Skip to main content
SpringerLink
Log in

Candidate gene variants of the immune system and sudden infant death syndrome

  • Original Article
  • Published:
International Journal of Legal Medicine Aims and scope Submit manuscript

Abstract

Background

Sudden infant death syndrome (SIDS) causes early infant death with an incidence between 0.5 and 2.5 cases among 1000 live births. Besides central sleep apnea and thermal dysregulation, infections have been repeatedly suggested to be implicated in SIDS etiology.

Methods

To test the risk contribution of common genetic variants related to infection, we genotyped 40 single-nucleotide polymorphisms (SNPs) from 15 candidate genes for association with SIDS in a total of 579 cases and 1124 controls from Germany and the UK in a two-stage case control design.

Results

The discovery-stage series (267 SIDS cases and 303 controls) revealed nominally significant associations for variants in interleukin 6 (IL6) (rs1880243), interleukin 10 (IL10) (rs1800871, rs1800872), and mannose-binding lectin 2 (MBL2) (rs930506), and for several other variants in subgroups. Meta-analyses were then performed in adding genotype information from a genome-wide association study of another 312 European SIDS cases and 821 controls. Overall associations were observed for two independent variants in MBL2: rs930506 in a co-dominant model (odds ratio (OR) = 0.82, p = 0.04) and rs1838065 in a dominant model (OR = 1.27, p = 0.03).

Conclusion

Our study did not replicate published associations of IL10 variants with SIDS. However, the evidence for two independent MBL2 variants in the combined analysis of two large series seems consistent with the hypothesis that infection may play a role in SIDS pathogenesis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Moon RY, Horne RSC, Hauck FR (2007) Sudden infant death syndrome. Lancet 370:1578–1587. doi:10.1016/S0140-6736(07)61662-6

    Article  Google Scholar 

  2. Publikation - Gesundheit - Ergebnisse der Todesursachenstatistik für Deutschland - Ausführliche vierstellige ICD10-Klassifikation - 2013 - Statistisches Bundesamt (Destatis)

  3. Beckwith JB (1970) Discussion of terminology and definition of sudden infant death syndrome. Univ. Washingt. Press

  4. Willinger M, James LS, Catz C (1991) Defining the sudden infant death syndrome (SIDS): deliberations of an expert panel convened by the National Institute of Child Health and Human Development. Pediatr Pathol 11:677–684

    Article  CAS  Google Scholar 

  5. Courts C, Madea B (2010) Genetics of the sudden infant death syndrome. Forensic Sci Int 203:25–33. doi:10.1016/j.forsciint.2010.07.008

    Article  CAS  Google Scholar 

  6. Stanley FJ, Byard RW (1991) The association between the prone sleeping position and sudden infant death syndrome (SIDS): an editorial overview. J Paediatr Child Health 27:325–328

    Article  CAS  Google Scholar 

  7. Kleemann WJ, Schlaud M, Poets CF et al (1996) Hyperthermia in sudden infant death. Int J Leg Med 109:139–142

    Article  CAS  Google Scholar 

  8. Blair PS, Fleming PJ, Bensley D et al (1996) Smoking and the sudden infant death syndrome: results from 1993-5 case-control study for confidential inquiry into stillbirths and deaths in infancy. Confidential Enquiry into Stillbirths and Deaths Regional Coordinators and Researchers. BMJ 313:195–198

    Article  CAS  Google Scholar 

  9. Hauck FR, Herman SM, Donovan M et al (2003) Sleep environment and the risk of sudden infant death syndrome in an urban population: the Chicago infant mortality study. Pediatrics 111:1207–1214. doi:10.1542/peds.111.5.S1.1207

    PubMed  Google Scholar 

  10. Douglas AS, Allan TM, Helms PJ (1996) Seasonality and the sudden infant death syndrome during 1987-9 and 1991-3 in Australia and Britain. BMJ 312:1381–1383

    Article  CAS  Google Scholar 

  11. Wang DW, Desai RR, Crotti L et al (2007) Cardiac sodium channel dysfunction in sudden infant death syndrome. Circulation 115:368–376. doi:10.1161/CIRCULATIONAHA.106.646513

    Article  CAS  Google Scholar 

  12. Opdal SH, Opstad A, Vege Å̊, Rognum TO (2003) IL-10 gene polymorphisms are associated with infectious cause of sudden infant death. Hum Immunol 64:1183–1189. doi:10.1016/j.humimm.2003.08.359

    Article  CAS  Google Scholar 

  13. Kinney HC (2009) Brainstem mechanisms underlying the sudden infant death syndrome: evidence from human pathologic studies. Dev Psychobiol 51:223–233. doi:10.1002/dev.20367

