/s00431-023-04843-2","article-title":"Association of food allergy in children with vitamin D insufficiency: a systematic review and meta-analysis","volume":"182","author":"Psaroulaki","year":"2023","journal-title":"Eur J Pediatr"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"1015","DOI":"10.3390\/nu13031015","article-title":"Vitamin D and allergy susceptibility during gestation and early life","volume":"13","author":"Briceno Noriega","year":"2021","journal-title":"Nutrients"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"1087","DOI":"10.1016\/j.jaci.2011.02.015","article-title":"Gut microbiota, probiotics, and vitamin D: interrelated exposures influencing allergy, asthma, and obesity?","volume":"127","author":"Ly","year":"2011","journal-title":"J Allergy Clin Immunol"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1053\/j.gastro.2011.11.040","article-title":"Higher predicted vitamin D status is associated with reduced risk of Crohn's disease","volume":"142","author":"Ananthakrishnan","year":"2012","journal-title":"Gastroenterology"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"362","DOI":"10.3390\/ijms22010362","article-title":"Vitamin D modulates intestinal microbiota in inflammatory bowel diseases","volume":"22","author":"Battistini","year":"2020","journal-title":"Int J Mol Sci"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.jaci.2012.11.019","article-title":"Early-life environmental determinants of allergic diseases and the wider pandemic of inflammatory noncommunicable diseases","volume":"131","author":"Prescott","year":"2013","journal-title":"J Allergy Clin Immunol"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1038\/ncpendmet0716","article-title":"Unexpected actions of vitamin D: new perspectives on the regulation of innate and adaptive immunity","volume":"4","author":"Adams","year":"2008","journal-title":"Nat Clin Pract Endocrinol Metab"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"151","DOI":"10.3389\/fphys.2014.00151","article-title":"Impact of vitamin D on immune function: lessons learned from genome-wide analysis","volume":"5","author":"Chun","year":"2014","journal-title":"Front Physiol"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1111\/all.12081","article-title":"Maternal and newborn vitamin D status and its impact on food allergy development in the German LINA cohort study","volume":"68","author":"Weisse","year":"2013","journal-title":"Allergy"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"e99856","DOI":"10.1371\/journal.pone.0099856","article-title":"Cord blood 25(OH)-vitamin D deficiency and childhood asthma, allergy and eczema: the COPSAC2000 birth cohort study","volume":"9","author":"Chawes","year":"2014","journal-title":"PLoS One"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"1309","DOI":"10.1016\/j.jaci.2015.04.017","article-title":"Association between vitamin D levels and allergy-related outcomes vary by race and other factors","volume":"136","author":"Wegienka","year":"2015","journal-title":"J Allergy Clin 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variants within the genes IL4, IL13, and IL4RA in German children: the German multicenter atopy study","volume":"113","author":"Liu","year":"2004","journal-title":"J Allergy Clin Immunol"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"906","DOI":"10.1164\/ajrccm.161.3.9903128","article-title":"A common FCER1B gene promoter polymorphism influences total serum IgE levels in a Japanese population","volume":"161","author":"Hizawa","year":"2000","journal-title":"Am J Respir Crit Care Med"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"1412","DOI":"10.1111\/j.1398-9995.2005.00869.x","article-title":"Beta 2-ADR haplotypes\/polymorphisms associate with bronchodilator response and total IgE in grass allergy","volume":"60","author":"Woszczek","year":"2005","journal-title":"Allergy"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1002\/ppul.23322","article-title":"Four-locus gene interaction between IL13, IL4, FCER1B, and ADRB2 for asthma in 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Clin Immunol"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"857","DOI":"10.1016\/j.jaci.2017.10.024","article-title":"Early life innate immune signatures of persistent food allergy","volume":"142","author":"Neeland","year":"2018","journal-title":"J Allergy Clin Immunol"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1038\/pr.2013.110","article-title":"Longitudinal trajectory of vitamin D status from birth to early childhood in the development of food sensitization","volume":"74","author":"Liu","year":"2013","journal-title":"Pediatr Res"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"i6583","DOI":"10.1136\/bmj.i6583","article-title":"Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant 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