Role of Mannose-binding Lectin-2 Promoter Genetic Variants in Susceptibility to Sepsis: A Meta and Trial Sequential Analysis
MBL-2 polymorphisms in Sepsis
Abstract
Mannose-binding lectin (MBL) is a critical component of the innate immune system, serving a vital role in the body’s initial defense against pathogens. Sepsis, a severe condition triggered by an excessive immune response to infection, has been linked to variations in the MBL2 gene that affect MBL levels and functionality. Numerous studies across various populations have examined the role of MBL-2 promoter polymorphisms (H>L and Y>X), but their results have been conflicting. This study aims to investigate the genetic connection between MBL promoter polymorphisms and susceptibility to sepsis through a meta-analysis of previously published articles.
A thorough literature search was conducted using PubMed, Scopus, and ScienceDirect to locate relevant articles for the meta-analysis. Rigorous inclusion and exclusion criteria were implemented to ensure data accuracy. All analyses were performed using Comprehensive Meta-Analysis Software v4.
Seven studies were included, examining the role of MBL-2 promoter genetic variants in sepsis (H>L: n=3, sepsis cases: 449, control: 687; Y>X: n=6, sepsis cases: 1211, control: 1694). Egger’s regression analysis and funnel plots suggested no publication bias. Heterogeneity analysis indicated homogeneity among the data. The meta-analysis showed no association between MBL-2 promoter variants and susceptibility to sepsis. The trial sequential analysis highlighted the need for further studies on MBL-2 promoter variants in sepsis to draw a definitive conclusion.
The promoter variants of the MBL-2 gene (H>L and Y>X) do not appear to increase the risk of sepsis. Further investigation is needed to confirm this conclusion, including more participants from diverse populations and larger sample sizes.
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2. Rudd KE, Johnson SC, Agesa KM, Shackelford KA, Tsoi D, Kievlan DR, et al. Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study. The Lancet. 2020;395(10219):200-11.
3. Markwart R, Saito H, Harder T, Tomczyk S, Cassini A, Fleischmann-Struzek C, et al. Epidemiology and burden of sepsis acquired in hospitals and intensive care units: a systematic review and meta-analysis. Intensive Care Med. 2020;46(8):1536-51.
4. Arefian H, Heublein S, Scherag A, Brunkhorst FM, Younis MZ, Moerer O, et al. Hospital-related cost of sepsis: a systematic review. Journal of Infection. 2017;74(2):107-17.
5. Honda TJ, Kazemiparkouhi F, Henry TD, Suh HH. Long-term PM2. 5 exposure and sepsis mortality in a US medicare cohort. BMC Public Health. 2022;22(1):1214.
6. Lu H, Wen D, Wang X, Gan L, Du J, Sun J, et al. Host genetic variants in sepsis risk: a field synopsis and meta-
analysis. Critical Care. 2019;23(1):26.
7. Pradeu T, Thomma BPHJ, Girardin SE, Lemaitre B. The conceptual foundations of innate immunity: Taking stock 30 years later. Immunity. 2024;57(4):613-31.
8. Nie J, Zhou L, Tian W, Liu X, Yang L, Yang X, et al. Deep insight into cytokine storm: from pathogenesis to treatment. Signal Transduction and Targeted Therapy. 2025;10(1):112.
9. Hotchkiss RS, Monneret G, Payen D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nature Reviews Immunology. 2013;13(12):862-74.
10. Wiersinga WJ, van der Poll T. Immunopathophysiology of human sepsis. eBioMedicine. 2022;86.
11. Takahashi K, Ezekowitz RA. The role of the mannose-binding lectin in innate immunity. Clin Infect Dis. 2005;41 Suppl 7:S440-4.
12. Eisen DP, Minchinton RM. Impact of mannose-binding lectin on susceptibility to infectious diseases. Clin Infect Dis. 2003;37(11):1496-505.
