Skip to main content

Advertisement

SpringerLink
Log in

Polymorphisms in genes of respiratory control and sudden infant death syndrome

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

Abstract

Sudden infant death syndrome (SIDS) is a multifactorial syndrome and assumingly, among other mechanisms, a deficit in respiratory control leads to a failure of arousal and autoresuscitation when the child is challenged by a stressful homeostatic event, e.g., hypoxia. We hypothesize that genetic polymorphisms involved in respiratory control mediated in the medulla oblongata contribute to SIDS. Therefore, a total of 366 SIDS cases and 421 controls were genotyped for 48 SNPs in 41 candidate genes. Genotyping was performed using Fluidigm nanofluidic technology. Results were obtained for 356 SIDS and 406 controls and 38 SNPs. After correction for multiple testing, one SNP retained a nominally significant association with seasonal SIDS: rs1801030 in the phenol sulfotransferase 1A1 gene (subgroup: death occurring during summer). A borderline association could be also observed for rs563649 in the opioid receptor μ1 gene in a recessive model (subgroup: death occurring during autumn). As a conclusion, although these data suggest two SNPs to be associated with different subgroups of SIDS cases, none of them can fully explain the SIDS condition, consistent with its multifactorial etiology. Given the great complexity of respiratory control and our initial findings reported here, we believe it is worthwhile to further investigate genes involved in the respiratory system.

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

Similar content being viewed by others

References

  1. Moon RY, Horne RSC, Hauck FR (2007) Sudden infant death syndrome. Lancet 370:1578–1587

    Article  PubMed  Google Scholar 

  2. Weese-Mayer DE, Berry-Kravis EM, Zhou L et al (2004) Sudden infant death syndrome: case-control frequency differences at genes pertinent to early autonomic nervous system embryologic development. Pediatr Res 56:391–395

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  4. Klintschar M, Reichenpfader B, Saternus KS (2008) A functional polymorphism in the tyrosine hydroxylase gene indicates a role of noradrenalinergic signaling in sudden infant death syndrome. J Pediatr 153(2):190–193

    Article  CAS  PubMed  Google Scholar 

  5. 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(6):1087–1091

    Article  PubMed  Google Scholar 

  6. Opdal SH, Opstad A, Vege A, Rognum TO (2003) IL-10 gene polymorphisms are associated with infectious cause of sudden infant death. Hum Immunol 64:1183–1189

    Article  CAS  PubMed  Google Scholar 

  7. 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(1):44–55

    Article  PubMed  Google Scholar 

  8. Kinney HC (2009) Brainstem mechanisms underlying the sudden infant death syndrome: evidence from human pathologic studies. Dev Psychobiol 51(3):223–233

    Article  CAS  PubMed  Google Scholar 

  9. Gaultier C (1999) Sleep apnea in infants. Sleep Med Rev 3(4):303–312

    Article  Google Scholar 

  10. Alheid GF, McCrimmon DR (2008) The chemical neuroanatomy of breathing. Respir Physiol Neurobiol 164(1–2):3–11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Doi A, Ramirez J (2008) Neuromodulation and the orchestration of the respiratory rhythm. Respir Physiol Neurobiol 164(1–2):96–104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Shao XM, Feldman JL (2005) Cholinergic neurotransmission in the pre-Bötzinger complex modulates excitability of inspiratory neurons and regulates respiratory rhythm. Neuroscience 130(4):1069–1081

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Quartara L, Maggi CA (1997) The tachykinin NK1 receptor. Part I: ligands and mechanisms of cellular activation. Neuropeptides 31(6):537–563

    Article  CAS  PubMed  Google Scholar 

  14. Ellenberger HH, Smith FM (1999) Sulfated cholecystokinin octapeptide in the rat: pontomedullary distribution and modulation of the respiratory pattern. Can J Physiol Pharmacol 77(7):490–504

    Article  CAS  PubMed  Google Scholar 

  15. Dekin MS, Richerson GB, Getting PA (1985) Thyrotropin-releasing hormone induces rhythmic bursting in neurons of the nucleus tractus solitarius. Science 229(4708):67–69

    Article  CAS  PubMed  Google Scholar 

  16. Dutschmann M, Bischoff AM, Büsselberg D, Richter DW (2003) Histaminergic modulation of the intact respiratory network of adult mice. Pflugers Arch 445(5):570–576

    CAS  PubMed  Google Scholar 

  17. Llona I, Eugenín J (2005) Central actions of somatostatin in the generation and control of breathing. Biol Res 38(4):347–352

    Article  CAS  PubMed  Google Scholar 

  18. Haji A, Takeda R (2001) Effects of a kappa-receptor agonist U-50488 on bulbar respiratory neurons and its antagonistic action against the mu receptor-induced respiratory depression in decerebrate cats. Jpn J Pharmacol 87(4):333–337

    Article  CAS  PubMed  Google Scholar 

  19. Manzke T, Guenther U, Ponimaskin EG et al (2003) 5-HT4(a) receptors avert opioid-induced breathing depression without loss of analgesia. Science 301(5630):226–229

    Article  CAS  PubMed  Google Scholar 

  20. Onimaru H, Shamoto A, Homma I (1998) Modulation of respiratory rhythm by 5-HT in the brainstem-spinal cord preparation from newborn rat. Pflugers Arch 435(4):485–494

