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

SIDS?SIDS?

Carl E. Hunt, MDCarl E. Hunt, MD

First Candle Symposium First Candle Symposium March 24, 2009March 24, 2009

OBJECTIVESOBJECTIVES

Review Genetic Risk Factors for sudden, Review Genetic Risk Factors for sudden, unexpected deaths in infancy (SUDI)unexpected deaths in infancy (SUDI)

Relation of genetic risk factors to Relation of genetic risk factors to environmental risk factorsenvironmental risk factors• Gene-environment Gene-environment

Final PerspectivesFinal Perspectives• How genetic research related to SUDI does How genetic research related to SUDI does

help ushelp us• Limitations Limitations • Next stepsNext steps

GENETIC RISK GENETIC RISK FACTORSFACTORS

26 Genes For Which Distribution of 26 Genes For Which Distribution of polymorphisms Differs in SIDS*polymorphisms Differs in SIDS*

Cardiac Channelopathies: Cardiac Channelopathies: EIGHTEIGHT Serotonin (5-HT): Serotonin (5-HT): THREETHREE Autonomic Nervous SystemAutonomic Nervous System

DevelopmentDevelopment EIGHT EIGHT Infection & Inflammation: Infection & Inflammation: SIX SIX

Energy Production: Energy Production: ONEONE

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.

CARDIAC CHANNELOPATHIES (8)CARDIAC CHANNELOPATHIES (8)(Arrhythmia Susceptibility Genes)(Arrhythmia Susceptibility Genes)

Long QT Syndrome (LQTS), SQTSLong QT Syndrome (LQTS), SQTS• Sodium channel (SCN5A)Sodium channel (SCN5A)• Sodium channel-interacting proteinsSodium channel-interacting proteins

CAV3CAV3 SCN4BSCN4B GPD1-LGPD1-L

• Potassium channel (KCNQ1,KCNH2, KCNE2)Potassium channel (KCNQ1,KCNH2, KCNE2)• RyR2-encoded cardiac ryanodine receptor RyR2-encoded cardiac ryanodine receptor

((CPVT1CPVT1) ) Normal resting ECGNormal resting ECG

Genetic Risk Factors, Genetic Risk Factors, cont.cont.

Serotonin (5-HT) Serotonin (5-HT) (3)(3)

Important neurotransmitterImportant neurotransmitter Polymorphisms in 3 genes:Polymorphisms in 3 genes:

• 5-HT transporter protein (5-HTT)5-HT transporter protein (5-HTT)• Intron 2 of SLC6A4Intron 2 of SLC6A4

VNTR polymorphismVNTR polymorphism

• 5-HT FEV gene 5-HT FEV gene

Genetic Risk Factors, Genetic Risk Factors, cont.cont.

Autonomic Nervous System Autonomic Nervous System Development Development (8)(8)

• Paired-like homeobox 2A PHOX2A)Paired-like homeobox 2A PHOX2A)• PHOX2BPHOX2B• Rearranged during transfection factor Rearranged during transfection factor

(RET)(RET)• Endothelin converting enzyme-1 (ECE1)Endothelin converting enzyme-1 (ECE1)• T-cell leukemia homeobox (TLX3)T-cell leukemia homeobox (TLX3)• Engrailed-1 (EN 1) Engrailed-1 (EN 1) • Tyrosine hydroxylase (THO1)Tyrosine hydroxylase (THO1)• Monoamine oxidase A (MAOA)Monoamine oxidase A (MAOA)

Genetic Risk Factors, Genetic Risk Factors, cont.cont.

Infection & Inflammation (6)Infection & Inflammation (6)((Activated Immune System)Activated Immune System)

Complement C4A Complement C4A (partial deletion)(partial deletion)

Complement C4B Complement C4B (partial deletion)(partial deletion)

Interleukin-10 (IL 10) Interleukin-10 (IL 10) (low levels)(low levels) IL-6*IL-6*

• Mixed results, but multiple polymorphismsMixed results, but multiple polymorphisms

VEGF*VEGF* (Dashash M. Human Immunol 2006)(Dashash M. Human Immunol 2006)

TNF-alpha TNF-alpha (Ferrante L, et al. Human Immunol 2008)(Ferrante L, et al. Human Immunol 2008)

*Increased levels in CSF in SIDS victims*Increased levels in CSF in SIDS victims

DEFINITIONSDEFINITIONS

GENOTYPEGENOTYPE• Genetic make-up, with various Genetic make-up, with various

combinations of polymorphismscombinations of polymorphisms PHENOTYPEPHENOTYPE

• Clinical manifestation of a genotype or Clinical manifestation of a genotype or combined manifestation of several combined manifestation of several different genotypesdifferent genotypes

• May not be evident on routine physical May not be evident on routine physical examination or routine clinical testingexamination or routine clinical testing

PHENOTYPESPHENOTYPESCardiac ChannelopathiesCardiac Channelopathies

Phenotype presumed, but not Phenotype presumed, but not confirmed confirmed

May be concealed (latent)* and May be concealed (latent)* and require provocationrequire provocation• Sympathetic stress Sympathetic stress

Epinephrine infusion**Epinephrine infusion** SleepSleep

• Acidosis Acidosis • HypoxiaHypoxia

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

CARDIAC CHANNELOPATHIESCARDIAC CHANNELOPATHIESScreeningScreening

PRO PRO • Could theoretically “prevent” 5-10 % of Could theoretically “prevent” 5-10 % of

SIDS SIDS CON (problems to overcome)CON (problems to overcome)

• Cost of testingCost of testing• Accuracy of interpretationAccuracy of interpretation• Frequency of false negative ECGsFrequency of false negative ECGs• Managing of false positive ECGsManaging of false positive ECGs

May raise socioeconomic and psychosocial May raise socioeconomic and psychosocial problemsproblems

• Effectiveness and safety of treatment for Effectiveness and safety of treatment for those positive with LQTSthose positive with LQTS

PhenotypesPhenotypes, cont., cont.