    Article  CAS  Google Scholar 

  14. Rand CM, Patwari PP, Carroll MS, Weese-Mayer DE (2013) Congenital central hypoventilation syndrome and sudden infant death syndrome: disorders of autonomic regulation. Semin Pediatr Neurol 20:44–55. doi:10.1016/j.spen.2013.01.005

    Article  Google Scholar 

  15. Klintschar M, Reichenpfader B, Saternus K-S (2008) A functional polymorphism in the tyrosine hydroxylase gene indicates a role of noradrenalinergic signaling in sudden infant death syndrome. J Pediatr 153:190–193. doi:10.1016/j.jpeds.2008.02.032

    Article  CAS  Google Scholar 

  16. Rognum IJ, Haynes RL, Vege A et al (2009) Interleukin-6 and the serotonergic system of the medulla oblongata in the sudden infant death syndrome. Acta Neuropathol 118:519–530. doi:10.1007/s00401-009-0535-y

    Article  CAS  Google Scholar 

  17. Vege A, Rognum TO, Scott H et al (1995) SIDS cases have increased levels of interleukin-6 in cerebrospinal fluid. Acta Paediatr 84:193–196

    Article  CAS  Google Scholar 

  18. Vege A, Rognum TO, Anestad G (1999) IL-6 cerebrospinal fluid levels are related to laryngeal IgA and epithelial HLA-DR response in sudden infant death syndrome. Pediatr Res 45:803–809. doi:10.1203/00006450-199906000-00004

    Article  CAS  Google Scholar 

  19. Hoffman HJ, Damus K, Hillman L, Krongrad E (1988) Risk factors for SIDS. results of the national institute of child health and human development SIDS cooperative epidemiological study. Ann N Y Acad Sci 533:13–30

    Article  CAS  Google Scholar 

  20. Wilson CE (1999) Sudden infant death syndrome and Canadian Aboriginals: bacteria and infections. FEMS Immunol Med Microbiol 25:221–226

    Article  CAS  Google Scholar 

  21. Heininger U, Kleemann WJ, Cherry JD (2004) A controlled study of the relationship between Bordetella pertussis infections and sudden unexpected deaths among German infants. Pediatrics 114:e9–e15. doi:10.1542/peds.114.1.e9

    Article  Google Scholar 

  22. Blackwell CC, Weir DM, Busuttil A (1995) Infectious agents, the inflammatory responses of infants and sudden infant death syndrome (SIDS). Mol Med Today 1:72–78

    Article  CAS  Google Scholar 

  23. Blackwell CC, Moscovis SM, Gordon AE et al (2004) Ethnicity, infection and sudden infant death syndrome. FEMS Immunol Med Microbiol 42:53–65. doi:10.1016/j.femsim.2004.06.007

    Article  CAS  Google Scholar 

  24. Blackwell CC, Moscovis SM, Gordon AE et al (2005) Cytokine responses and sudden infant death syndrome: genetic, developmental, and environmental risk factors. J Leukoc Biol 78:1242–1254. doi:10.1189/jlb.0505253

    Article  CAS  Google Scholar 

  25. Opdal SH, Rognum TO (2011) Gene variants predisposing to SIDS: current knowledge. Forensic Sci Med Pathol 7:26–36. doi:10.1007/s12024-010-9182-9

    Article  Google Scholar 

  26. Summers AM, Summers CW, Drucker DB et al (2000) Association of IL-10 genotype with sudden infant death syndrome. Hum Immunol 61:1270–1273. doi:10.1016/S0198-8859(00)00183-X

    Article  CAS  Google Scholar 

  27. Korachi M, Pravica V, Barson AJ et al (2004) Interleukin 10 genotype as a risk factor for sudden infant death syndrome: determination of IL-10 genotype from wax-embedded postmortem samples. FEMS Immunol Med Microbiol 42:125–129. doi:10.1016/j.femsim.2004.06.008

    Article  CAS  Google Scholar 

  28. Findeisen M, Vennemann M, Brinkmann B et al (2004) German study on sudden infant death (GeSID): design, epidemiological and pathological profile. Int J Leg Med 118:163–169. doi:10.1007/s00414-004-0433-8

    Article  CAS  Google Scholar 

  29. Prtak L, Al-Adnani M, Fenton P et al (2010) Contribution of bacteriology and virology in sudden unexpected death in infancy. Arch Dis Child 95:371–376. doi:10.1136/adc.2009.162792

    Article  CAS  Google Scholar 

  30. Holle R, Happich M, Lowel H et al (2005) KORA--a research platform for population based health research. Gesundheitswesen 67(Suppl 1):S19–S25. doi:10.1055/s-2005-858235

