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

1. CAN GENETIC STUDIES HELP TO BETTER UNDERSTAND & TO REDUCE RISK FOR SIDS? Carl E. Hunt, MD First Candle Symposium March 24, 2009

2. 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

3. GENETIC RISK FACTORS

4. 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.

5. 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

6. 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

7. 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)

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. GENE INTERACTIONS

16. 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

17. Environmental risk factors Genetic risk factors 5-HTT polymorphism Smoking ANS polymorphism Soft bedding Impaired autonomic regulation and arousal Prone or side sleeping Cardiac ion channel polymorphism Sudden Infant Death Prematurity Complement or Interleukin polymorphism Hunt & Hauck, in press

18. 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

19. 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

20. 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