Toll-like receptor 4 (TLR-4) polymorphisms and asthma risk in rural and urban settings: findings from the UK biobank
Keywords:
Polymorphisms within the TLR4gene, asthma, residential area such as rural versus urban, early/late onset asthma, asthma with allergy
Abstract
Introduction and aim: The risk of asthma and its phenotypes may be modified by gene-environmental interactions. The previous studies on the interactions between genetic variations in the toll like 4 (TLR4), the main receptor for bacterial endotoxin, and asthma were contradictory as they were underpowered and did not consider different asthma phenotypes. The main aim of this study was to identify interactions between two single nucleotide polymorphisms (SNPs) within the TLR4 gene, Asp299Gly and Thr399Ile, and residential area (urban or rural) in females and males with asthma and different asthma phenotypes.
Method: This study was performed on 38,332 asthmatics and 322,852 non-asthma (both British Caucasians) subjects from the UK Biobank database. Asthma was also divided into phenotypes, such as asthma with/without allergy and early/late onset asthma. The residential area was based on the population area density and classified as urban or rural living. Multivariate regression models adjusted for age, body mass index, and smoking status were used to analyze interactions between the SNPs, residential area in asthma, and asthma phenotypes. The association between asthma and residential area or the SNPs was also determined.
Result: There were no significant associations between the SNPs and asthma risk (for Asp299Gly: OR (95% CI): 1.00 (0.97–1.02), for Thr399Ile: 0.99 (0.96–1.02) or between the SNPs and asthma phenotypes in either sex or combined cohorts. The effects of the SNPs were not modified by residential area population density in either sex with asthma or across asthma phenotypes. Asthma and its phenotypes were not associated with the SNPs or residential area.
Conclusions: Our study found no statistically significant association between TLR4 polymorphisms and asthma, regardless of sex or residential area. Further studies are needed to clarify the functional impact of TLR4 variation in asthma pathophysiology.
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References
1. Wang Z, Li Y, Gao Y, Fu Y, Lin J, Lei X, et al. Global, regional, and national burden of asthma and its attributable risk factors from 1990 to 2019: a systematic analysis for the Global Burden of Disease Study 2019. Respir Res. 2023;24:169. doi: 10.1186/s12931-023-02475-6
2. Ricciardolo FLM, Guida G, Bertolini F, Di Stefano A, Carriero V. Phenotype overlap in the natural history of asthma. Eur Respir Rev. 2023;32: e220201. doi: 10.1183/16000617.0201-2022
3. Kisiel MA, Zhou X, Sundh J, Stallberg B, Lisspers K, Malinovschi A, et al. Data-driven questionnaire-based cluster analysis of asthma in Swedish adults. NPJ Prim Care Respir Med. 2020;30:14. doi: 10.1038/s41533-020-0168-0
4. Kaur R, Chupp G. Phenotypes and endotypes of adult asthma: moving toward precision medicine. J Allergy Clin Immunol. 2019;144:1–12. doi: 10.1016/j.jaci.2019.05.031
5. Singh J, Schwartz DA. Endotoxin and the lung: insight into the host-environment interaction. J Allergy Clin Immunol. 2005;115:330–3. doi: 10.1016/j.jaci.2004.11.021
6. Strachan DP. Hay fever, hygiene, and household size. BMJ. 1989;299:1259–60. doi: 10.1136/bmj.299.6710.1259
7. Tang HHF, Teo SM, Sly PD, Holt PG, Inouye M. The intersect of genetics, environment, and microbiota in asthma-perspectives and challenges. J Allergy Clin Immunol. 2021;147:781–93. doi: 10.1016/j.jaci.2020.08.026
8. Suarez-Martinez C, Santaella-Pascual M, Yague-Guirao G, Garcia-Marcos L, Ros G, Martinez-Gracia C. The early appearance of asthma and its relationship with gut microbiota: a narrative review. Microorganisms. 2024;12:e1471. doi: 10.3390/microorganisms12071471
