CAN GENETIC STUDIES HELP TO BETTER UNDERSTAND

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CAN GENETIC STUDIES HELP TO BETTER UNDERSTAND
TO REDUCE RISK FOR SIDS?

• Carl E. Hunt, MD
• First Candle Symposium
• March 24, 2009

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OBJECTIVES

• Review Genetic Risk Factors for sudden,
  unexpected deaths in infancy (SUDI)
• Relation of genetic risk factors to environmental
  risk factors
• Gene-environment
• Final Perspectives
• How genetic research related to SUDI does help us
• Limitations
• Next steps

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GENETIC RISK FACTORS
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26 Genes For Which Distribution of polymorphisms
Differs in SIDS

• Cardiac Channelopathies EIGHT
• Serotonin (5-HT) THREE
• Autonomic Nervous System
• Development EIGHT
• Infection Inflammation SIX
• Energy Production ONE
• TOTAL 26

Hunt CE, Hauck FR. SIDS Gene-environment
interactions, in Clinical Care in Inherited
Syndromes, ed. R Brugada, J Brugada, P Brugada.
Springer-Verlag London Ltd. Guilford, UK, in
press.
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CARDIAC CHANNELOPATHIES (8)(Arrhythmia
Susceptibility Genes)

• Long QT Syndrome (LQTS), SQTS
• Sodium channel (SCN5A)
• Sodium channel-interacting proteins
• CAV3
• SCN4B
• GPD1-L
• Potassium channel (KCNQ1,KCNH2, KCNE2)
• RyR2-encoded cardiac ryanodine receptor (CPVT1)
• Normal resting ECG

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Genetic Risk Factors, cont.Serotonin (5-HT) (3)

• Important neurotransmitter
• Polymorphisms in 3 genes
• 5-HT transporter protein (5-HTT)
• Intron 2 of SLC6A4
• VNTR polymorphism
• 5-HT FEV gene

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Genetic Risk Factors, cont.Autonomic Nervous
System Development (8)

• Paired-like homeobox 2A PHOX2A)
• PHOX2B
• Rearranged during transfection factor (RET)
• Endothelin converting enzyme-1 (ECE1)
• T-cell leukemia homeobox (TLX3)
• Engrailed-1 (EN 1)
• Tyrosine hydroxylase (THO1)
• Monoamine oxidase A (MAOA)

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Genetic Risk Factors, cont.Infection
Inflammation (6)(Activated Immune System)

• Complement C4A (partial deletion)
• Complement C4B (partial deletion)
• Interleukin-10 (IL 10) (low levels)
• IL-6
• Mixed results, but multiple polymorphisms
• VEGF (Dashash M. Human Immunol 2006)
• TNF-alpha (Ferrante L, et al. Human Immunol 2008)

Increased levels in CSF in SIDS victims
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DEFINITIONS

• GENOTYPE
• Genetic make-up, with various combinations of
  polymorphisms
• PHENOTYPE
• Clinical manifestation of a genotype or combined
  manifestation of several different genotypes
• May not be evident on routine physical
  examination or routine clinical testing

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PHENOTYPESCardiac Channelopathies

• Phenotype presumed, but not confirmed
• May be concealed (latent) and require
  provocation
• Sympathetic stress
• Epinephrine infusion
• Sleep
• Acidosis
• Hypoxia

Plant LD et al. JCI 2006 Tester DJ, et al.
Heart Rhythm 2007 Ackerman MJ. Heart Rhythm
2008
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CARDIAC CHANNELOPATHIESScreening

• PRO
• Could theoretically prevent 5-10 of SIDS
• CON (problems to overcome)
• Cost of testing
• Accuracy of interpretation
• Frequency of false negative ECGs
• Managing of false positive ECGs
• May raise socioeconomic and psychosocial problems
• Effectiveness and safety of treatment for those
  positive with LQTS

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Phenotypes, cont.Serotonin (5-HT)

• No matched phenotypes and genotypes
• Potential phenotypes
• Cardiorespiratory regulation
• 5-HTT knockout mice reduced ventilatory
  response to CO2 (especially males)
• Other autonomic regulation
• Other..?

Li A, Nattie E. J Physiol 2008
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Phenotypes, cont. Autonomic Nervous System
Polymorphisms

• No matched phenotypes/genotypes
• Consistent with
• Clinical studies (limited) in young infants later
  dying of SIDS
• Clinical studies in ALTE and preterm infants
• Postmortem studies indicating abnormalities in
  CNS areas involved with autonomic and
  cardio-respiratory regulation

Morley ME et al. Am J Med Genetics Part A. 2008
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Phenotypes, cont. Infection Inflammation

• No matched phenotypes/genotypes
• Consistent with epidemiology studies indicating
  increased frequency of infections in SIDS infants
• Identified polymorphisms
• Gain-of-function in pro-inflammatory cytokines
• Loss-of-function in anti-inflammatory cytokines

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GENE INTERACTIONS
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Gene Interactions

• Gene-environment
• Genetics loads the gun and environment pulls the
  trigger
• Genes predispose, environment disposes

Dr. Francis Collins, Past Director, National
Human Genome Research Institute, NIH
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Environmental risk factors
Genetic risk factors
5-HTT polymorphism
Smoking
ANS polymorphism
Soft bedding
Impaired autonomic regulation and arousal
Cardiac ion channel polymorphism
Prone or side sleeping
Sudden Infant Death
Prematurity
Complement or Interleukin polymorphism
Hunt Hauck, in press
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FUTURE DIRECTIONSResearch to Practice
(Translation)

• Antemortem phenotyping essential
• Screening
• Intervention
• Broaden our focus to include other sudden death
  groups
• Sudden Intrauterine Unexplained Death (SIUD)
• 1-2 of pregnancies end in stillbirth
• Many shared features with SUDI and SIDS
• Sudden Unexplained Death in Childhood (SUDC)
• 0.013 per 1 000 live births
• Sudden unexplained death in epilepsy

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SUMMARYThe Take Home Message on Genetic
Research

• Provides biologic mechanisms for SUDI when no
  apparent explanation at autopsy
• Genetic autopsies not yet feasible
• Especially important in those rare occurrences of
  multiple SUDI in families
• Helps to understand how environmental risk
  factors may lead to SUDI in infants genetically
  predisposed
• MAJOR CHALLENGE
• Not yet feasible to recognize in early infancy
  which infants are genetically predisposed to SUDI
  if when confronted with relevant environmental
  risks

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SUMMARY, cont.The Take Home Message on Genetic
Research

• SUDI is a complex disorder
• No single cause
• Complex interactions between genetic and
  environmental risk factor
• No immediate help for families
• Highlights the importance of minimizing
  environmental risk factors that are modifiable
• Expanding knowledge of genetic risk factors will
  progressively lead to improved understanding
  regarding potential strategies for clinical
  testing and (ultimately) intervention