Hostname: page-component-8448b6f56d-c47g7 Total loading time: 0 Render date: 2024-04-24T23:51:23.861Z Has data issue: false hasContentIssue false
  • English
  • Français

MBL and MASP-2 concentrations in serum and MBL2 promoter polymorphisms are associated to schizophrenia

Published online by Cambridge University Press:  24 June 2014

Leslie Foldager ,
Rudi Steffensen ,
Steffen Thiel ,
Thomas Damm Als ,
Hans Jørgen Nielsen ,
Merete Nordentoft ,
Preben Bo Mortensen ,
Ole Mors  and
Jens Christian Jensenius
Leslie Foldager*
Affiliation:
Centre for Psychiatric Research, Aarhus University Hospital, Risskov, Denmark Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark
Rudi Steffensen
Affiliation:
Department of Clinical Immunology, Aalborg University Hospital, Aalborg, Denmark
Steffen Thiel
Affiliation:
Institute of Medical Microbiology and Immunology, Aarhus University, Aarhus, Denmark
Thomas Damm Als
Affiliation:
Centre for Psychiatric Research, Aarhus University Hospital, Risskov, Denmark National Institute of Aquatic Resources, Technical University of Denmark, Silkeborg, Denmark
Hans Jørgen Nielsen
Affiliation:
Department of Surgical Gastroenterology 435, Hvidovre University Hospital, Hvidovre, Denmark
Merete Nordentoft
Affiliation:
Psychiatric Centre Copenhagen, University of Copenhagen, Copenhagen, Denmark
Preben Bo Mortensen
Affiliation:
National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark
Ole Mors
Affiliation:
Centre for Psychiatric Research, Aarhus University Hospital, Risskov, Denmark
Jens Christian Jensenius
Affiliation:
Institute of Medical Microbiology and Immunology, Aarhus University, Aarhus, Denmark
*
Leslie Foldager, Centre for Psychiatric Research, Aarhus University Hospital, Risskov, Skovagervej 2, DK8240 Risskov, Denmark. Tel: +45 7847 1119; Fax: +45 7847 1108; E-mail: Leslie.Foldager@ps.rm.dk
Get access Rights & Permissions [Opens in a new window]

Extract

Objective: Causative relations between infections and psychosis, especially schizophrenia, have been speculated for more than a century, suggesting a hypothesis of association between schizophrenia and hereditary immune defects. Mannan-binding lectin (MBL) is a pattern-recognition molecule of the innate immune defence. MBL deficiency is the most common hereditary defect in the immune system and may predispose to infection and autoimmunity. Mannan-binding lectin serine protease-2 (MASP-2) is an MBL-associated serine protease mediating complement activation upon binding of MBL/MASP to microorganisms. The objective was to investigate if schizophrenia is associated with serum concentrations of MBL and MASP-2 or with genetic variants of the genes MBL2 and MASP2 encoding these proteins.

Methods: The sample consisted of 100 patients with schizophrenia and 350 controls. Concentrations of MBL and MASP-2 in serum were measured and seven single nucleotide polymorphisms known to influence these concentrations were genotyped.

Results: Significant association of disease with genetic markers was found in MBL2 but not in MASP2. Significant difference in MBL serum concentration was found between patients and controls when adjusting for MBL2 haplotypes. For concentrations of MASP-2, a significant interaction effect between a MASP2 variant and disease was found. Interestingly, MASP-2 levels also depended significantly on variants in MBL2 exon 1.

Conclusion: This study supports previous studies showing increased complement activity in patients with schizophrenia, indicates aetiological heterogeneity among patients and underlines that multilocus genotypes have to be considered when investigating effects on MBL level. It appears that inclusion of additional components from the system of complement activation is warranted.