9. Yu J, Liu X, Li Y, Meng S, Wu F, Yan B, et al. Maternal exposure to farming environment protects offspring against allergic diseases by modulating the neonatal TLR-Tregs-Th axis. Clin Transl Allergy. 2018;8:34. doi: 10.1186/s13601-018-0220-0
10. van Beveren GJ, Said H, van Houten MA, Bogaert D. The respiratory microbiome in childhood asthma. J Allergy Clin Immunol. 2023;152:1352–67. doi: 10.1016/j.jaci.2023.10.001
11. Zakeri A, Russo M. Dual role of toll-like receptors in human and experimental asthma models. Front Immunol. 2018;9:1027. doi: 10.3389/fimmu.2018.01027
12. Gauthier AE, Rotjan RD, Kagan JC. Lipopolysaccharide detection by the innate immune system may be an uncommon defence strategy used in nature. Open Biol. 2022;12:220146. doi: 10.1098/rsob.220146
13. Wenger M, Grosse-Kathoefer S, Kraiem A, Pelamatti E, Nunes N, Pointner L, et al. When the allergy alarm bells toll: the role of Toll-like receptors in allergic diseases and treatment. Front Mol Biosci. 2023;10:1204025. doi: 10.3389/fmolb.2023.1204025
14. Guo N, Tian H, Song T, Peng Y. Association of TLR4 gene rs4986790 and rs4986791 polymorphisms with asthma susceptibility: meta-analysis and trial sequential analysis. Ann Saudi Med. 2024;44:183–94. doi: 10.5144/0256-4947.2024.183
15. Arbour NC, Lorenz E, Schutte BC, Zabner J, Kline JN, Jones M, et al. TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet. 2000;25:187–91. doi: 10.1038/76048
16. Adjers K, Karjalainen J, Pessi T, Eklund C, Hurme M. Epistatic effect of TLR4 and IL4 genes on the risk of asthma in females. Int Arch Allergy Immunol. 2005;138:251–6. doi: 10.1159/000088726
17. Hussein YM, Awad HA, Shalaby SM, Ali AS, Alzahrani SS. Toll-like receptor 2 and Toll-like receptor 4 polymorphisms and susceptibility to asthma and allergic rhinitis: a case-control analysis. Cell Immunol. 2012;274:34–8. doi: 10.1016/j.cellimm.2012.02.006
18. Li S, Xie X, Song Y, Jiang H, Wu X, Su X, et al. Association of TLR4 (896A/G and 1196C/T) gene polymorphisms with asthma risk: a meta-analysis. Med Sci Monit. 2015;21:3591–9. doi: 10.12659/MSM.895380
19. Smit LA, Bongers SI, Ruven HJ, Rijkers GT, Wouters IM, Heederik D, et al. Atopy and new-onset asthma in young Danish farmers and CD14, TLR2, and TLR4 genetic polymorphisms: a nested case-control study. Clin Exp Allergy. 2007;37:1602–8. doi: 10.1111/j.1365-2222.2007.02831.x
20. Tizaoui K, Kaabachi W, Hamzaoui K, Hamzaoui A. Association of single nucleotide polymorphisms in toll-like receptor genes with asthma risk: a systematic review and meta-analysis. Allergy Asthma Immunol Res. 2015;7:130–40. doi: 10.4168/aair.2015.7.2.130
21. Debinska A, Danielewicz H, Drabik-Chamerska A, Kalita D, Boznanski A. Genetic polymorphisms in pattern recognition receptors are associated with allergic diseases through gene-gene interactions. Adv Clin Exp Med. 2019;28:1087–94. doi: 10.17219/acem/104538
22. Sudlow C, Gallacher J, Allen N, Beral V, Burton P, Danesh J, et al. UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med. 2015;12:e1001779. doi: 10.1371/journal.pmed.1001779
23. Bycroft C, Freeman C, Petkova D, Band G, Elliott LT, Sharp K, et al. The UK Biobank resource with deep phenotyping and genomic data. Nature. 2018;562:203–9. doi: 10.1038/s41586-018-0579-z
24. Tan DJ, Walters EH, Perret JL, Lodge CJ, Lowe AJ, Matheson MC, et al. Age-of-asthma onset as a determinant of different asthma phenotypes in adults: a systematic review and meta-analysis of the literature. Expert Rev Respir Med. 2015;9:109–23. doi: 10.1586/17476348.2015.1000311
25. Office for National Statistics (ONS). 2011 Census: Rural-Urban Classification; 2013. Available from: https://www.ons.gov.uk/ [cited 20 June 2025].
