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TODAY WE ARE HONOR TO HAVE OUR
SPEAKER DR. DAVID GOLDMAN,
CLINICAL DIRECTOR OF THE
NATIONAL INSTITUTE ON ALCOHOL
ABUSE AND ALCOHOLISM AND CHIEF
OF THE LABORATORY OF
NEUROGENETICS.
DR. GOLDMAN EARNED HIS BACHELOR
OF SCIENCE FROM YALE, MEDICAL
DEGREE FROM THE UNIVERSITY OF
TEXAS GALVESTON BRANCH
GRADUATING SUMMA CUM LAUDE, AND
COMPLETED INTERNSHIPS AT THE
NIH.
A YEAR LATER DR. GOLDMAN JOINED
THE NIH AS A RESEARCH FELLOW AND
HAS BEEN PART OF THE NIH EVER
SINCE, BOTH AT NIAARK, AND NIMH,
AN INSTITUTION WITHIN AN
INSTITUTION.
THANK YOU.
A DISTINGUISHED INVESTIGATOR
DR. GOLDMAN HAS BEEN 1 OF THE
MOST CITED DOCTORS IN GENETICS.
HE IDENTIFIED GENES THAT
INCREASE GENES TO VULNERABILITY
TO ALCOHOLIC DISORDER AND
PSYCHIATRIC DECS INCLUDING IN
FOUNDER POPULATIONS SUCH AS
NATIVE AMERICAN TRIBES AND
FINLAND.
HIS LABORATORY USED THE
COMBINATION OF PHENOTYPE AND
GENETIC METHODS TO IDENTIFY
CAUSAL INFLUENCE VULNERABILITY
TO PSYCHIATRIC DISORDERS.
DR. GOLD MAN HAS AUTHORED OVER
500 PAPERS INCLUDING IMAGING
STUDIES, DR. GOLDMAN AND HIS
GROUP DISCOVERED INHERITED GENE
VARIATIONS THAT INFLUENCE
VULNERABILITY AND TRACER
MUTATIONS THROUGH COMPLEX
BEHAVIORS, BOTH IN HUMAN
RESEARCH STUDIES AND MODEL
ORGANISMS.
AMONG HIS MANY AWARDS,
DR. GOLDMAN HAS BEEN HONORED
WITH HIS MENTORING AWARDS, FOR
THE RESEARCH SOCIETY ON
ALCOHOLISM, THE OUTSTANDING
RESEARCHER JAMES ISAAC SON
RESEARCH AWARD OF THE
INTERNATIONAL SOCIETY FOR
BIOLOGICAL RESEARCH ON
ALCOHOLISM AND MULTIPLE NIH
DIRECTORS AWARDS.
HE HAS SERVED ON EDITORIAL
BOARDS OF MANY LEADING JOURNALS
AND AUTHOR OF SEVERAL BOOKS,
INCLUDING OUR GENES, OUR CHOICES
WHICH WON THE BRITISH MEDICAL
ASSOCIATION TOP PRIZE.
HIS LATEST BOOK IMMORAL IS ABOUT
THE NATURE OF LIFE.
THE TITLE OF HIS TALK TODAY IS
GENETICS AND EPIGENETICS OF
ALCOHOL USE DISORDER.
NOW PLEASE JOIN ME IN WELCOMING
TODAY'S SPEAKER DR. GOLDMAN.
[ APPLAUSE ]
>> THANK YOU.
FIRST I WOULD LIKE TO THANK TOM
BURKLOW FOR THAT GENEROUS
INTRODUCTION AND ALSO RITA
STEPHENS FOR HELPING ORGANIZE
THIS AND TO SAY THAT IT'S GOOD
TO SEE SOME OF YOU WHO I KNOW
WELL IN THE AUDIENCE AND THOSE
WHO HAVE JOINED ONLINE, ALSO,
THANK YOU.
AND SO, THIS TALK TITLE COULD
HAVE BEEN GENOMICS AND
EPIGENERATED NOAMICS OF ALCOHOL
USE DISORDER BECAUSE OF WHERE
THE FIELD HAS REALLY MOVED.
ALCOHOL USE DISORDER IS A GENE
BY ENVIRONMENT INTERACTION
WITHOUT ALCOHOL, THERE'S NO
ALCOHOL USE DISORDER, SO THIS IS
ONLY A SOCIOLOGICAL CULTURAL
CONTEXT OF AUD IS DISCUSSED BUT
THERE ARE ALSO GENE BY
ENVIRONMENT CORRELATIONS BECAUSE
HUMANS UNIQUELY AMONGST SPECIES
HAVE AN ABILITY TO CHOOSE AND
SHAPE THEIR ENVIRONMENT.
AND THESE GENE BY ENVIRONMENT
INTERACT CORRELATIONS INCLUDE
PASSIVE 1S, WE NEED TO CHOOSE
OUR PARENTS WISELY BECAUSE
THEY'RE GOING TO TRANSMIT GENES
TO US AND THEY'RE ALSO GOING TO
SUBJECT US TO BEHAVIORS THAT WE
CAN'T REALLY CONTROL.