    Article  CAS  PubMed  Google Scholar 

  21. Wang J, Lin M, Crenshaw A et al (2009) High-throughput single nucleotide polymorphism genotyping using nanofluidic dynamic arrays. BMC Genomics 10:561

    Article  PubMed  PubMed Central  Google Scholar 

  22. Paterson DS, Hilaire G, Weese-Mayer DE (2009) Medullary serotonin defects and respiratory dysfunction in sudden infant death syndrome. Respir Physiol Neurobiol 168(1–2):133–143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Stornetta RL (2008) Identification of neurotransmitters and co-localization of transmitters in brainstem respiratory neurons. Respir Physiol Neurobiol 164(1–2):18–27

    Article  CAS  PubMed  Google Scholar 

  24. Shabalina SA, Zaykin DV, Gris P et al (2009) Expansion of the human mu-opioid receptor gene architecture: novel functional variants. Hum Mol Genet 18(6):1037–1051

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Diatchenko L (2011) Elucidation of mu-opioid gene structure: how genetics can help predict responses to opioids. Eur J Pain Suppl 5(2):433–438

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Nagar S, Walther S, Blanchard RL (2006) Sulfotransferase (SULT) 1A1 polymorphic variants *1, *2, and *3 are associated with altered enzymatic activity, cellular phenotype, and protein degradation. Mol Pharmacol 69(6):2084–2092

    Article  CAS  PubMed  Google Scholar 

  27. Rebbeck TR, Troxel AB, Shatalova EG et al (2007) Lack of effect modification between estrogen metabolism genotypes and combined hormone replacement therapy in postmenopausal breast cancer risk. Cancer Epidemiol Biomarkers Prev 16(6):1318–1320

    Article  CAS  PubMed  Google Scholar 

  28. Ung D, Nagar S (2007) Variable sulfation of dietary polyphenols by recombinant human sulfotransferase (SULT) 1A1 genetic variants and SULT1E1. Drug Metab Dispos 35(5):740–746

    Article  CAS  PubMed  Google Scholar 

  29. Eagle K (2012) Hypothesis: holiday sudden cardiac death: food and alcohol inhibition of SULT1A enzymes as a precipitant. J Appl Toxicol 32(10):751–755

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Liu XG, Tan LJ, Lei SF et al (2009) Genome-wide association and replication studies identified TRHR as an important gene for lean body mass. Am J Hum Genet 84(3):418–423

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Liebrechts-Akkerman G, Liu F, Lao O, Ooms AH, van Duijn K, Vermeulen M, Jaddoe VW, Hofman A, Engelberts AC, Kayser M (2014) PHOX2B polyalanine repeat length is associated with sudden infant death syndrome and unclassified sudden infant death in the Dutch population. Int J Legal Med 128:621–629

    PubMed  Google Scholar 

  32. Studer J, Bartsch C, Haas C (2014) Sodium/proton exchanger 3 (NHE3) and sudden infant death syndrome (SIDS). Int J Legal Med 128:939–943

    Article  PubMed  Google Scholar 

  33. Klintschar M, Heimbold C (2012) No association of SIDS with two polymorphisms in genes relevant for the noradrenergic system: COMT and DBH. Acta Paediatr 101:1079–1082

    Article  CAS  PubMed  Google Scholar 

  34. Poetsch M, Todt R, Vennemann MM, Bajanowski T (2015) It’s not that, either - neither polymorphisms in PHOX2B nor in MIF are involved in Sudden Infant Death Syndrome (SIDS). Int J Legal Med

Download references

Acknowledgments

The authors would like to thank all persons who provided samples, especially Prof. K.-S. Saternus, Göttingen, as well as Doris Engmann, Claudia Schütz, and Peter Schürmann for excellent technical support. Moreover, they would like to thank K. Eagle, Katy, TX, USA, for the suggestion to include SULT1A1 into the analysis.

Author information

Authors and Affiliations

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

    Katharina Läer, Marielle Vennemann, Thomas Rothämel & Michael Klintschar

  2. Gynaecology Research Unit, Clinics of Obstetrics and Gynaecology, Hannover Medical School, Carl-Neuberg-Str.1, D-30625, Hannover, Germany

    Thilo Dörk

  3. Institute of Legal Medicine, University Hospital Münster, Röngtenstr. 23, D-48149, Münster, Germany

    Marielle Vennemann

Authors
  1. Katharina Läer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Thilo Dörk
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marielle Vennemann
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Thomas Rothämel
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Michael Klintschar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael Klintschar.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM Table 1

Primer sequences developed for typing the SNP loci. ASP1 allele-specific primer 1, ASP2 allele-specific primer 2, LSP locus-specific primer, STA specific target (pre)amplification primer. The reaction involves a specific target preamplification using primers LSP and STA followed by a nested PCR using LSP, ASP1, and ASP2. (XLSX 12 kb)

ESM Table 2

Full results for the statistical analysis of 764 samples (358 SIDS and 406 controls) for 38 single nucleotide polymorphisms (SNPs) in genes involved in respiratory control. (XLSX 27 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00414-015-1232-0

Keywords

Search

Navigation