Serotonin (5-HT) Serotonin (5-HT)

No matched phenotypes and No matched phenotypes and genotypesgenotypes

Potential phenotypesPotential phenotypes• Cardiorespiratory regulationCardiorespiratory regulation

5-HTT knockout mice*: reduced ventilatory 5-HTT knockout mice*: reduced ventilatory response to COresponse to CO22 (especially males)(especially males)

• Other autonomic regulationOther autonomic regulation• Other…..?Other…..?

Li A, Nattie E. J Physiol 2008

PhenotypesPhenotypes, cont., cont. Autonomic Nervous System PolymorphismsAutonomic Nervous System Polymorphisms

No matched phenotypes/genotypesNo matched phenotypes/genotypes Consistent with Consistent with

• Clinical studies (limited) in young infants Clinical studies (limited) in young infants later dying of SIDS later dying of SIDS

• Clinical studies in ALTE and preterm Clinical studies in ALTE and preterm infants infants

• Postmortem studies indicating Postmortem studies indicating abnormalities in CNS areas involved abnormalities in CNS areas involved with autonomic and cardio-respiratory with autonomic and cardio-respiratory regulation*regulation*

*Morley ME et al. Am J Med Genetics Part A. 2008

PhenotypesPhenotypes, cont. , cont.

Infection & InflammationInfection & Inflammation No matched phenotypes/genotypesNo matched phenotypes/genotypes Consistent with epidemiology studies Consistent with epidemiology studies

indicating increased frequency of indicating increased frequency of infections in SIDS infantsinfections in SIDS infants

Identified polymorphisms:Identified polymorphisms:• Gain-of-function in pro-inflammatory cytokinesGain-of-function in pro-inflammatory cytokines• Loss-of-function in anti-inflammatory cytokinesLoss-of-function in anti-inflammatory cytokines

GENE INTERACTIONSGENE INTERACTIONS

Gene InteractionsGene Interactions Gene-environmentGene-environment

• ““Genetics loads the gun and Genetics loads the gun and environment pulls the trigger*”environment pulls the trigger*”

• ““Genes predispose, environment Genes predispose, environment disposes”disposes”

*Dr. Francis Collins, Past Director, National Human Genome

Research Institute, NIH

Smoking

Cardiac ion channelpolymorphism

ANSpolymorphism

5-HTTpolymorphism

Complement or Interleukin

polymorphism

Soft bedding

Prone or sidesleeping

Environmental risk factors Genetic risk factors

Prematurity Sudden Infant Death

Impaired autonomic regulation

and arousal

Hunt & Hauck, in press

FUTURE DIRECTIONSFUTURE DIRECTIONSResearch to Practice (Translation)Research to Practice (Translation)

Antemortem phenotyping essentialAntemortem phenotyping essential• Screening Screening • InterventionIntervention

Broaden our focus to include other sudden Broaden our focus to include other sudden death groupsdeath groups• Sudden Intrauterine Unexplained Death (SIUD) Sudden Intrauterine Unexplained Death (SIUD)

1-2% of pregnancies end in stillbirth1-2% of pregnancies end in stillbirth Many shared features with SUDI and SIDSMany shared features with SUDI and SIDS

• Sudden Unexplained Death in Childhood Sudden Unexplained Death in Childhood (SUDC)(SUDC)

0.013 per 1 000 live births0.013 per 1 000 live births• Sudden unexplained death in epilepsySudden unexplained death in epilepsy

SUMMARYSUMMARYThe “Take Home” Message on Genetic Research The “Take Home” Message on Genetic Research

Provides biologic mechanisms for SUDI Provides biologic mechanisms for SUDI when no “apparent” explanation at when no “apparent” explanation at autopsy autopsy • Genetic autopsies not yet feasibleGenetic autopsies not yet feasible

Especially important in those rare Especially important in those rare occurrences of multiple SUDI in familiesoccurrences of multiple SUDI in families

Helps to understand how environmental Helps to understand how environmental risk factors may lead to SUDI in infants risk factors may lead to SUDI in infants genetically predisposedgenetically predisposed

MAJOR CHALLENGE: MAJOR CHALLENGE: • Not yet feasible to recognize in early infancy which Not yet feasible to recognize in early infancy which

infants are genetically predisposed to SUDI if & when infants are genetically predisposed to SUDI if & when confronted with relevant environmental risksconfronted with relevant environmental risks

SUMMARYSUMMARY, cont., cont.

The “Take Home” Message on Genetic Research The “Take Home” Message on Genetic Research

SUDI is a complex disorderSUDI is a complex disorder• No single cause No single cause • Complex interactions between genetic and Complex interactions between genetic and

environmental risk factorenvironmental risk factor No immediate help for familiesNo immediate help for families

• Highlights the importance of minimizing Highlights the importance of minimizing environmental risk factors that are environmental risk factors that are modifiablemodifiable

Expanding knowledge of genetic risk Expanding knowledge of genetic risk factors will progressively lead to factors will progressively lead to improved understanding regarding improved understanding regarding potential strategies for clinical testing potential strategies for clinical testing and (ultimately) interventionand (ultimately) intervention