EVOCATIVE WHAT WE TRIGGER, AND
THEN ACTIVE, WHAT WE CHOOSE AND
CREATE AND IT'S GOING TO BE
RECOGNIZED THAT ALCOHOL USE
DISORDER AS THE OTHER SUBSTANCE
USE DISORDERS INVOLVES
EVOLUTIONAL COMPONENT.
NEVERTHELESS THE VULNERABILITY
IS SO HIGH IN THE GENERAL
POPULATION THAT 29.1% OF PEOPLE
ON A LIFETIME BASIS HAVE ALCOHOL
USE DISORDER.
SO WE CAN SEE THAT MANY OF US
ARE VULNERABLE.
THIS CAPTURES THE EFFECT OF A
CULTURES COMSUMPTION OF ALCOHOL
ON ALCOHOL USE DISORDER BY
LOOKING AT CIRRHOSIS DEATHS AND
YOU SEE PLOTTED HERE IS PER
CAPITA ALCOHOL COMSUMPTION IN
LITERS PER YEAR, IN THE UNITED
STATES IT'S NOW ABOUT MIDWAY IN
PERCAPITTA COMSUMPTION AND IT'S
ALSO ABOUT MIDWAY IN CIRRHOSIS
DEATHS PER YEAR.
NOW THIS IS EXPANDING DUE TO
METABOLIC ASSOCIATED DATA
HEPATITIS AND OF COURSE THERE
ARE OTHER FACTORS, BUT JUST ON A
CRUDE BASIS, YOU CAN SEE THAT
WHERE YOU LIVE STRONGLY
INFLUENCES, YOUR VULNERABILITY
AND I REALIZED I MANAGED TO HIT
THE WRONG BUTTON ALREADY.
THIS IS THE TEMPORAL VARIATION
IN CIRRHOSIS WITHIN 1 COUNTRY,
THE UNITED STATES.
THE UNITED STATES IS UNIQUE IN
HAVING 2 CONSTITUTIONAL
AMENDMENTS THAT WERE ACTUALLY
DEVOTED TO 1 SUBSTANCE, ALCOHOL
AND THERE WAS A DROP IN
CIRRHOSIS RELATED DEATHS BOTH
SEEN PREPROHIBITION AND THEN
AFTERWARDS AND THEN THE SOLDIERS
RETURNING FROM OVERSEAS AFTER
WORLD WAR II WERE MORE PRONE TO
DRINK HEAVILY AND DEVELOP A. U.
D.
SO DESPITE THIS TOTAL DEPENDENCE
ON EXPOSURE, ALCOHOL USE
DISORDER AND OTHER SUBSTANCE USE
DISORDERS ARE HERITABLE.
HERE YOU SEE THAT A. U. D. IS
ABOUT MIDWAY INHERITABILITY AND
THE HERITABILITY IS ABOUT 50%,
THAT'S THE COMPONENT OF
VARIABILITY THAT IS DIRECTLY
CAPTURED BY TWIN STUDIES.
AND ON THE OTHER HAND WE HAVE
CROSS TRANSMISSION OF THE
SUBSTANCE USE DISORDERS.
THERE'S NOT A UNIQUE GENETIC
FACTOR THAT GOVERNS 1 SUBSTANCE
USE DISORDER AND IT'S NOT SHARED
WITH OTHERS.
WELL, THERE MAY BE A FEW IN
TERMS OF THE METABOLIC GENE
POLYMORPHISMS THAT I WILL TALK
ABOUT LATER, BUT MUCH OF THE
VULNERABILITY IS A GENERAL
VULNERABILITY TO ADDICTION, THIS
IS FROM THE NESARC III STUDY,
WHERE IN COLLABORATION WITH
PATRICIA CHOU AND HAITAO ZHANG,
WE LOOKEDDA THE TRANSMISSION OF
AUDs IN THE LARGE HOUSEHOLD
SURVEY SAMPLE THAT HAS BEEN
COLLECTED BY NIAAA.
IN USING THE NP MARKERS, THE
SINGLE NUCLEOTIDE POLYMORPHISMS,
WERE ABLE TO ESTIMATE A
POLYGENIC SCORE FOR RISK OF
THESE SUBSTANCE USE DISORDERS
AND SO THE ALCOHOL POLYGENIC
SCORE IS HERE PREDICTIVE OF
NICOTINE USE DISORDER RISK AND
ON THE OTHER HAND, THE NICOTINE
USE DISORDER POLYGENIC SCORE
PREDICTS ALCOHOL USE DISORDER.
AND SO THIS CROSS TRANSMISSION
HAS BEEN REPEATEDLY OBSERVED
ANDEN THIS OF COURSE, AS I SAID
THERE ARE ALSO SUBSTANCE
SPECIFIC YEENS WHICH MIGHT BE
THE GATEWAY MOLECULE IT IS OF
THIS PARTICULAR SUBSTANCE.