26. Keller MC. Gene x environment interaction studies have not properly controlled for potential confounders: the problem and the (simple) solution. Biol Psychiatry. 2014;75:18–24. doi: 10.1016/j.biopsych.2013.09.006
27. Team RC. R: a language and environment for statistical computing. Vienna: R Foundation for Statistical Computing; 2021. Available from: https://www.R-project.org/ [cited 20 June 2025].
28. Lau MY, Dharmage SC, Burgess JA, Win AK, Lowe AJ, Lodge C, et al. The interaction between farming/rural environment and TLR2, TLR4, TLR6 and CD14 genetic polymorphisms in relation to early- and late-onset asthma. Sci Rep. 2017;7:43681. doi: 10.1038/srep43681
29. Schurman SH, Bravo MA, Innes CL, Jackson WB, McGrath JA, Miranda ML, et al. Toll-like receptor 4 pathway polymorphisms interact with pollution to influence asthma diagnosis and severity. Sci Rep. 2018;8:12713. doi: 10.1038/s41598-018-30865-0
30. Yang IA, Barton SJ, Rorke S, Cakebread JA, Keith TP, Clough JB, et al. Toll-like receptor 4 polymorphism and severity of atopy in asthmatics. Genes Immun. 2004;5:41–5. doi: 10.1038/sj.gene.6364037
31. Fageras Bottcher M, Hmani-Aifa M, Lindstrom A, Jenmalm MC, Mai XM, Nilsson L, et al. A TLR4 polymorphism is associated with asthma and reduced lipopolysaccharide-induced interleukin-12(p70) responses in Swedish children. J Allergy Clin Immunol. 2004;114:561–7. doi: 10.1016/j.jaci.2004.04.050
32. Sackesen C, Karaaslan C, Keskin O, Tokol N, Tahan F, Civelek E, et al. The effect of polymorphisms at the CD14 promoter and the TLR4 gene on asthma phenotypes in Turkish children with asthma. Allergy. 2005;60:1485–92. doi: 10.1111/j.1398-9995.2005.00874.x
33. Chiarella P, Capone P, Sisto R. Contribution of genetic polymorphisms in human health. Int J Environ Res Public Health. 2023;20:e912. doi: 10.3390/ijerph20020912
34. Lee AJ, Ro M, Cho KJ, Kim JH. Lipopolysaccharide/TLR4 stimulates IL-13 production through a MyD88-BLT2-linked cascade in mast cells, potentially contributing to the allergic response. J Immunol. 2017;199:409–17. doi: 10.4049/jimmunol.1602062
35. Yang IV, Lozupone CA, Schwartz DA. The environment, epigenome, and asthma. J Allergy Clin Immunol. 2017;140:14–23. doi: 10.1016/j.jaci.2017.05.011
36. Wieringa MH, Weyler JJ, Van Bastelaer FJ, Nelen VJ, Van Sprundel MP, Vermeire PA. Higher asthma occurrence in an urban than a suburban area: role of house dust mite skin allergy. Eur Respir J. 1997;10:1460–6. doi: 10.1183/09031936.97.10071460
37. Wieringa MH, Vermeire PA, Van Bever HP, Nelen VJ, Weyler JJ. Higher occurrence of asthma-related symptoms in an urban than a suburban area in adults, but not in children. Eur Respir J. 2001;17:422–7. doi: 10.1183/09031936.01.17304220
38. Nicolaou N, Siddique N, Custovic A. Allergic disease in urban and rural populations: increasing prevalence with increasing urbanization. Allergy. 2005;60:1357–60. doi: 10.1111/j.1398-9995.2005.00961.x
39. Batty GD, Gale CR, Kivimaki M, Deary IJ, Bell S. Comparison of risk factor associations in UK Biobank against representative, general population based studies with conventional response rates: prospective cohort study and individual participant meta-analysis. BMJ. 2020;368:m131. doi: 10.1136/bmj.m131