13. Ip WE, Takahashi K, Moore KJ, Stuart LM, Ezekowitz RAB. Mannose-binding lectin enhances Toll-like receptors 2 and 6 signaling from the phagosome. The Journal of experimental medicine. 2008;205(1):169-81.
14. Tegla CA, Cudrici C, Patel S, Trippe R, Rus V, Niculescu F, et al. Membrane attack by complement: the assembly and biology of terminal complement complexes. Immunologic Research. 2011;51(1):45-60.
15. Panda AK, Parida JR, Tripathy R, Pattanaik SS, Ravindran B, Das BK. Low producer MBL genotypes are associated with susceptibility to systemic lupus erythematosus in Odisha, India. Hum Immunol. 2013;74(1):114-9.
16. Panda AK, Parida JR, Tripathy R, Pattanaik SS, Ravindran B, Das BK. Mannose binding lectin: a biomarker of systemic lupus erythematosus disease activity. Arthritis Res Ther. 2012;14(5):R218.
17. Graudal NA, Homann C, Madsen HO, Svejgaard A, Jurik AG, Graudal HK, et al. Mannan binding lectin in rheumatoid arthritis. A longitudinal study. J Rheumatol. 1998;25(4):629-35.
18. Gupta K, Gupta RK, Hajela K. Disease associations of mannose-binding lectin & potential of replacement therapy. Indian J Med Res. 2008;127(5):431-40.
19. Jacobson S, Larsson P, Åberg AM, Johansson G, Winsö O, Söderberg S. Levels of mannose-binding lectin (MBL) associates with sepsis-related in-hospital mortality in women. J Inflamm (Lond). 2020;17:28.
20. Frakking FN, Brouwer N, van Eijkelenburg NK, Merkus MP, Kuijpers TW, Offringa M, et al. Low mannose-binding lectin (MBL) levels in neonates with pneumonia and sepsis. Clin Exp Immunol. 2007;150(2):255-62.
21. Gordon AC, Waheed U, Hansen TK, Hitman GA, Garrard CS, Turner MW, et al. Mannose-binding lectin polymorphisms in severe sepsis: relationship to levels, incidence, and outcome. Shock. 2006;25(1):88-93.
22. Mao Y, Wei H, Gong Y, Peng L, Chen Y. Association of MBL2 gene polymorphisms and MBL levels with dilated cardiomyopathy in a Chinese Han population. BMC Medical Genomics. 2024;17(1):11.
23. Tsakanova G, Stepanyan A, Steffensen R, Soghoyan A, Jensenius JC, Arakelyan A. Pattern recognition molecules of lectin complement pathway in ischemic stroke. Pharmacogenomics and personalized medicine. 2021:1347-68.
24. Das BK, Panda AK. MBL-2 polymorphisms (codon 54 and Y-221X) and low MBL levels are associated with susceptibility to multi organ dysfunction in P. falciparum malaria in Odisha, India. Front Microbiol. 2015;6:778.
25. Huh JW, Song K, Yum J-S, Hong S-B, Lim C-M, Koh Y. Association of mannose-binding lectin-2 genotype and serum levels with prognosis of sepsis. Critical Care. 2009;13:1-9.
26. Garred P, J. Strøm J, Quist L, Taaning E, Madsen HO. Association of mannose-binding lectin polymorphisms with sepsis and fatal outcome, in patients with systemic inflammatory response syndrome. The Journal of infectious diseases. 2003;188(9):1394-403.
27. Eisen DP, Dean MM, Thomas P, Marshall P, Gerns N,
Heatley S, et al. Low mannose-binding lectin function is associated with sepsis in adult patients. FEMS Immunology & Medical Microbiology. 2006;48(2):274-82.
28. Davis SM, Clark EA, Nelson LT, Silver RM. The association of innate immune response gene polymorphisms and puerperal group A streptococcal sepsis. American Journal of Obstetrics and Gynecology. 2010;202(3):308. e1-8.