I WILL GET THE HANG OF THIS, I
PROMISE.
SO WHEN WE THINK ABOUT THE
GENERAL COMPONENT OF
VULMERRABILITY, WHAT MIGHT BE
INHERITED AND THIS IS THE
ADDICTIONS NEUROCLINICAL
ASSESSMENT IN 2 PAPERS WHICH ARE
SHOWN HERE AT THE BOTTOM AND
THEN ACTUALLY A NEW PAPER
SUBMITTED BY TOMMY
[INDISCERNIBLE] WHO'S IN THE
AUDIENCE, WE'VE BEEN ABLE TO
DERIVE THESE 3 MAJOR FACTORS OR
DOMAINS OF VULNERABILITY AND
PROGRESSION OF A. U. D.
PREOCCUPATION AND ANTICIPATION
BEING THE LAST 1, EXEC TEF
TOCKSICATION AND THEN
WITHDRAWAL, NEGATIVE AFFECT HERE
SOMEWHERE IN THE MIDDLE.
HOWEVER, THIS WORK WHICH IS AS
YOU SEE LED BY LAURA KWAKO ALSO
DOESN'T FULLY CAPTURE THE FACT
THAT PEOPLE WITH ALCOHOL USE
DISORDERS MAY BE ALREADY
VULNERABLE IN THESE DIFFERENT
DOMAINS.
THEY MAY ALREADY HAVE NEGATIVE
AFFECT BEFORE THEY'RE EVER
EXPOSED TO THE DRUG.
THEY MAY ALREADY HAVE DIMINISHED
EXECUTIVE FUNCTION BEFORE AN
EXPOSURE.
SO BOTH AS A CONSEQUENCE OF
EXPOSURE, THESE DOMAINS ARE
AFFECTED AND AS IS COMMON TO
PROBABLY MOST PEOPLE WITH
ALCOHOL USE DISORDER, BUT ALSO
AS A PRECURSOR TO ALCOHOL USE
DISORDER, THIS ALREADY
PREEXISTING VULNERABILITY IN
MANY.
ARE THEN, THE GENE BY
ENVIRONMENT AND INTERMEDIATE
PHENOTYPE STUDIES THE WAY
FORWARD.
SHOULD WE BE DOING GENETIC
STUDIES ON THESE ADDICTIONS
NEUROCLINICAL ASSESSMENT DOMAINS
AND OTHER SORTS OF INTERMEDIATE
PHENOTYPE, SORTS OF PHENOTYPES.
INSTEAD OF ALCOHOL USE DISORDER,
WHICH IS ITSELF SO COMMON AND SO
MULTICAUSAL AND FACTORIAL, WELL,
WE USED TO THINK SO.
WE USED TO THINK THAT--AND MUCH
OF THE ACTIVITY AT MY LAB WAS
DEVOTED TO THAT COMSUMPTION THAT
THE WAY FORWARD WAS THESE SORTS
OF GX E INTERMEDIATE PHENOTYPE
TODAYS BUT AS I WILL SHOW YOU AS
MATTERS AND IT TURNS OUT THAT IN
THE VERY LARGE STUDIES, THE
LARGEST STUDIES, THE GWAS
STUDIES THESE PHENOTYPES ARE NOT
REALLY WHAT IS COLLECTED AND
TREMENDOUS PROGRESS HAS BEEN
MADE.
SO HERE FIRST OF ALL THOUGH, IS
THE CONCEPT THAT CONTEXT
MATTERS.
THIS IS A SERIES OF FUNCTIONAL
WELL, OCI ON THE LEFT WHICH ARE
AT NEUROGENETIC CANDIDATE GENES
AND THE INFORMATION THAT 2 OF
THESE FUNCTIONAL LOCI PRODUCE
SYMPTOMS IN THE CONTEXT OF EARLY
LIFE TRAUMA, SO THE SEROTONIN
TRANSPORTER POLYMORPHISM IS--HAS
A CONSEQUENCE OF SELF-REPORTED
DEPRESSIVE SYMPTOMS BUT ONLY IN
THE INDIVIDUALS WHO HAVE HAD 3
OR 4 OF THESE STRESSFUL EVENTS
IN EARLY LIFE AND SIMILARLY, WE
DON'T HAVE THE WAXES LABELS HERE
BUT THIS IS CONTROLLED BEHAVIOR,
THE DISCONTROL IS OBSERVED IN
PEOPLE WHO HAD THE LOW MAOA
ACTIVITY POLYMORPHISM BUT HAD
UNDERGONE SEVERE EARLY TRAUMA.
I PROMISE THAT I WOULD GET THE
HANG OF THIS AND I HAVE NOT YET.
THIS IS A FURTHER EXAMPLE OF
INTERACTION.
