International Journal of Legal Medicine

, Volume 130, Issue 4, pp 1025–1033 | Cite as

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

  • Delnaz Fard
  • Katharina Läer
  • Thomas Rothämel
  • Peter Schürmann
  • Matthias Arnold
  • Marta Cohen
  • Mechtild Vennemann
  • Heidi Pfeiffer
  • Thomas Bajanowski
  • Arne Pfeufer
  • Thilo Dörk
  • Michael Klintschar
Original Article



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.


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.


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).


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.


SIDS Infection Genetic predisposition Mannose-binding lectin Polymorphism Association study 


Compliance with ethical standards

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.

Supplementary material

414_2016_1347_MOESM1_ESM.pdf (149 kb)
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)
414_2016_1347_MOESM2_ESM.pdf (104 kb)
Online Resource 2 (PDF 104 kb)
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Online Resource 3 (PDF 72 kb)
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Online Resource 4 (PDF 73 kb)
414_2016_1347_MOESM5_ESM.pdf (80 kb)
Online Resource 5 (PDF 79 kb)
414_2016_1347_MOESM6_ESM.pdf (104 kb)
Online Resource 6 (PDF 103 kb)


  1. 1.
    Moon RY, Horne RSC, Hauck FR (2007) Sudden infant death syndrome. Lancet 370:1578–1587. doi: 10.1016/S0140-6736(07)61662-6 CrossRefPubMedGoogle Scholar
  2. 2.
    Publikation - Gesundheit - Ergebnisse der Todesursachenstatistik für Deutschland - Ausführliche vierstellige ICD10-Klassifikation - 2013 - Statistisches Bundesamt (Destatis)Google Scholar
  3. 3.
    Beckwith JB (1970) Discussion of terminology and definition of sudden infant death syndrome. Univ. Washingt. PressGoogle Scholar
  4. 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 11:677–684CrossRefPubMedGoogle Scholar
  5. 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 CrossRefPubMedGoogle Scholar
  6. 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 27:325–328CrossRefPubMedGoogle Scholar
  7. 7.
    Kleemann WJ, Schlaud M, Poets CF et al (1996) Hyperthermia in sudden infant death. Int J Leg Med 109:139–142CrossRefGoogle Scholar
  8. 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 313:195–198CrossRefPubMedPubMedCentralGoogle Scholar
  9. 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 PubMedGoogle Scholar
  10. 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 312:1381–1383CrossRefPubMedPubMedCentralGoogle Scholar
  11. 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 CrossRefPubMedGoogle Scholar
  12. 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 CrossRefPubMedGoogle Scholar
  13. 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 CrossRefPubMedGoogle Scholar
  14. 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 CrossRefPubMedGoogle Scholar
  15. 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 CrossRefPubMedGoogle Scholar
  16. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Vege A, Rognum TO, Scott H et al (1995) SIDS cases have increased levels of interleukin-6 in cerebrospinal fluid. Acta Paediatr 84:193–196CrossRefPubMedGoogle Scholar
  18. 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 CrossRefPubMedGoogle Scholar
  19. 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 533:13–30CrossRefPubMedGoogle Scholar
  20. 20.
    Wilson CE (1999) Sudden infant death syndrome and Canadian Aboriginals: bacteria and infections. FEMS Immunol Med Microbiol 25:221–226CrossRefPubMedGoogle Scholar
  21. 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 CrossRefPubMedGoogle Scholar
  22. 22.
    Blackwell CC, Weir DM, Busuttil A (1995) Infectious agents, the inflammatory responses of infants and sudden infant death syndrome (SIDS). Mol Med Today 1:72–78CrossRefPubMedGoogle Scholar
  23. 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 CrossRefPubMedGoogle Scholar
  24. 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 CrossRefPubMedGoogle Scholar
  25. 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 CrossRefPubMedGoogle Scholar
  26. 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 CrossRefPubMedGoogle Scholar
  27. 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 CrossRefPubMedGoogle Scholar
  28. 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 CrossRefGoogle Scholar
  29. 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 CrossRefPubMedGoogle Scholar
  30. 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 CrossRefPubMedGoogle Scholar
  31. 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 CrossRefPubMedGoogle Scholar
  32. 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 CrossRefPubMedGoogle Scholar
  33. 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 103:775–779PubMedGoogle Scholar
  34. 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 CrossRefPubMedGoogle Scholar
  35. 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 CrossRefPubMedGoogle Scholar
  36. 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 CrossRefPubMedGoogle Scholar
  37. 37.
    Kilpatrick DC, James VS, Blackwell CC et al (1998) Mannan binding lectin and the sudden infant death syndrome. Forensic Sci Int 97:135–138CrossRefPubMedGoogle Scholar
  38. 38.
    Marra MN, Wilde CG, Griffith JE et al (1990) Bactericidal/permeability-increasing protein has endotoxin-neutralizing activity. J Immunol 144:662–666PubMedGoogle Scholar
  39. 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 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Delnaz Fard
    • 1
  • Katharina Läer
    • 1
  • Thomas Rothämel
    • 1
  • Peter Schürmann
    • 2
  • Matthias Arnold
    • 3
  • Marta Cohen
    • 4
  • Mechtild Vennemann
    • 5
  • Heidi Pfeiffer
    • 5
  • Thomas Bajanowski
    • 6
  • Arne Pfeufer
    • 3
  • Thilo Dörk
    • 2
  • Michael Klintschar
    • 1
  1. 1.Institute of Legal MedicineHannover Medical SchoolHannoverGermany
  2. 2.Gynaecology Research UnitHannover Medical SchoolHannoverGermany
  3. 3.Institute of Bioinformatics and Systems BiologyHelmholtz Zentrum München – German Research Center for Environmental HealthNeuherbergGermany
  4. 4.Sheffield Children’s Hospital NHS Trust, Western BankSheffieldUK
  5. 5.Institute of Legal MedicineUniversität MünsterMünsterGermany
  6. 6.Institut of Legal MedicineUniversität EssenEssenGermany

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