    Article  Google Scholar 

  31. Krous HF, Beckwith JB, Byard RW et al (2004) Sudden infant death syndrome and unclassified sudden infant deaths: a definitional and diagnostic approach. Pediatrics 114:234–238. doi:10.1542/peds.114.1.234

    Article  Google Scholar 

  32. Läer K, Dörk T, Vennemann M et al (2015) Polymorphisms in genes of respiratory control and sudden infant death syndrome. Int J Legal Med 129:977–984. doi:10.1007/s00414-015-1232-0

    Article  Google Scholar 

  33. Läer K, Vennemann M, Rothämel T, Klintschar M (2014) Mitochondrial deoxyribonucleic acid may play a role in a subset of sudden infant death syndrome cases. Acta Paediatr 103:775–779

    PubMed  Google Scholar 

  34. Läer K, Vennemann M, Rothämel T, Klintschar M (2013) Association between polymorphisms in the P2RY1 and SSTR2 genes and sudden infant death syndrome. Int J Legal Med 127:1087–1091. doi:10.1007/s00414-013-0887-7

    Article  Google Scholar 

  35. Arnold M, Raffler J, Pfeufer A et al (2015) SNiPA: an interactive, genetic variant-centered annotation browser. Bioinformatics 31:1334–1336. doi:10.1093/bioinformatics/btu779

    Article  Google Scholar 

  36. Bouwman LH, Roep BO, Roos A (2006) Mannose-binding lectin: clinical implications for infection, transplantation, and autoimmunity. Hum Immunol 67:247–256. doi:10.1016/j.humimm.2006.02.030

    Article  CAS  Google Scholar 

  37. Kilpatrick DC, James VS, Blackwell CC et al (1998) Mannan binding lectin and the sudden infant death syndrome. Forensic Sci Int 97:135–138

    Article  CAS  Google Scholar 

  38. Marra MN, Wilde CG, Griffith JE et al (1990) Bactericidal/permeability-increasing protein has endotoxin-neutralizing activity. J Immunol 144:662–666

    CAS  PubMed  Google Scholar 

  39. Schultz H, Weiss JP (2007) The bactericidal/permeability-increasing protein (BPI) in infection and inflammatory disease. Clin Chim Acta 384:12–23. doi:10.1016/j.cca.2007.07.005

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Legal Medicine, Hannover Medical School, Carl-Neuberg-Str.1, 30625, Hannover, Germany

    Delnaz Fard, Katharina Läer, Thomas Rothämel & Michael Klintschar

  2. Gynaecology Research Unit, Hannover Medical School, Carl-Neuberg-Str.1, 30625, Hannover, Germany

    Peter Schürmann & Thilo Dörk

  3. Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München – German Research Center for Environmental Health, Ingolstädter Landstraße 1, 85764, Neuherberg, Germany

    Matthias Arnold & Arne Pfeufer

  4. Sheffield Children’s Hospital NHS Trust, Western Bank, Sheffield, S10 2TH, UK

    Marta Cohen

  5. Institute of Legal Medicine, Universität Münster, Roentgenstr. 23, 48149, Münster, Germany

    Mechtild Vennemann & Heidi Pfeiffer

  6. Institut of Legal Medicine, Universität Essen, Hufelandstr. 55, 45122, Essen, Germany

    Thomas Bajanowski

Authors
  1. Delnaz Fard
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Katharina Läer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thomas Rothämel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Peter Schürmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Matthias Arnold
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Marta Cohen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mechtild Vennemann
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Heidi Pfeiffer
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Thomas Bajanowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Arne Pfeufer
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Thilo Dörk
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Michael Klintschar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael Klintschar.

Ethics declarations

The local ethics committee at Hannover Medical School has approved this study.

Statement of financial support

Intramural funding from Hannover Medical School and Financial assistance from the Foundation for the study of Infant Deaths (FSID), 11 Belgrave Road, London SW1V 1RB UK is kindly acknowledged.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Online Resource 1

Study design. From 65 intended SNPs, 46 were successfully designed as a SNPtype assay. Six of them dropped out of the study because of poor clustering. Accordingly, 40 SNPs were part of the discovery and replication stage. A list of all 65 SNPs with rs codes is provided in the Study design. QC, Quality control (PDF 148 kb)

Online Resource 2

(PDF 104 kb)

Online Resource 3

(PDF 72 kb)

Online Resource 4

(PDF 73 kb)

Online Resource 5

(PDF 79 kb)

Online Resource 6

(PDF 103 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fard, D., Läer, K., Rothämel, T. et al. Candidate gene variants of the immune system and sudden infant death syndrome. Int J Legal Med 130, 1025–1033 (2016). https://doi.org/10.1007/s00414-016-1347-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00414-016-1347-y

Keywords

Search

Navigation