HAD IS AGAIN THE MONOMEANOX DACE
A POLYMORPHISM, AND ON THE LEFT
YOU SEE THAT IN THE CONTEXT OF
HIGH TESTOSTERONE LEVEL THAT
THERE IS A HIGHER LIFETIME
AGGRESSION SCORE BUT THAT IS
ONLY IN THE INDIVIDUALS WHO
CARRY THE LOW ACTIVITY MAOA
POLYMORPHISM, NOT IN THOSE WHO
CARRY THE HIGH MAOA ACTIVITY
ALLELE.
ASK MORE ON INTERMEDIATE
PHENOTYPES.
THIS IS--THERE IS A FUNCTIONAL
POLYMORPHISM IN THE NEUROPEPTIDE
MPY GENE AND THAT FUNCTIONAL
POLYMORPHISM PREDICTS VERY
STRONGLY BRAIN IMAGING RESPONSES
TO EMOTIONAL STIMULI AND YOUEE
THAT HERE FOR PEOPLE WITH A LOW
ACTIVITY, MPY GENO TYPE OR DIP
LO TYPE HAD THE STRONGEST
ACTIVATIONS OF THE HYPOCAMPUS
AND AMYGDALA IN RESPONSE TO THAT
EMOTIONAL CHALLENGE.
PEOPLE WITH THE HIGH ACTIVITY,
FORM, DO NOT.
AND HERE YOU SEE THE OVERALL
AFFECT OF THIS POLYMORPHISM ON
BEHAVIOR WHERE IF YOU MOVE FROM
THE LEVEL OF HOLDING COMPANY
KIEWL AND THEN THROUGH BRAIN,
AND THEN FINALLY TO BEHAVIOR,
THE AFFECT OF THE POLYMORPHISM
IS PROGRESSIVELY DILUTED.
STRONG EFFECTS ON MRNA
EXPRESSION AND PLASMA
NEUROPEPTIDE Y LEVELS BUT WEAK
EFFECTSOT EMERGENT BEHAVIOR OF
TRADE ANXIETY OR PAIN THRESH
OLD.
SO WE HAVE A PROBLEM THAT THE
WHICH IS THAT THE CLINICAL
RELEVANCE IS STRONGEST DOWN HERE
BUT ON THE OTHER HAND, THE GENE
EFFECTS ARE STRONGEST UP HERE SO
WHAT HAS HAPPENED THEN--OH, 1
MORE CANDIDATE GENE IF YOU WILL.
THIS WAS ACTUALLY FOUND AS A
RESULT OF A SEQUENCING STUDY, WE
FOUND A STOP CODON IN 1 OF THE
SEROTONIN RECEPTORS HCR2 B AND
YOU SEE THE LOCATION OF THIS
STOP CODON HERE AND IT
TRUNCATING THIS PROTEIN, SO
THERE'S A LACK OF THE PROTEIN IN
PEOPLE WHO HAVE THE STOP CODON,
IT'S LIKE A YEEN KNOCK OUT.
IT'S COMMON IN FINNS, IT'S LIKE
1 AND HALF% FREQUENCY IN ALLELES
IN FINMS, AND IT IS ALSO
ASSOCIATED WITH MULTIPLE
PERSONALITY DISORDER AND ALCOHOL
USE DISORDER AND LINKED TO
FAMILIES IN THESE BEHAVIORS AND
THEN THERE'S PREDICTIVE VALIDITY
WHERE WE SHOW, WE KNOCKED OUT
THIS YEEN IN THE MOUSE AND THIS
MICE THAT HAVE IT KNOCKED OUT,
YOU SEE THAT THEY HAVE
IMPAIRMENTS AND DELAYED
DISCOUNTING.
THEY HAVE MORE LOCOMOTION AND
RESPONSE TO A NOVEL ENVIRONMENT.
THEY ARE LIKELY TO TOUCH NOVEL
OBLIGATIONS YECTS THAT THEY'RE
PRESENTED, LET'S SEE WHERE THE
NEXT SLIDE IS.
AH, AND HERE'S THE CUTE FIGURE
THAT LUKE [INDISCERNIBLE]
DEVISED WHICH SHOWS THAT THE 2 B
MOUSE THAT HAS THE HCRG2 B
RECEPTOR WHICH PATIENTLY--BUT
ALSO ON THE OTHER HAND THE MOUSE
WITH THIS GENE KNOCKED DOWN IF
YOU PUT IT IN A CLOSURE WHERE
THERE'S FOOD IN THE MIDDLE, IT
KNOWS THAT, IT WILL VENTURE TO
THE DANGEROUS MIDDLE WHERE AS A
HAWK MIGHT SWOOP DOWN OR A CAT
MIGHT POUNCE ON IT IN ORDER TO
GET THAT PELLET OF FOOD.
SO NOW LET'S MOVE TO WHERE THE
FIELD WENT AND WHERE THE FIELD
WENT WAS TO GENOME STUDIES.
