{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T12:21:02Z","timestamp":1783426862103,"version":"3.54.6"},"reference-count":38,"publisher":"IMR Press","issue":"2","license":[{"start":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T00:00:00Z","timestamp":1779321600000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Kursk State Medical University"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Front. Biosci. (Schol Ed)"],"abstract":"<jats:p>Background: Despite significant advances in identifying susceptibility genes for bronchial asthma (BA), the immunogenetic and other molecular mechanisms underlying disease risk and progression remain incompletely understood. This study aimed to investigate the association between two common single-nucleotide polymorphisms (SNPs), rs17293632 and rs2033784, located within the SMAD3 (SMAD family member 3) gene\u2014previously identified in genome-wide association studies\u2014and susceptibility to atopic asthma and allergen sensitivity in Russian children. Methods: This study included DNA samples from 999 unrelated children from the Kursk region, comprising 526 patients with BA (316 boys and 210 girls) and 473 healthy children. SNP genotyping was performed using the MassARRAY-4 system. Results: Both SNPs were associated with an increased risk of BA under the additive genetic model (p \u2264 0.001). In the sex-stratified analysis, the rs17293632 (odds ratio (OR) = 1.79, 95% confidence interval (CI): 1.15\u20132.77; p = 9.0 \u00d7 10-4) and rs2033784 (OR = 1.80, 95% CI: 1.28\u20132.52; p = 6.0 \u00d7 10-4) variants were exclusively associated with asthma risk among girls, whereas no significant associations were observed in boys. The rs17293632T-rs2033784G haplotype was associated with an increased risk of asthma in girls (OR = 2.01, 95% CI: 1.38\u20132.92, p = 3.0 \u00d7 10-4). Notably, SMAD3 gene polymorphisms were associated with an increased risk of asthma exclusively among children living in urban environments (p \u2264 0.0001). Polymorphisms in the SMAD3 gene have also been linked to specific allergies, including those to horsehair, chicken eggs, beef, wheat, oatmeal, barley, and foxtail. Conclusions: The present study of Russian children confirmed that the rs17293632 and rs2033784 polymorphisms of the SMAD3 gene are significant genetic markers associated with BA and allergies. However, an association between these SMAD3 variants and asthma was observed only among girls, marking the first time this association has been reported. Further research is necessary to determine whether the SMAD3 gene constitutes a viable therapeutic target for treating asthma and allergic diseases.<\/jats:p>","DOI":"10.31083\/fbs46479","type":"journal-article","created":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T12:05:49Z","timestamp":1783425949000},"source":"Crossref","is-referenced-by-count":0,"title":["Sex-Dependent Association of SMAD3 Gene Polymorphisms With Asthma and Allergy Risk in Russian Children"],"prefix":"10.31083","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0283-2498","authenticated-orcid":true,"given":"Alexandra V","family":"Serezhkina","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Kursk State Medical University, 305041 Kursk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3333-0623","authenticated-orcid":true,"given":"Olga Yu","family":"Bushueva","sequence":"additional","affiliation":[{"name":"Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, 305041 Kursk, Russia"},{"name":"Laboratory of Genomic Research, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 305041 Kursk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1439-6259","authenticated-orcid":true,"given":"Maxim B","family":"Freidin","sequence":"additional","affiliation":[{"name":"Department of Twin Research and Genetic Epidemiology, King\u2019s College London, SE1 7EH London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4636-1819","authenticated-orcid":true,"given":"Alexey D","family":"Bogomazov","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kursk State Medical University, 305041 Kursk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vyacheslav I.","family":"Puchkov","sequence":"additional","affiliation":[{"name":"Laboratory of Statistical Genetics and Bioinformatics, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 305041 Kursk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6280-247X","authenticated-orcid":true,"given":"Alexey V","family":"Polonikov","sequence":"additional","affiliation":[{"name":"Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, 305041 Kursk, Russia"},{"name":"Laboratory of Statistical Genetics and Bioinformatics, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 305041 Kursk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,5,21]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Cookson W. Genetics and genomics of asthma and allergic diseases. Immunological Reviews. 