Keywords

geneticslectin pathwaymannan-binding lectin deficiencymannan-binding lectin serine protease type 2schizophrenia
Type
Research Article
Information
Acta Neuropsychiatrica , Volume 24 , Issue 4 , August 2012 , pp. 199 - 207
Copyright
Copyright © Cambridge University Press 2011

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

References

1.Yolken, RH, Torrey, EF.Viruses, schizophrenia, and bipolar disorder. Clin Microbiol Rev 1995;8:131–145.Google Scholar
2.Eaton, WW, Byrne, M, Ewald, H et al. Association of schizophrenia and autoimmune diseases: linkage of Danish national registers. Am J Psychiatry 2006;163:521–528.CrossRefGoogle ScholarPubMed
3.Buka, SL, Tsuang, MT, Torrey, EF, Klebanoff, MA, Bernstein, D, Yolken, RH.Maternal infections and subsequent psychosis among offspring. Arch Gen Psychiatry 2001;58:1032–1037.CrossRefGoogle ScholarPubMed
4.Yolken, RH, Torrey, EF.Are some cases of psychosis caused by microbial agents? A review of the evidence. Mol Psychiatry 2008;13:470–479.Google Scholar
5.Xiao, JC, Buka, SL, Cannon, TD et al. Serological pattern consistent with infection with type I Toxoplasma gondii in mothers and risk of psychosis among adult offspring. Microbes Infect 2009;11:1011–1018.CrossRefGoogle ScholarPubMed
6.Hävik, B, Hellard, SL, Rietschel, M et al. The complement control-related genes CSMD1 and CSMD2 associate to schizophrenia. Biol Psychiatry 2011;70:35–42.Google Scholar
7.Kraus, DM, Elliott, GS, Chute, H et al. CSMD1 is a novel multiple domain complement-regulatory protein highly expressed in the central nervous system and epithelial tissues. J Immunol 2006;176:4419–4430.Google Scholar
8.Stefansson, H, Ophoff, RA, Steinberg, S et al. Common variants conferring risk of schizophrenia. Nature 2009;460: 744–747.Google Scholar
9.International Schizophrenia Consortium, Wray, NR, Stone, JL et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 2009;460: 748–752.Google Scholar
10.Shi, J, Levinson, DF, Duan, J et al. Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature 2009;460:753–757.CrossRefGoogle ScholarPubMed
11.Thiel, S, Frederiksen, PD, Jensenius, JC.Clinical manifestations of mannan-binding lectin deficiency. Mol Immunol 2006;43:86–93.Google Scholar
12.Mayilyan, KR, Weinberger, DR, Sim, RB.The complement system in schizophrenia. Drug News Perspect 2008;21: 200–210.Google ScholarPubMed
13.Garred, P, Honore, C, Ma, YJ, Munthe-Fog, L, Hummelshøj, T.MBL2, FCN1, FCN2 and FCN3-The genes behind the initiation of the lectin pathway of complement. Mol Immunol 2009;46:2737–2744.Google Scholar
14.Garred, P, Larsen, F, Seyfarth, J, Fujita, R, Madsen, HO.Mannose-binding lectin and its genetic variants. Genes Immun 2006;7:85–94.CrossRefGoogle ScholarPubMed
15.Wing, JK, Sartorius, N, Üstün, TB.Diagnosis and clinical measurement in psychiatry. A reference manual for SCAN. Cambridge: Cambridge University Press, 1998.Google Scholar
16.World Health Organization. The ICD-10 classification of mental and behavioural disorders. Diagnostic criteria for research. Geneva: World Health Organization, 1993.Google Scholar
17.American Psychiatric Association. Diagnostic and statistical manual of mental disorders. DSM-IV, 4th edn.Washington, DC: American Psychiatric Association, 1994.Google Scholar
18.Henckaerts, L, Nielsen, KR, Steffensen, R et al. Polymorphisms in innate immunity genes predispose to bacteremia and death in the medical intensive care unit. Crit Care Med 2009;37:192–201.Google Scholar
19.Mølle, I, Steffensen, R, Thiel, S, Peterslund, NA.Chemotherapy-related infections in patients with multiple myeloma: associations with mannan-binding lectin genotypes. Eur J Haematol 2006;77:19–26.Google Scholar
20.Van, HE, Houtmeyers, F, Massonet, C et al. Detection of single nucleotide polymorphisms in the mannose-binding lectin gene using minor groove binder-DNA probes. J Immunol Methods 2004;287:227–230.Google Scholar
