Exploration of single nucleotide polymorphisms (SNPs) within four genes involved with cardiac function and their association with sudden unexplained death.

  • Tierney Mullaney Center for Health Sciences, Oklahoma State University
  • Jane Pritchard Center for Health Sciences, Oklahoma State University
  • Mark Payton Department of Statistics, Oklahoma State University.
  • Jun Fu Center for Health Sciences, Oklahoma State University
  • Shen Di Center for Health Sciences, Oklahoma State University
  • Robert Allen Oklahoma State University Center for Health Sciences College of Osteopathic Medicine (OSU-COM)
Keywords: Single nucleotide polymorphism, cardiac-related death, Cardiomyopathy, Genotyping

Abstract

Seventeen blood samples obtained at autopsy from individuals determined to have died from cardiac-related causes were subjected to DNA analysis to explore possible associations of single nucleotide variations in a panel of 4 genes known to be involved in cardiac function. DNA was extracted from the autopsy samples as well as from a panel of 49 unaffected, presumably normal individuals and was subjected to nucleotide sequencing at selected sites within the EYA4, MYH6, TNNI3, and NEXN genes known to be involved with cardiac function. A total of 5 single nucleotide polymorphisms (SNPs) in the 4 genes (2 SNPs within the EYA4 gene) were interrogated through DNA sequencing. Each SNP site harbored either a nucleotide considered to represent a wild type allele, or a nucleotide considered a variant capable of impacting the normal functioning of the product of the gene. The purpose of the study was to determine if a greater number of variant alleles exist in the samples from the Medical Examiner than in the general population, and whether any particular SNP phenotypes or combinations of phenotypes are significantly linked to cardiac-related death. Results from the analysis showed individuals who died from cardiac-related causes had a significantly higher frequency of variant SNPs within the four genes than did the normal group. Moreover, particular combinations of variant nucleotide phenotypes were associated with cardiac death among the cohort of samples provided by the Medical Examiner. Our results support the notion that death from cardiac-related causes can result from single nucleotide polymorphisms that, by themselves are not lethal, but result in less than optimal performance of their respective gene products. Variant SNPs in several genes may collectively compromise cardiac function sufficiently to critically elevate the risk of death when elevated demands are placed on cardiac function.

Author Biographies

Tierney Mullaney, Center for Health Sciences, Oklahoma State University
School of Forensic Sciences, Recent graduate, MSFS
Jane Pritchard, Center for Health Sciences, Oklahoma State University
School of Forensic Sciences, Director or Quality, BS, MT(ASCP)MB,
Mark Payton, Department of Statistics, Oklahoma State University.
Department of Statistics, PhD, Chair
Jun Fu, Center for Health Sciences, Oklahoma State University
School of Forensic Sciences, PhD, Research Associate and Director Designee of the Human Identity Laboratory
Shen Di, Center for Health Sciences, Oklahoma State University
School of Forensic Sciences, PhD, Visiting Research Scientist
Robert Allen, Oklahoma State University Center for Health Sciences College of Osteopathic Medicine (OSU-COM)
School of Forensic Sciences, PhD, Chair, Professor of Forensic Sciences

References

Semsarian C., Ingles J., and Wilde A., Sudden cardiac death in the young: the molecular autopsy and a practical approach to surviving relatives. Eur. Heart J. 2015;36:1290-1296.

Deo, R., Albert C.M., Epidemiology and genetics of sudden cardiac death. Circulation 2012;125:620-637.

Towards European recommendations integrating genetic testing into multidisciplinary management of sudden cardiac death. Draft summary of an expert workshop of the European Society for Human Genetics held in Geneva, Switzerland, November 23-25, 2016. Published March 2018. https://www.eshg.org/fileadmin/eshg/consultations/Draft_Recommendations_SCD_March_2018_for_consultation.pdf

Schwartz P.J., Ackerman M.J., George A.L., Wilde A.A.M, Impact of genetics on the clinical management of channelopathies. J. Am. Coll. Cardiol. 2013;62:169-180.

Neubauer J., Lecca M.R., Russo G., Bartsch C., Medeiros-Domingo A., Berger W., Haas C., Post-mortem whole-exome analysis in a large sudden infant death syndrome cohort with a focus on cardiovascular and metabolic genetic diseases. Eur. J. Human Genet. 2017;25:404-409.

Sudmant P.H., Rausch T., Gardner E.J., Handsaker R.E., Abyzov A., Huddleston J., Zhang Y., et.al. An integrated map of structural variation in 2504 human genomes. Nature 2015;526:75-81.

Auton A., Abecasis G.R., A global reference for human genetic variation. Nature 2015;526:68-74.

Van Driest SL, Wells Q.S., Stallings S., Bush W.S., Gordon A., Nickerson D.A., Kim J.H., Crosslin D.R., Jarvik G.P., et.al., Association of arrhythmia-related genetic variants with phenotypes documented in electronic medical records. JAMA, 2016;5:47-57.

Karki R., Pandya D., Elston R.C., Ferlini C., Defining “mutation†and “polymorphism†in the era of personal genomics. BMC Medical Genomics 2015;8:37-44.

Hartl D.L., Clarke A.G. Principles of population genetics. Sinauer, Sunderland, MA, c2007

Carvajal-Zarrabal O., Hayward-Jones P.M., Nolasco-Hipolito C., Barradas-Dermitz D.M., Calderon-Garciduenas A.L., Lopez-Amador N., Use of cardiac injury markers in the postmortem diagnosis of sudden cardiac death. J. Forensic Sci. 2017;62:1332-1335.

Basso C., Burke M., Fornes P., Gallagher P.J., Henriques de Gouveia R., Sheppard M., et.al. Guidelines for autopsy investigation of sudden cardiac death. Virchows Arch. 2008;452:11-18.

Published
2019-04-17
Section
Forensics