40. Burrows B, Martinez FD, Halonen M, Barbee RA, Cline MG. Association of asthma with serum IgE levels and skin-test reactivity to allergens. N Engl J Med. 1989;320:271–7. doi: 10.1056/NEJM198902023200502
41. Abdellaoui A, Yengo L, Verweij KJH, Visscher PM. 15 years of GWAS discovery: realizing the promise. Am J Hum Genet. 2023;110:179–94. doi: 10.1016/j.ajhg.2022.12.011
42. Majumdar A, Burch KS, Haldar T, Sankararaman S, Pasaniuc B, Gauderman WJ, et al. A two-step approach to testing overall effect of gene-environment interaction for multiple phenotypes. Bioinformatics. 2021;36:5640–8. doi: 10.1093/bioinformatics/btaa1083
2. Ricciardolo FLM, Guida G, Bertolini F, Di Stefano A, Carriero V. Phenotype overlap in the natural history of asthma. Eur Respir Rev. 2023;32: e220201. doi: 10.1183/16000617.0201-2022
3. Kisiel MA, Zhou X, Sundh J, Stallberg B, Lisspers K, Malinovschi A, et al. Data-driven questionnaire-based cluster analysis of asthma in Swedish adults. NPJ Prim Care Respir Med. 2020;30:14. doi: 10.1038/s41533-020-0168-0
4. Kaur R, Chupp G. Phenotypes and endotypes of adult asthma: moving toward precision medicine. J Allergy Clin Immunol. 2019;144:1–12. doi: 10.1016/j.jaci.2019.05.031
5. Singh J, Schwartz DA. Endotoxin and the lung: insight into the host-environment interaction. J Allergy Clin Immunol. 2005;115:330–3. doi: 10.1016/j.jaci.2004.11.021
6. Strachan DP. Hay fever, hygiene, and household size. BMJ. 1989;299:1259–60. doi: 10.1136/bmj.299.6710.1259
7. Tang HHF, Teo SM, Sly PD, Holt PG, Inouye M. The intersect of genetics, environment, and microbiota in asthma-perspectives and challenges. J Allergy Clin Immunol. 2021;147:781–93. doi: 10.1016/j.jaci.2020.08.026
8. Suarez-Martinez C, Santaella-Pascual M, Yague-Guirao G, Garcia-Marcos L, Ros G, Martinez-Gracia C. The early appearance of asthma and its relationship with gut microbiota: a narrative review. Microorganisms. 2024;12:e1471. doi: 10.3390/microorganisms12071471
9. Yu J, Liu X, Li Y, Meng S, Wu F, Yan B, et al. Maternal exposure to farming environment protects offspring against allergic diseases by modulating the neonatal TLR-Tregs-Th axis. Clin Transl Allergy. 2018;8:34. doi: 10.1186/s13601-018-0220-0
10. van Beveren GJ, Said H, van Houten MA, Bogaert D. The respiratory microbiome in childhood asthma. J Allergy Clin Immunol. 2023;152:1352–67. doi: 10.1016/j.jaci.2023.10.001
11. Zakeri A, Russo M. Dual role of toll-like receptors in human and experimental asthma models. Front Immunol. 2018;9:1027. doi: 10.3389/fimmu.2018.01027
12. Gauthier AE, Rotjan RD, Kagan JC. Lipopolysaccharide detection by the innate immune system may be an uncommon defence strategy used in nature. Open Biol. 2022;12:220146. doi: 10.1098/rsob.220146
13. Wenger M, Grosse-Kathoefer S, Kraiem A, Pelamatti E, Nunes N, Pointner L, et al. When the allergy alarm bells toll: the role of Toll-like receptors in allergic diseases and treatment. Front Mol Biosci. 2023;10:1204025. doi: 10.3389/fmolb.2023.1204025