29. Hellemann D, Larsson A, Madsen HO, Bonde J, Jarløv JO, Wiis J, et al. Heterozygosity of mannose-binding lectin (MBL2) genotypes predicts advantage (heterosis) in relation to fatal outcome in intensive care patients. Human molecular genetics. 2007;16(24):3071-80.
30. Mills TC, Chapman S, Hutton P, Gordon AC, Bion J, Chiche J-D, et al. Variants in the mannose-binding lectin gene MBL2 do not associate with sepsis susceptibility or survival in a large European cohort. Clinical Infectious Diseases. 2015;61(5):695-703.
31. Van Der Zwet W, Catsburg A, Van Elburg R, Savelkoul P, Vandenbroucke-Grauls C. Mannose-binding lectin (MBL) genotype in relation to risk of nosocomial infection in pre-term neonates in the neonatal intensive care unit. Clinical Microbiology and Infection. 2008;14(2):130-5.
32. Borenstein M, Hedges LV, Higgins JP, Rothstein HR. Introduction to meta-analysis: John Wiley & Sons; 2021.
33. Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. 2000.
34. Erdfelder E, Faul F, Buchner A. GPOWER: A general power analysis program. Behavior research methods, instruments, & computers. 1996;28:1-11.
35. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta‐analysis. Statistics in medicine. 2002;21(11): 1539-58.
36. Copas J, Shi JQ. Meta-analysis, funnel plots and sensitivity analysis. Biostatistics. 2000;1(3):247-62.
37. Wetterslev J, Thorlund K, Brok J, Gluud C. Trial sequential analysis may establish when firm evidence is reached in cumulative meta-analysis. Journal of clinical epidemiology. 2008;61(1):64-75.
38. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. bmj. 2021;372.
39. Panda AK. Maintaining ethics, Integrity, and accountability: Best practices for reporting a meta-
analysis. Account Res. 2024:1-3.
40. Mahto H, Pati A, Sahu SK, Sharma HP, Padhi A, Panda AK. Association of MBL-2 gene polymorphisms with systemic lupus erythematosus: an updated meta-analysis and trial sequential analysis. Lupus. 2020;29(10):1227-37.
41. Mullighan CG, Marshall SE, Welsh KI. Mannose binding lectin polymorphisms are associated with early age of disease onset and autoimmunity in common variable immunodeficiency. Scand J Immunol. 2000;51(2):111-22.
42. Rantala A, Lajunen T, Juvonen R, Bloigu A, Silvennoinen-Kassinen S, Peitso A, et al. Mannose-binding lectin concentrations, MBL2 polymorphisms, and susceptibility to respiratory tract infections in young men. Journal of Infectious Diseases. 2008;198(8):1247-53.
43. Turner MW. Mannose-binding lectin (MBL) in health and disease. Immunobiology. 1998;199(2):327-39.
44. van Engelen TSR, Joost Wiersinga W, van der Poll T. Pathogenesis of Sepsis. In: Wiersinga WJ, Seymour CW, editors. Handbook of Sepsis. Cham: Springer International Publishing; 2018. p. 31-43.
45. Beltrame MH, Boldt AB, Catarino SJ, Mendes HC, Boschmann SE, Goeldner I, et al. MBL-associated serine proteases (MASPs) and infectious diseases. Mol Immunol. 2015;67(1):85-100.
46. Meijvis SCA, Herpers BL, Endeman H, de Jong B, van Hannen E, van Velzen-Blad H, et al. Mannose-binding lectin (MBL2) and ficolin-2 (FCN2) polymorphisms in patients on peritoneal dialysis with staphylococcal peritonitis. Nephrology Dialysis Transplantation. 2010;26(3):1042-5.
47. Luo J, Xu F, Lu GJ, Lin HC, Feng ZC. Low mannose-binding lectin (MBL) levels and MBL genetic polymorphisms associated with the risk of neonatal sepsis: An updated meta-analysis. Early Hum Dev. 2014;90(10):557-64.