2002; 190: 195\u2013206.","DOI":"10.1034\/j.1600-065x.2002.19015.x"},{"key":"ref2","doi-asserted-by":"publisher","unstructured":"Polonikov AV, Ivanov VP, Solodilova MA. Genetic variation of genes for xenobiotic-metabolizing enzymes and risk of bronchial asthma: the importance of gene-gene and gene-environment interactions for disease susceptibility. Journal of Human Genetics. 2009; 54: 440\u2013449.","DOI":"10.1038\/jhg.2009.58"},{"key":"ref3","doi-asserted-by":"publisher","unstructured":"Ntontsi P, Photiades A, Zervas E, Xanthou G, Samitas K. Genetics and Epigenetics in Asthma. International Journal of Molecular Sciences. 2021; 22: 2412.","DOI":"10.3390\/ijms22052412"},{"key":"ref4","doi-asserted-by":"publisher","unstructured":"Willis-Owen SAG, Cookson WOC, Moffatt MF. The Genetics and Genomics of Asthma. Annual Review of Genomics and Human Genetics. 2018; 19: 223\u2013246.","DOI":"10.1146\/annurev-genom-083117-021651"},{"key":"ref5","doi-asserted-by":"publisher","unstructured":"DeVries A, Vercelli D. Epigenetics in allergic diseases. Current Opinion in Pediatrics. 2015; 27: 719\u2013723.","DOI":"10.1097\/MOP.0000000000000285"},{"key":"ref6","doi-asserted-by":"publisher","unstructured":"Habib N, Pasha MA, Tang DD. Current Understanding of Asthma Pathogenesis and Biomarkers. Cells. 2022; 11: 2764.","DOI":"10.3390\/cells11172764"},{"key":"ref7","doi-asserted-by":"publisher","unstructured":"Nolte H, Backer V, Porsbjerg C. Environmental factors as a cause for the increase in allergic disease. Annals of Allergy, Asthma & Immunology: Official Publication of the American College of Allergy, Asthma, & Immunology. 2001; 87: 7\u201311.","DOI":"10.1016\/s1081-1206(10)62333-2"},{"key":"ref8","doi-asserted-by":"publisher","unstructured":"Chatkin J, Correa L, Santos U. External Environmental Pollution as a Risk Factor for Asthma. Clinical Reviews in Allergy & Immunology. 2022; 62: 72\u201389.","DOI":"10.1007\/s12016-020-08830-5"},{"key":"ref9","doi-asserted-by":"publisher","unstructured":"Shi F, Zhang Y, Qiu C. Gene polymorphisms in asthma: a narrative review. Annals of Translational Medicine. 2022; 10: 711.","DOI":"10.21037\/atm-22-2170"},{"key":"ref10","doi-asserted-by":"publisher","unstructured":"Polonikov AV, Ivanov VP, Bogomazov AD, Freidin MB, Illig T, Solodilova MA. Antioxidant defense enzyme genes and asthma susceptibility: gender-specific effects and heterogeneity in gene-gene interactions between pathogenetic variants of the disease. BioMed Research International. 2014; 2014: 708903.","DOI":"10.1155\/2014\/708903"},{"key":"ref11","doi-asserted-by":"publisher","unstructured":"Demenais F, Margaritte-Jeannin P, Barnes KC, Cookson WOC, Altm\u00fcller J, Ang W, et al. Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks. Nature Genetics. 2018; 50: 42\u201353.","DOI":"10.1038\/s41588-017-0014-7"},{"key":"ref12","doi-asserted-by":"publisher","unstructured":"Dai F, Lin X, Chang C, Feng XH. Nuclear export of Smad2 and Smad3 by RanBP3 facilitates termination of TGF-beta signaling. Developmental Cell. 2009; 16: 345\u2013357.","DOI":"10.1016\/j.devcel.2009.01.022"},{"key":"ref13","doi-asserted-by":"publisher","unstructured":"Gu W, Lei J, Zhu H, Xiao Y, Zhang Z, Zhao L. Effect of the BMPR-II-SMAD3\/MRTF pathway on proliferation and migration of ASMCs and the mechanism in asthma. Molecular Biology Reports. 2022; 49: 9283\u20139296.","DOI":"10.1007\/s11033-022-07764-9"},{"key":"ref14","doi-asserted-by":"publisher","unstructured":"Anthoni M, Fyhrquist-Vanni N, Wolff H, Alenius H, Lauerma A. Transforming growth factor-beta\/Smad3 signalling regulates inflammatory responses in a murine model of contact hypersensitivity. The British Journal of Dermatology. 