21.Boldt, AB, Petzl-Erler, ML.A new strategy for mannose-binding lectin gene haplotyping. Hum Mutat 2002;19: 296–306.Google Scholar
22.Cedzynski, M, Szemraj, J, Swierzko, AS et al. Mannan-binding lectin insufficiency in children with recurrent infections of the respiratory system. Clin Exp Immunol 2004;136: 304–311.CrossRefGoogle ScholarPubMed
23.Skalnikova, H, Freiberger, T, Chumchalova, J, Grombirikova, H, Sediva, A.Cost-effective genotyping of human MBL2 gene mutations using multiplex PCR. J Immunol Methods 2004;295:139–147.Google Scholar
24.Boldt, AB, Messias-Reason, IJ, Meyer, D et al. Phylogenetic nomenclature and evolution of mannose-binding lectin (MBL2) haplotypes. BMC Genet 2010;11:38.Google Scholar
25.Olesen, HV, Jensenius, JC, Steffensen, R, Thiel, S, Schiøtz, PO.The mannan-binding lectin pathway and lung disease in cystic fibrosis – dysfunction of mannan-binding lectin-associated serine protease 2 (MASP-2) may be a major modifier. Clin Immunol 2006;121:324–331.CrossRefGoogle ScholarPubMed
26.Thiel, S, Møller-Kristensen, M, Jensen, L, Jensenius, JC.Assays for the functional activity of the mannan-binding lectin pathway of complement activation. Immunobiology 2002;205:446–454.Google Scholar
27.Møller-Kristensen, M, Jensenius, JC, Jensen, L et al. Levels of mannan-binding lectin-associated serine protease-2 in healthy individuals. J Immunol Methods 2003;282: 159–167.Google Scholar
28.Dommett, RM, Klein, N, Turner, MW.Mannose-binding lectin in innate immunity: past, present and future. Tissue Antigens 2006;68:193–209.CrossRefGoogle ScholarPubMed
29.Petersen, SV, Thiel, S, Jensenius, JC.The mannan-binding lectin pathway of complement activation: biology and disease association. Mol Immunol 2001;38:133–149.CrossRefGoogle ScholarPubMed
30.Browning, SR, Browning, BL.Rapid and accurate haplotype phasing and missing-data inference for whole-genome association studies by use of localized haplotype clustering. Am J Hum Genet 2007;81:1084–1097.CrossRefGoogle ScholarPubMed
31.Balding, DJ.A tutorial on statistical methods for population association studies. Nat Rev Genet 2006;7:781–791.Google Scholar
32.Amemiya, T.Tobit models - a Survey. J Econom 1984;24: 3–61.Google Scholar
33.Dudoit, S, Shaffer, JP, Boldrick, JC.Multiple hypothesis testing in microarray experiments. Stat Sci 2003;18:71–103.Google Scholar
34.Steffensen, R, Hoffmann, K, Varming, K.Rapid genotyping of MBL2 gene mutations using real-time PCR with fluorescent hybridisation probes. J Immunol Methods 2003;278: 191–199.Google Scholar
35.Dahl, M, Tybjærg-Hansen, A, Schnohr, P, Nordestgaard, BG.A population-based study of morbidity and mortality in mannose-binding lectin deficiency. J Exp Med 2004;199:1391–1399.Google Scholar
36.Capuron, L, Miller, AH.Immune system to brain signaling: neuropsychopharmacological implications. Pharmacol Ther 2011;130:266–238.Google Scholar
37.Mayilyan, KR, Arnold, JN, Presanis, JS, Soghoyan, AF, Sim, RB.Increased complement classical and mannan-binding lectin pathway activities in schizophrenia. Neurosci Lett 2006;404:336–341.CrossRefGoogle ScholarPubMed
38.Sørensen, R, Thiel, S.Jensenius JC. Mannan-binding-lectin-associated serine proteases, characteristics and disease associations. Springer Semin Immunopathol 2005;27: 299–319.Google Scholar

Supporting Information

The following Supporting information is available for this article:

Appendix S1. Methods.

Table S1. Estimated median MBL concentration in serum.

Table S2. Estimated median MASP-2 concentration in serum.

Additional Supporting information may be found in the online version of this article.

Please note: Wiley-Blackwell Publishing is not responsible for the content or functionality of any supplementary materials supplied by the authors. Any queries (other than missing material) should be directed to the corresponding author for the article.