48. Sljivancanin Jakovljevic T, Martic J, Jacimovic J, Nikolic N, Milasin J, Mitrović TL. Association between innate immunity gene polymorphisms and neonatal sepsis development: a systematic review and meta-analysis. World J Pediatr. 2022;18(10):654-70.
49. Zhang AQ, Yue CL, Pan W, Gao JW, Zeng L, Gu W, et al. Mannose-binding lectin polymorphisms and the risk of sepsis: evidence from a meta-analysis. Epidemiol Infect. 2014;142(10):2195-206.
50. Westwood ME, Whiting PF, Kleijnen J. How does study quality affect the results of a diagnostic meta-analysis? BMC Med Res Methodol. 2005;5:20.
2. Rudd KE, Johnson SC, Agesa KM, Shackelford KA, Tsoi D, Kievlan DR, et al. Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study. The Lancet. 2020;395(10219):200-11.
3. Markwart R, Saito H, Harder T, Tomczyk S, Cassini A, Fleischmann-Struzek C, et al. Epidemiology and burden of sepsis acquired in hospitals and intensive care units: a systematic review and meta-analysis. Intensive Care Med. 2020;46(8):1536-51.
4. Arefian H, Heublein S, Scherag A, Brunkhorst FM, Younis MZ, Moerer O, et al. Hospital-related cost of sepsis: a systematic review. Journal of Infection. 2017;74(2):107-17.
5. Honda TJ, Kazemiparkouhi F, Henry TD, Suh HH. Long-term PM2. 5 exposure and sepsis mortality in a US medicare cohort. BMC Public Health. 2022;22(1):1214.
6. Lu H, Wen D, Wang X, Gan L, Du J, Sun J, et al. Host genetic variants in sepsis risk: a field synopsis and meta-
analysis. Critical Care. 2019;23(1):26.
7. Pradeu T, Thomma BPHJ, Girardin SE, Lemaitre B. The conceptual foundations of innate immunity: Taking stock 30 years later. Immunity. 2024;57(4):613-31.
8. Nie J, Zhou L, Tian W, Liu X, Yang L, Yang X, et al. Deep insight into cytokine storm: from pathogenesis to treatment. Signal Transduction and Targeted Therapy. 2025;10(1):112.
9. Hotchkiss RS, Monneret G, Payen D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nature Reviews Immunology. 2013;13(12):862-74.
10. Wiersinga WJ, van der Poll T. Immunopathophysiology of human sepsis. eBioMedicine. 2022;86.
11. Takahashi K, Ezekowitz RA. The role of the mannose-binding lectin in innate immunity. Clin Infect Dis. 2005;41 Suppl 7:S440-4.
12. Eisen DP, Minchinton RM. Impact of mannose-binding lectin on susceptibility to infectious diseases. Clin Infect Dis. 2003;37(11):1496-505.
13. Ip WE, Takahashi K, Moore KJ, Stuart LM, Ezekowitz RAB. Mannose-binding lectin enhances Toll-like receptors 2 and 6 signaling from the phagosome. The Journal of experimental medicine. 2008;205(1):169-81.
14. Tegla CA, Cudrici C, Patel S, Trippe R, Rus V, Niculescu F, et al. Membrane attack by complement: the assembly and biology of terminal complement complexes. Immunologic Research. 2011;51(1):45-60.
15. Panda AK, Parida JR, Tripathy R, Pattanaik SS, Ravindran B, Das BK. Low producer MBL genotypes are associated with susceptibility to systemic lupus erythematosus in Odisha, India. Hum Immunol. 2013;74(1):114-9.
16. Panda AK, Parida JR, Tripathy R, Pattanaik SS, Ravindran B, Das BK. Mannose binding lectin: a biomarker of systemic lupus erythematosus disease activity. Arthritis Res Ther. 2012;14(5):R218.
17. Graudal NA, Homann C, Madsen HO, Svejgaard A, Jurik AG, Graudal HK, et al. Mannan binding lectin in rheumatoid arthritis. A longitudinal study. J Rheumatol. 1998;25(4):629-35.