2008; 159: 546\u2013554.","DOI":"10.1111\/j.1365-2133.2008.08696.x"},{"key":"ref15","doi-asserted-by":"publisher","unstructured":"Ferreira MAR, Mathur R, Vonk JM, Szwajda A, Brumpton B, Granell R, et al. Genetic Architectures of Childhood- and Adult-Onset Asthma Are Partly Distinct. American Journal of Human Genetics. 2019; 104: 665\u2013684.","DOI":"10.1016\/j.ajhg.2019.02.022"},{"key":"ref16","doi-asserted-by":"publisher","unstructured":"Johansson \u00c5, Rask-Andersen M, Karlsson T, Ek WE. Genome-wide association analysis of 350 000 Caucasians from the UK Biobank identifies novel loci for asthma, hay fever and eczema. Human Molecular Genetics. 2019; 28: 4022\u20134041.","DOI":"10.1093\/hmg\/ddz175"},{"key":"ref17","doi-asserted-by":"publisher","unstructured":"Han Y, Jia Q, Jahani PS, Hurrell BP, Pan C, Huang P, et al. Genome-wide analysis highlights contribution of immune system pathways to the genetic architecture of asthma. Nature Communications. 2020; 11: 1776.","DOI":"10.1038\/s41467-020-15649-3"},{"key":"ref18","unstructured":"Federal clinical recommendations for the diagnosis and treatment of bronchial asthma\/Russian Association of Allergists and Immunologists. 2024. Available at: https:\/\/spulmo.ru\/upload\/kr\/BA_2024_draft.pdf?ysclid=m6fewuppeg855379756 (Accessed: 17 October 2024)."},{"key":"ref19","doi-asserted-by":"publisher","unstructured":"Polonikov AV, Ivanov VP, Solodilova MA, Khoroshaya IV, Kozhuhov MA, Panfilov VI. The relationship between polymorphisms in the glutamate cysteine ligase gene and asthma susceptibility. Respiratory Medicine. 2007; 101: 2422\u20132424.","DOI":"10.1016\/j.rmed.2007.06.012"},{"key":"ref20","doi-asserted-by":"publisher","unstructured":"Polonikov AV, Solodilova MA, Ivanov VP. Genetic variation of myeloperoxidase gene contributes to atopic asthma susceptibility: a preliminary association study in Russian population. The Journal of Asthma: Official Journal of the Association for the Care of Asthma. 2009; 46: 523\u2013528.","DOI":"10.1080\/02770900902818389"},{"key":"ref21","doi-asserted-by":"publisher","unstructured":"Polonikov AV, Ivanov VP, Solodilova MA, Khoroshaya IV, Kozhuhov MA, Panfilov VI. Promoter polymorphism G-50T of a human CYP2J2 epoxygenase gene is associated with common susceptibility to asthma. Chest. 2007; 132: 120\u2013126.","DOI":"10.1378\/chest.07-0371"},{"key":"ref22","doi-asserted-by":"publisher","unstructured":"Stetskaya TA, Kobzeva KA, Zaytsev SM, Shilenok IV, Komkova GV, Goryainova NV, et al. HSPD1 gene polymorphism is associated with an increased risk of ischemic stroke in smokers. Research Results in Biomedicine. 2024; 10: 175\u2013186.","DOI":"10.18413\/2658-6533-2024-10-2-0-1"},{"key":"ref23","doi-asserted-by":"publisher","unstructured":"Sol\u00e9 X, Guin\u00f3 E, Valls J, Iniesta R, Moreno V. SNPStats: a web tool for the analysis of association studies. Bioinformatics (Oxford, England). 2006; 22: 1928\u20131929.","DOI":"10.1093\/bioinformatics\/btl268"},{"key":"ref24","doi-asserted-by":"publisher","unstructured":"Waage J, Standl M, Curtin JA, Jessen LE, Thorsen J, Tian C, et al. Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis. Nature Genetics. 2018; 50: 1072\u20131080.","DOI":"10.1038\/s41588-018-0157-1"},{"key":"ref25","doi-asserted-by":"publisher","unstructured":"Tanaka N, Koido M, Suzuki A, Otomo N, Suetsugu H, Kochi Y, et al. Eight novel susceptibility loci and putative causal variants in atopic dermatitis. The Journal of Allergy and Clinical Immunology. 2021; 148: 1293\u20131306.","DOI":"10.1016\/j.jaci.2021.04.019"},{"key":"ref26","doi-asserted-by":"publisher","unstructured":"Ellinghaus D, Jostins L, Spain SL, Cortes A, Bethune J, Han B, et al. Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci. Nature Genetics. 2016; 48: 510\u2013518.","DOI":"10.1038\/ng.3528"},{"key":"ref27","doi-asserted-by":"publisher","unstructured":"Li YR, Li J, Zhao SD, Bradfield JP, Mentch FD, Maggadottir SM, et al. Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases. Nature Medicine. 2015; 21: 1018\u20131027.","DOI":"10.1038\/nm.3933"},{"key":"ref28","doi-asserted-by":"publisher","unstructured":"Palomares O, Mart\u00edn-Fontecha M, Lauener R, Traidl-Hoffmann C, Cavkaytar O, Akdis M, et al. Regulatory T cells and immune regulation of allergic diseases: roles of IL-10 and TGF-\u03b2. Genes and Immunity. 