AND SO WHAT IS A GENOME WIDE
ASSOCIATION STUDY?
WELL IT IS ABASED LINKAGE
INSTEAD OF FAMILY BASED LINKAGE
WHICH IS LOCUST BASED LINKAGE,
IT'S DISASSOCIATION STUDY WITH
HUNDREDS OF THOUSANDS OF
MARKERS, USUALLY THE SNPs,
BECAUSE THEY CAN BE EFFICIENTLY
AND CHEAPLY GENO TYPED ON ARRAY
AND THEN MILLIONS OF ARK
DITIONAL SNPs, MAY BE
INFORMATICLY IMPUTED AND WHAT
THAT YIELDS IS THE PLOT LIKE
THIS WITH A LEVEL OF GENOME WIDE
SIGNIFICANCE AND THEN ACROSS THE
CHROMOSOMES, YOU LOOK FOR THE
SIGNALS, EACH DOT REPRESENTING
THE SNP AND THERE'S CERTAIN
PLACES WHERE THESE SIGNALS RISE
TO THE LEVEL OF SIGNIFICANCE, SO
THEY LOOK LIKE, RATHER LIKE A
SKYSCRAPER IN MANNA HAT AN AND
THIS LOOKS LIKE A, WHAT DO YOU
CALL IT, A SKY LINE, SO IT'S A
MANHATTAN PLOT AND FOR THOSE WHO
ARE INTERESTED, YOU CAN DOWNLOAD
FROM THE INTERNET THISART WORK
BY A FORMER PRESIDENT SHOWING
THE MANHATTAN CHI LINE WHICH AS
YOU OBSERVATION LOOKS EXACTLY
LIKE A MANHATTAN PLOT.
THIS ISN'T TO SAY THAT THIS IS
AN ESPECIALLY VALUABLE PIECE OF
ART BUT IT'S READILY OBTAINED
AND YOU SEE HIS NAME THERE WHICH
MAY NOT BE READABLE BUT HE'S
CURRENTLY ON TRIAL IN MANHATTAN.
LET'S SEE, YES, ARE AND SO, THIS
METHOD THEN WAS USED TO DO
GENOME WIDE ASSOCIATION STUDIES
AND YOU SEE THE RESULT OF 1
LARGEST OF THESE GENOME WIDE
ASSOCIATIONS, THIS IS SEVERAL
YEARS AGO WHERE THERE ARE QUITE
A NUMBER OF LOCI THAT RISE TO
THE LEVEL OF SIGNIFICANCE, BUT
ALSO THE POLYGENIC SCORE FROM
THESE GWAS HAVE BEEN USED TO
LOOK AT WHAT IS CROSS
TRANSMITTED, WHAT IS CROSS
TRANSMITTED AND ALSO WHAT IS
ANTITRANSMITTED WITH THE
VULNERABILITY TO A. U. D.?
SO SHARED WITH THE VULNERABILITY
TO A. U. D. IS LIFETIME CANNABIS
USE, WHETHER 1 IS A SMOKER AND
THEN NEGATIVELY CORRELATED ARE
THINGS SUCH AS THE AGE AT FIRST
BIRTH, THE EDUCATIONAL
ATTAINMENT OF THE INDIVIDUAL, IN
THE COGNITIVE PERFORMANCE OF THE
INDIVIDUAL, SO YOU CAN SEE THAT
SOME OF THESE PREEXISTING
VULNERABILITY FACTORS ARE ALSO
PREDICTED BY POLYGENIC CORE FOR
A. U. D.
I SEEM TO LINK THE ORDER OF THIS
BECAUSE USUALLY BIGGER COMES
AFTER BIG INSTEAD OF THE OTHER
WAY AROUND BUT HERE YOU SEE THE
BIG GWAS OF A. U. D., ON THE
SLIDE IT'S NICE BECAUSE YOU CAN
SEE A MAJOR CLUSTER OF HITS
WHICH ARE RIGHT AT THE ALCOHOL
DEHODGE NAS CLUSTER 4, THAT'S
THIS CLUSTER HERE.
SO WHAT DID WE FIND?
WHAT WE FOUND WITH THE GWAS
STUDIES WELL, THERE ARE 281 GWAS
LISTINGS FOR A. U. D. CURRENTLY
IN THE GWAS CATALOG, AND THERE
ARE OVER A THOUSAND LISTINGS FOR
DRINKING AND WE FIND SOME OLD
FRIENDS, WE FIND YEENS LIKE ALD
HIDE DEHYDROGENASE 1 B WHICH
WERE WELL KNOWN TO BE RISK LOCI
FOR ALCOHOL USE DISORDER AND I
WILL SHOW YOU WHY IN A MOMENT.