18. Gupta K, Gupta RK, Hajela K. Disease associations of mannose-binding lectin & potential of replacement therapy. Indian J Med Res. 2008;127(5):431-40.
19. Jacobson S, Larsson P, Åberg AM, Johansson G, Winsö O, Söderberg S. Levels of mannose-binding lectin (MBL) associates with sepsis-related in-hospital mortality in women. J Inflamm (Lond). 2020;17:28.
20. Frakking FN, Brouwer N, van Eijkelenburg NK, Merkus MP, Kuijpers TW, Offringa M, et al. Low mannose-binding lectin (MBL) levels in neonates with pneumonia and sepsis. Clin Exp Immunol. 2007;150(2):255-62.
21. Gordon AC, Waheed U, Hansen TK, Hitman GA, Garrard CS, Turner MW, et al. Mannose-binding lectin polymorphisms in severe sepsis: relationship to levels, incidence, and outcome. Shock. 2006;25(1):88-93.
22. Mao Y, Wei H, Gong Y, Peng L, Chen Y. Association of MBL2 gene polymorphisms and MBL levels with dilated cardiomyopathy in a Chinese Han population. BMC Medical Genomics. 2024;17(1):11.
23. Tsakanova G, Stepanyan A, Steffensen R, Soghoyan A, Jensenius JC, Arakelyan A. Pattern recognition molecules of lectin complement pathway in ischemic stroke. Pharmacogenomics and personalized medicine. 2021:1347-68.
24. Das BK, Panda AK. MBL-2 polymorphisms (codon 54 and Y-221X) and low MBL levels are associated with susceptibility to multi organ dysfunction in P. falciparum malaria in Odisha, India. Front Microbiol. 2015;6:778.
25. Huh JW, Song K, Yum J-S, Hong S-B, Lim C-M, Koh Y. Association of mannose-binding lectin-2 genotype and serum levels with prognosis of sepsis. Critical Care. 2009;13:1-9.
26. Garred P, J. Strøm J, Quist L, Taaning E, Madsen HO. Association of mannose-binding lectin polymorphisms with sepsis and fatal outcome, in patients with systemic inflammatory response syndrome. The Journal of infectious diseases. 2003;188(9):1394-403.
27. Eisen DP, Dean MM, Thomas P, Marshall P, Gerns N,
Heatley S, et al. Low mannose-binding lectin function is associated with sepsis in adult patients. FEMS Immunology & Medical Microbiology. 2006;48(2):274-82.
28. Davis SM, Clark EA, Nelson LT, Silver RM. The association of innate immune response gene polymorphisms and puerperal group A streptococcal sepsis. American Journal of Obstetrics and Gynecology. 2010;202(3):308. e1-8.
29. Hellemann D, Larsson A, Madsen HO, Bonde J, Jarløv JO, Wiis J, et al. Heterozygosity of mannose-binding lectin (MBL2) genotypes predicts advantage (heterosis) in relation to fatal outcome in intensive care patients. Human molecular genetics. 2007;16(24):3071-80.
30. Mills TC, Chapman S, Hutton P, Gordon AC, Bion J, Chiche J-D, et al. Variants in the mannose-binding lectin gene MBL2 do not associate with sepsis susceptibility or survival in a large European cohort. Clinical Infectious Diseases. 2015;61(5):695-703.
31. Van Der Zwet W, Catsburg A, Van Elburg R, Savelkoul P, Vandenbroucke-Grauls C. Mannose-binding lectin (MBL) genotype in relation to risk of nosocomial infection in pre-term neonates in the neonatal intensive care unit. Clinical Microbiology and Infection. 2008;14(2):130-5.
32. Borenstein M, Hedges LV, Higgins JP, Rothstein HR. Introduction to meta-analysis: John Wiley & Sons; 2021.
33. Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. 2000.
34. Erdfelder E, Faul F, Buchner A. GPOWER: A general power analysis program. Behavior research methods, instruments, & computers. 1996;28:1-11.
35. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta‐analysis. Statistics in medicine. 2002;21(11): 1539-58.
36. Copas J, Shi JQ. Meta-analysis, funnel plots and sensitivity analysis. Biostatistics. 2000;1(3):247-62.
37. Wetterslev J, Thorlund K, Brok J, Gluud C. Trial sequential analysis may establish when firm evidence is reached in cumulative meta-analysis. Journal of clinical epidemiology. 2008;61(1):64-75.
38. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. bmj. 2021;372.
39. Panda AK. Maintaining ethics, Integrity, and accountability: Best practices for reporting a meta-
analysis. Account Res. 2024:1-3.
40. Mahto H, Pati A, Sahu SK, Sharma HP, Padhi A, Panda AK. Association of MBL-2 gene polymorphisms with systemic lupus erythematosus: an updated meta-analysis and trial sequential analysis. Lupus. 2020;29(10):1227-37.
41. Mullighan CG, Marshall SE, Welsh KI. Mannose binding lectin polymorphisms are associated with early age of disease onset and autoimmunity in common variable immunodeficiency. Scand J Immunol. 2000;51(2):111-22.
42. Rantala A, Lajunen T, Juvonen R, Bloigu A, Silvennoinen-Kassinen S, Peitso A, et al. Mannose-binding lectin concentrations, MBL2 polymorphisms, and susceptibility to respiratory tract infections in young men. Journal of Infectious Diseases. 2008;198(8):1247-53.
43. Turner MW. Mannose-binding lectin (MBL) in health and disease. Immunobiology. 1998;199(2):327-39.
44. van Engelen TSR, Joost Wiersinga W, van der Poll T. Pathogenesis of Sepsis. In: Wiersinga WJ, Seymour CW, editors. Handbook of Sepsis. Cham: Springer International Publishing; 2018. p. 31-43.
45. Beltrame MH, Boldt AB, Catarino SJ, Mendes HC, Boschmann SE, Goeldner I, et al. MBL-associated serine proteases (MASPs) and infectious diseases. Mol Immunol. 2015;67(1):85-100.
46. Meijvis SCA, Herpers BL, Endeman H, de Jong B, van Hannen E, van Velzen-Blad H, et al. Mannose-binding lectin (MBL2) and ficolin-2 (FCN2) polymorphisms in patients on peritoneal dialysis with staphylococcal peritonitis. Nephrology Dialysis Transplantation. 2010;26(3):1042-5.
47. Luo J, Xu F, Lu GJ, Lin HC, Feng ZC. Low mannose-binding lectin (MBL) levels and MBL genetic polymorphisms associated with the risk of neonatal sepsis: An updated meta-analysis. Early Hum Dev. 2014;90(10):557-64.
48. Sljivancanin Jakovljevic T, Martic J, Jacimovic J, Nikolic N, Milasin J, Mitrović TL. Association between innate immunity gene polymorphisms and neonatal sepsis development: a systematic review and meta-analysis. World J Pediatr. 2022;18(10):654-70.
49. Zhang AQ, Yue CL, Pan W, Gao JW, Zeng L, Gu W, et al. Mannose-binding lectin polymorphisms and the risk of sepsis: evidence from a meta-analysis. Epidemiol Infect. 2014;142(10):2195-206.
50. Westwood ME, Whiting PF, Kleijnen J. How does study quality affect the results of a diagnostic meta-analysis? BMC Med Res Methodol. 2005;5:20.
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| Genetic predisposition to disease Innate immunity Mannose-binding iectin Meta-analysis Polymorphism Sepsis | ||
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How to Cite
1.
Shao H, Zhang J, Wu D, Zhang X, Hu C. Role of Mannose-binding Lectin-2 Promoter Genetic Variants in Susceptibility to Sepsis: A Meta and Trial Sequential Analysis. Iran J Allergy Asthma Immunol. 2026;:1-14.