14. Guo N, Tian H, Song T, Peng Y. Association of TLR4 gene rs4986790 and rs4986791 polymorphisms with asthma susceptibility: meta-analysis and trial sequential analysis. Ann Saudi Med. 2024;44:183–94. doi: 10.5144/0256-4947.2024.183
15. Arbour NC, Lorenz E, Schutte BC, Zabner J, Kline JN, Jones M, et al. TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet. 2000;25:187–91. doi: 10.1038/76048
16. Adjers K, Karjalainen J, Pessi T, Eklund C, Hurme M. Epistatic effect of TLR4 and IL4 genes on the risk of asthma in females. Int Arch Allergy Immunol. 2005;138:251–6. doi: 10.1159/000088726
17. Hussein YM, Awad HA, Shalaby SM, Ali AS, Alzahrani SS. Toll-like receptor 2 and Toll-like receptor 4 polymorphisms and susceptibility to asthma and allergic rhinitis: a case-control analysis. Cell Immunol. 2012;274:34–8. doi: 10.1016/j.cellimm.2012.02.006
18. Li S, Xie X, Song Y, Jiang H, Wu X, Su X, et al. Association of TLR4 (896A/G and 1196C/T) gene polymorphisms with asthma risk: a meta-analysis. Med Sci Monit. 2015;21:3591–9. doi: 10.12659/MSM.895380
19. Smit LA, Bongers SI, Ruven HJ, Rijkers GT, Wouters IM, Heederik D, et al. Atopy and new-onset asthma in young Danish farmers and CD14, TLR2, and TLR4 genetic polymorphisms: a nested case-control study. Clin Exp Allergy. 2007;37:1602–8. doi: 10.1111/j.1365-2222.2007.02831.x
20. Tizaoui K, Kaabachi W, Hamzaoui K, Hamzaoui A. Association of single nucleotide polymorphisms in toll-like receptor genes with asthma risk: a systematic review and meta-analysis. Allergy Asthma Immunol Res. 2015;7:130–40. doi: 10.4168/aair.2015.7.2.130
21. Debinska A, Danielewicz H, Drabik-Chamerska A, Kalita D, Boznanski A. Genetic polymorphisms in pattern recognition receptors are associated with allergic diseases through gene-gene interactions. Adv Clin Exp Med. 2019;28:1087–94. doi: 10.17219/acem/104538
22. Sudlow C, Gallacher J, Allen N, Beral V, Burton P, Danesh J, et al. UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med. 2015;12:e1001779. doi: 10.1371/journal.pmed.1001779
23. Bycroft C, Freeman C, Petkova D, Band G, Elliott LT, Sharp K, et al. The UK Biobank resource with deep phenotyping and genomic data. Nature. 2018;562:203–9. doi: 10.1038/s41586-018-0579-z
24. Tan DJ, Walters EH, Perret JL, Lodge CJ, Lowe AJ, Matheson MC, et al. Age-of-asthma onset as a determinant of different asthma phenotypes in adults: a systematic review and meta-analysis of the literature. Expert Rev Respir Med. 2015;9:109–23. doi: 10.1586/17476348.2015.1000311
25. Office for National Statistics (ONS). 2011 Census: Rural-Urban Classification; 2013. Available from: https://www.ons.gov.uk/ [cited 20 June 2025].
26. Keller MC. Gene x environment interaction studies have not properly controlled for potential confounders: the problem and the (simple) solution. Biol Psychiatry. 2014;75:18–24. doi: 10.1016/j.biopsych.2013.09.006
27. Team RC. R: a language and environment for statistical computing. Vienna: R Foundation for Statistical Computing; 2021. Available from: https://www.R-project.org/ [cited 20 June 2025].