WE ALSO FIND OLD FRIENDS LIKE
THE DRD2 DOPAMINE RECEPTOR, THIS
DOPAMINE RECEPTOR OF COURSE
CRITICAL IN REWARD BUT ALSO MOST
IMPORTANTLY WE FIND NEW GENES
AND NEW PATHWAYS AND SO SOME OF
THESE ARE LISTED HERE, A METAL
ION TRANSPORTER, AN FGP
KORESEPTORSOR, A GLUE KINASE
REGULATOR AND A CYTOPLASM
NUCLEAR PROTEIN FOR TRANSPORT,
BY AND LARGE THE FUNCTIONAL LOCI
HAD NOT BEEN IDENTIFIED AT THIS
GENES AND SO THEY'RE NOT IN THE
STATUS OF ALPHA DEHYDROGENASE 2
OR DRD2, AND THOSE ARE RS
NUMBERS FOR THEM, BUT THE
IMPORTANCE IS THAT THEY HAVE
SHOWN US NEW PATHWAYS TO A. U.
D.
WE ALSO KNOW THAT ONLY A PORTION
OF RISK OF THE A. U. D. IS
CAPTURED SO FAR, BUT EVEN WITH
THAT PORTION OF RISK BEING
CAPTURED, WERE ABLE TO
UNDERSTAND THAT THERE ARE
PATHWAYS TO JUST METAL ION
TRANSPORT OR FGF OR GLUE O
KINASE WHICH MAY BE IMPORTANT IN
A. U. D. RISK AND SO AS PROMISED
HE HEARS THE--HERE'S THE
POLYMORPHISMS OF ALD H1 AND
ADHWORKS BEFORE ACCIDENT AND
THERE ARE MOW SUBTUITIONS,
THEY'RE COMMON IN POPULATIONS
ESPECIALLY IN SOUTHEAST ASIA
WHERE THERE ARE MORE THAN HALF A
BILLION PEOPLE WHO ACTUALLY CARE
THEM, AS A RESULT THESE
INDIVIDUALS WILL ACCUMULATE ALD
HIDE LEADING TO THE FLUSHING
ACTION, AND HOWEVER, EVEN THOUGH
THEY'RE RELATIVELY PROTECTED
AGAINST A. U. D., THEY ARE A
HIGHER UPPER GI AND BREAST
CANCER RISK AS A RESULT.
HERE'S WHAT THAT FLUSHING
REACTION LOOKS LIKE.
A MAJOR PROBLEM TODAY IS THAT
PEOPLE ARE BLOCKING THE FLUSHING
REACTION WITHIN ANTIHISTAMINE
DRUGS AND THOSE ANTIHISTAMINE
DRUGS DO NOTHING TO ELIMINATE
THE GENO TOXICITY OF ALCOHOL
WHICH IS SO MUCH GREATER IN
PEOPLE WHO CARRY THESE VARIANTS
INCRUCKING ALDA HIDE LEVELS.
SO THEN WHAT IS CONSEQUENT TO
ALCOHOL EXPOSURE OTHER THAN
FLUSHING, WELL, THERE'S A BROAD
IMPACT ON THE GENOME.
AND INVESTIGATOR AT NIAAA WITH
MY HELP HAS BEEN STUDYING THIS,
THIS IS [INDISCERNIBLE] WHO YOU
SEE HERE, THIS IS
[INDISCERNIBLE] WHOSE FIRST
AUTHOR ON THIS RECENT PAPER AND
WHAT YOU ARE SEEING IS THAT
PEOPLE WHO DRINK HEAVILY HAVE AN
EPIGENETIC AGE ACCELERATION OF
ABOUT 2 YEARS AND FURTHER MORE,
IF THEY HAVE HAD THE EARLY LIFE
TRAUMA, THEY HAVE AN EPIGENETIC
AGE ACCELERATION OF ABOUT 2
YEARS AND THESE EFFECTS ARE
ROUGHLY ADDITIVE.
HOW DO WE DO THIS WORK?
WELL WE RUN AN ARRAY WITH
850,000 FEATURES, CPG CITES ON
IT AND MEASURE THE METHYLATION
AT THESE SITES, MANY OF WHICH
ARE ONLY NEARBY GENES.