2014; 15: 511\u2013520.","DOI":"10.1038\/gene.2014.45"},{"key":"ref29","doi-asserted-by":"publisher","unstructured":"Frischmeyer-Guerrerio PA, Guerrerio AL, Oswald G, Chichester K, Myers L, Halushka MK, et al. TGF\u03b2 receptor mutations impose a strong predisposition for human allergic disease. Science Translational Medicine. 2013; 5: 195ra94.","DOI":"10.1126\/scitranslmed.3006448"},{"key":"ref30","doi-asserted-by":"publisher","unstructured":"Anthoni M, Wang G, Leino MS, Lauerma AI, Alenius HT, Wolff HJ. Smad3 -signalling and Th2 cytokines in normal mouse airways and in a mouse model of asthma. International Journal of Biological Sciences. 2007; 3: 477\u2013485.","DOI":"10.7150\/ijbs.3.477"},{"key":"ref31","doi-asserted-by":"publisher","unstructured":"Anthoni M, Fyhrquist N, Lehtim\u00e4ki S, Alenius H, Wolff H, Lauerma A. Smad3 regulates dermal cytokine and chemokine expression and specific antibody production in murine responses to a respiratory chemical sensitizer. International Archives of Allergy and Immunology. 2010; 151: 155\u2013167.","DOI":"10.1159\/000236006"},{"key":"ref32","doi-asserted-by":"publisher","unstructured":"Ghozal M, Kadawathagedara M, Delvert R, Divaret-Chauveau A, Raherison C, Varraso R, et al. Prenatal dietary exposure to mixtures of chemicals is associated with allergy or respiratory diseases in children in the ELFE nationwide cohort. Environmental Health: a Global Access Science Source. 2024; 23: 5.","DOI":"10.1186\/s12940-023-01046-y"},{"key":"ref33","doi-asserted-by":"publisher","unstructured":"Ghozal M, Delvert R, Adel-Patient K, Tafflet M, Annesi-Maesano I, Cr\u00e9pet A, et al. Dietary exposure to mixtures of chemicals in the first year of life and allergic and respiratory diseases up to 8 years in the French EDEN mother-child cohort. Food and Chemical Toxicology: an International Journal Published for the British Industrial Biological Research Association. 2025; 196: 115167.","DOI":"10.1016\/j.fct.2024.115167"},{"key":"ref34","doi-asserted-by":"publisher","unstructured":"Schnabl B, Kweon YO, Frederick JP, Wang XF, Rippe RA, Brenner DA. The role of Smad3 in mediating mouse hepatic stellate cell activation. Hepatology (Baltimore, Md.). 2001; 34: 89\u2013100.","DOI":"10.1053\/jhep.2001.25349"},{"key":"ref35","doi-asserted-by":"publisher","unstructured":"Shafi T, Rasool R, Ayub S, Bhat IA, Gull A, Hussain S, et al. Analysis of intronic SNP (rs4147358) and expression of SMAD3 gene in Atopic Dermatitis: A case-control study. Immunobiology. 2023; 228: 152390.","DOI":"10.1016\/j.imbio.2023.152390"},{"key":"ref36","doi-asserted-by":"publisher","unstructured":"Shafi T, Rasool Wani R, Hussain S, Bhat IA, Makhdoomi R, Bashir SA, et al. Investigating dysregulation of TGF-\u03b21\/SMAD3 signaling in atopic dermatitis: a molecular and immunohistochemical analysis. Clinical and Experimental Immunology. 2024; 216: 192\u2013199.","DOI":"10.1093\/cei\/uxad130"},{"key":"ref37","unstructured":"Solodilova MA, Ivanov VP, Polonikov AV, Khoroshaia IV, Kozhukhov MA, Panfilov VI. Heterozygosity of 198LEU mutant allele in glutathione peroxidase-1 gene as a risk factor of bronchial asthma associated with smoking. Terapevticheskii Arkhiv. 2007; 79: 33\u201336."},{"key":"ref38","unstructured":"Polonikov AV, Ivanov VP, Solodilova MA, Kozhukhov MA, Panfilov VI, Bulgakova IV. Polymorphism -930A > G of the cytochrome b gene is a novel genetic marker of predisposition to bronchial asthma. Terapevticheskii Arkhiv. 2009; 81: 31\u201335."}],"container-title":["Frontiers in Bioscience-Scholar"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.imrpress.com\/journal\/FBS\/18\/2\/10.31083\/FBS46479","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T12:06:54Z","timestamp":1783426014000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.imrpress.com\/journal\/FBS\/18\/2\/10.31083\/FBS46479"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,21]]},"references-count":38,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2026]]}},"alternative-id":["S1945-0516(26)02857-0"],"URL":"https:\/\/doi.org\/10.31083\/fbs46479","relation":{},"ISSN":["1945-0516","1945-0524"],"issn-type":[{"value":"1945-0516","type":"print"},{"value":"1945-0524","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,21]]},"article-number":"46479"}}