28. Lau MY, Dharmage SC, Burgess JA, Win AK, Lowe AJ, Lodge C, et al. The interaction between farming/rural environment and TLR2, TLR4, TLR6 and CD14 genetic polymorphisms in relation to early- and late-onset asthma. Sci Rep. 2017;7:43681. doi: 10.1038/srep43681
29. Schurman SH, Bravo MA, Innes CL, Jackson WB, McGrath JA, Miranda ML, et al. Toll-like receptor 4 pathway polymorphisms interact with pollution to influence asthma diagnosis and severity. Sci Rep. 2018;8:12713. doi: 10.1038/s41598-018-30865-0
30. Yang IA, Barton SJ, Rorke S, Cakebread JA, Keith TP, Clough JB, et al. Toll-like receptor 4 polymorphism and severity of atopy in asthmatics. Genes Immun. 2004;5:41–5. doi: 10.1038/sj.gene.6364037
31. Fageras Bottcher M, Hmani-Aifa M, Lindstrom A, Jenmalm MC, Mai XM, Nilsson L, et al. A TLR4 polymorphism is associated with asthma and reduced lipopolysaccharide-induced interleukin-12(p70) responses in Swedish children. J Allergy Clin Immunol. 2004;114:561–7. doi: 10.1016/j.jaci.2004.04.050
32. Sackesen C, Karaaslan C, Keskin O, Tokol N, Tahan F, Civelek E, et al. The effect of polymorphisms at the CD14 promoter and the TLR4 gene on asthma phenotypes in Turkish children with asthma. Allergy. 2005;60:1485–92. doi: 10.1111/j.1398-9995.2005.00874.x
33. Chiarella P, Capone P, Sisto R. Contribution of genetic polymorphisms in human health. Int J Environ Res Public Health. 2023;20:e912. doi: 10.3390/ijerph20020912
34. Lee AJ, Ro M, Cho KJ, Kim JH. Lipopolysaccharide/TLR4 stimulates IL-13 production through a MyD88-BLT2-linked cascade in mast cells, potentially contributing to the allergic response. J Immunol. 2017;199:409–17. doi: 10.4049/jimmunol.1602062
35. Yang IV, Lozupone CA, Schwartz DA. The environment, epigenome, and asthma. J Allergy Clin Immunol. 2017;140:14–23. doi: 10.1016/j.jaci.2017.05.011
36. Wieringa MH, Weyler JJ, Van Bastelaer FJ, Nelen VJ, Van Sprundel MP, Vermeire PA. Higher asthma occurrence in an urban than a suburban area: role of house dust mite skin allergy. Eur Respir J. 1997;10:1460–6. doi: 10.1183/09031936.97.10071460
37. Wieringa MH, Vermeire PA, Van Bever HP, Nelen VJ, Weyler JJ. Higher occurrence of asthma-related symptoms in an urban than a suburban area in adults, but not in children. Eur Respir J. 2001;17:422–7. doi: 10.1183/09031936.01.17304220
38. Nicolaou N, Siddique N, Custovic A. Allergic disease in urban and rural populations: increasing prevalence with increasing urbanization. Allergy. 2005;60:1357–60. doi: 10.1111/j.1398-9995.2005.00961.x
39. Batty GD, Gale CR, Kivimaki M, Deary IJ, Bell S. Comparison of risk factor associations in UK Biobank against representative, general population based studies with conventional response rates: prospective cohort study and individual participant meta-analysis. BMJ. 2020;368:m131. doi: 10.1136/bmj.m131
40. Burrows B, Martinez FD, Halonen M, Barbee RA, Cline MG. Association of asthma with serum IgE levels and skin-test reactivity to allergens. N Engl J Med. 1989;320:271–7. doi: 10.1056/NEJM198902023200502
41. Abdellaoui A, Yengo L, Verweij KJH, Visscher PM. 15 years of GWAS discovery: realizing the promise. Am J Hum Genet. 2023;110:179–94. doi: 10.1016/j.ajhg.2022.12.011
42. Majumdar A, Burch KS, Haldar T, Sankararaman S, Pasaniuc B, Gauderman WJ, et al. A two-step approach to testing overall effect of gene-environment interaction for multiple phenotypes. Bioinformatics. 2021;36:5640–8. doi: 10.1093/bioinformatics/btaa1083
Published
2025-07-04
How to Cite
Kisiel , M. A., Rask-Andersen , M., Johansson , Åsa, Ek , W. E., & Rask-Andersen , A. (2025). Toll-like receptor 4 (TLR-4) polymorphisms and asthma risk in rural and urban settings: findings from the UK biobank. Upsala Journal of Medical Sciences, 130, e12243. https://doi.org/10.48101/ujms.v130.12243
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