SO WHY ARE WE CONCERNED AS
PHYSICIANS ABOUT A. U. D. AND
HEAVY DRINKING, WELL, CONCERN
BECAUSE AS YOU SEE THE 1 YEAR
PREVALENCE OF A. U. D. IS HIGH,
IT'S 13 PBT 9% BY THE
NESEA HOUSEHOLD SURVEY EMPLOY
WHEN WE LOOK AT MEDICAL
PATIENTS, JUST LESS THAN HALF OF
THEM MEET CRITERIA, ALCOHOL'S
DIVERSE EFFECTS ON ORGANS, IT
INTERACTS WITH THE MEDICATIONS
ISSUES AVAILABILITY OF
TREATMENT, LOW STAFF AND PATIENT
BURDEN OF ASSESSING IT AND IN
FACT, ON THE KREEN WHICH I WILL
SHOW YOU IN A MOMENT, IS NOW
ROUTINE AT MOST HEALTH
MAINTENANCE ORGANIZATIONS IN THE
VA BUT UNTIL A YEAR AGO, WE
DIDN'T ACTUALLY HAVE A FORM AT
SCREENING FOR AUD AND HEAVY
DRINKING AT THE CLINICAL CENTER,
SO A GROUP OF US ORGANIZED AND
LED BY JENNY [INDISCERNIBLE] GOT
TOGETHER TO IMPLEMENT THIS AND
SO HERE IS THE AUDIT C AND YOU
SEE THAT JUST THESE 3 SIMPLE
QUESTIONS WHICH SOMEBODY
NEEDS--WHICH A PERSON NEEDS TO
ANSWER AND THEY'RE GIVEN THIS
QUESTIONNAIRE AT ADMISSION AND
THEY'RE SHOWN WHAT A STANDARD
DRINK IS WITH THIS LITTLE CHART
HERE ON THE RIGHT.
THIS IS THE AREA UNDERTHE CURVE
FOR THE SENSITIVITY AND
SPECIFICITY OF THE SCREENING FOR
ALCOHOL USE DISORDER, BY THE
AUC, THIS IS OUR INTRAMURAL
CLINICAL SAMPLE WHICH IS QUITE
POWERFUL FOR ARK ASSESSING THE
VALIDITY AND POWER OF THE AUDIT
C, IF THE PERSON HAS AN AUDIT C
SCORE OF GREATER THAN 5, THE
AREA OF THE CURVE IS ABOUT .97
WHICH MEANS THAT WE REALLY, FOR
MOST PEOPLE DON'T NEED A TEST
FOR ALCOHOL USE DISORDER.
WE COULD JUST ASK THEM.
THESE 3 SIMPLE QUESTIONS SO NOW
WE'RE DOING THAT AND THIS IS THE
1 YEAR EXPERIENCE, WE JUST
ABOUT--WE HAVE MORE THAN DOUBLED
THE CLINICAL TRUSTEES ADDICTIONS
CONSULTS WHICH IS VERY GOOD
CONSEQUENCE.
[INDISCERNIBLE] WHO DID MEDICAL
EDOCCASION OF THE NURSES FOR
THIS AND SURVEYED 620 CLINICAL
CENTER NURSES, 554 OF WHOM
ACTUALLY RESPONDED TO THE SURVEY
AND YOU SEE THEY'RE RESPONDING
ON THE LACK ARD SCALE WHETHER
THEY STRONGLY DISAGREE OR
STRONGLY AGREE, AND I THINK THE
IMPORTANT TAKE HOME MESSAGE HERE
IS THAT THE SCALE HERE ONLY GOES
FROM 4.1 TO 5.
SO, THAT TELLS YOU WHAT THE
LEVEL OF ACCEPTANCE OF THE AUDIT
C SURVEY AS BEEN BY CLINICAL
CENTER NURSING.
AND HERE I PUT IN THE RED BOX IT
DOES NOT INTERFERE WITH THE WORK
LOAD ON ADMISSION AND THAT ALL
PATIENTS SHOULD BE SCREENED FOR
ALCOHOL USE DISORDER WHERE
THERE'S REALLY UNANIMITY FOR
BOTH OF THOSE.
MEAN WHILE WITHIN THE NIAA UNIT,
WE HAVE A BONA FIDE COLLECTION
OF PHENOTYPE AND GENO TYPE WHICH
IS GOING TO BE IMPORTANT FOR
STUDIES THAT I'M GOING TO SHOW
YOU NEXT AND SO THIS IS DONE VIA
A NATURAL HISTORY PROTOCOL WHICH
NANCY DIAZ [INDISCERNIBLE] IS A
PI ON.
AND THE GENOMICS WHICH IS EXOME
SNPs, A RAY ARE ALL IN MY LABS
AND THEN SAVED AND SHARED IN
MANY WAYS INCLUDING AMONGST THE
NIAAA PIs AND ALSO INTO THE
CONSORTIA NIAAA DATA ARCHIVE.
SO WITH THE LONG RUN A VERY
DEEPLY GENO TYPED AND ALSO
GENOMIC DATA SET IS CREATED.
SO HERE'S 1 OF THE WAYS THAT
WE'VE USED THAT.
WE USED THAT TO EXPLORE HOW IT
IS THAT ONLY SOME DRINKERS
DEVELOP ALCOHOL USE DISORDER AND
ONLY SOME HEAVY DRINKERS DEVELOP
LIVER DISEASE, SO JUST ABOUT ALL
PEOPLE WITH A. U. D. WILL
DEVELOP ALCOHOL FATTY LIVER
DISEASE AND YOU SEE THE
HISTOLOGY THERE WITH THE--OF THE
LIVER, BUT THEN ONLY 10-35%
PROGRESS TO ALCOHOL ASSOCIATED
ASSOCIATED
HEPATITIS AND ONLY 20% TO
ALCOHOL RELATED CIRRHOSIS.
SO GWAS OF WHOLE CIRRHOSIS WAS
DONE BY US AND THIS ALCOHOL
CIRRHOSIS GWAS, THE INTRAMURAL
AUD PEASHTS WITHOUT CIRRHOSIS
WERE ESPECIALLY VALUABLE.
AND FROM THAT GWAS, 3 OF THE TOP
GENES THAT WERE IMPLICATED WERE
ACTUALLY 1S THAT WERE INVOLVED
IN LIPID DROPLET FORMATION AND
THERE IS THE PI OF THIS--OF THIS
GENOME OUT CONSORTIUM AND I WILL
JUST EMPHASIZE 1 THING THAT THE
JEEPS THAT HAVE BEEN FOUND SO
FAR FOR CIRRHOSIS ARE 1S OF VERY
LARGE EFFECT.
YOU SEE THESE ODDS RATIOS SUCH
AS 2 OR .78 OR .79, THESE ARE
MUCH LARGER THAN THE TYPICAL
ODDS RATIOS THAT ARE SEEN WITH
GWAS STUDIES.
NOW, GWAS STUDIES REQUIRING
HUNDREDS OF THOUSANDS OF
INDIVIDUALS WITHIN DETECT LOCI,
BUT THE LOCI THAT REQUIRE SUCH
LARGE SAMPLE SIZES ARE 1S THAT
VERY SMALL EFFECT, NOT 1'S LIKE
THIS.
WHICH ARE LARGE AND WHICH EMERGE
FROM EVEN SMALLER GWAS STUDIES,
WE KNOW THAT AS THE STUDIES GET
LARGER THAT ADDITIONAL GENES
WILL BE REVEALED BUT IT'S VERY
INTERESTING OF THE GENES THAT E
HAVE SO FAR THAT THEY OF LARGE
EFFECT.
SO WE'VE ALWAYS STUDIED ALCOHOL
HEPA TITIS, THIS IS DONE WITH A
DIFFERENT CONSORTIUM LED BY
LAUREN NAGEY, SO ALCOHOL PEP A
TITIS, IS UNLIKE CIRRHOSIS IS
ALSO MARKED BY INFILTRATION OF
CELLS AND OTHER CELLS AND
DELIVER CUTE PHASE REACTANTS AND
ACUTE SYMPTOMS INCLUDE ABDOMINAL
PAIN, NAUSEA, [INDISCERNIBLE]
AND JAUNDICE, SO WE SEQUENCED
ALCOHOL AS PART OF THIS
CONSORTIUM.
THERE WAS A LARGE NUMBER OF
HEAVY DRINKERS.
THE HEAVY DRINKERS WITHOUT
CIRRHOSIS--SORRY WITHOUT ALCOHOL
HEPATITIS PREDOMINANTLY BEING
FROM OUR INTRAMURAL PROGRAM AND
THIS' A 58 MEGABASE GENOME
TARGET AND ACCURACY AND
COMPLETENESS AND YOU SEE THAT
THEY'RE ARE 45 OR 50,000
SEQUENCE VARIANTS WITHIN THIS
EXOME TARGET PER INDIVIDUAL.
AND DEPENDING UPON THE
POPULATION OF ORIGIN, AFRICANS
HAVING MORE VARIATION, I WOULD
JUST LIKE TO DRAW ATTENTION TO
QIAOPING YUAN, FROM OUR LAB WHO
WAS THE FIRST AUTHOR ON THIS
PAPER SUBMITTED.
SO WE FOUND EXOME WIDE SNPs,
INCLUDING MRS. BIG IN THIS FIELD
OR MRS. BIG IN THIS FIELD,
PASMMENT 3 WHICH IS A GENE
INVOLVED IN LIPID DROPLET
FORMATION, THESE ARE ALL ABOVE
THE RED LINE AND THEN THESE 2
ADDITIONAL GENES, THESE 2
ADDITIONAL GENES BEING INVOLVED
IN INFLAMMATION.
SO YOU HAVE THE FINDINGS
SUMMARIZED HERE AND I WON'T GO
INTO REALLY GREAT DETAIL EXCEPT
AGAIN TO SAY THAT THE ODDS RATIO
EFFECTS OF THESE ARE LARGE AND
RECENTLY FOR ALCOHOL CIRRHOSIS,
THE YEENS HAVE BEEN PUT TOGETHER
TO MAKE A POLYGENIC SCORE, THE
POLYGENIC SCORE FOR ALCOHOL
CIRRHOSIS AND A PAPER THAT JUST
CAME OUT 2 DAYS AGO FROM OUR
GENOME OUT CONSORTIUM, THAT
POLYGENIC CORE IS BASED UPON 20
GENES AND THERE'S A RISK OF
ABOUT--JUST AN ODDS RATIO EFFECT
OF ABOUT 3 DEPENDING UPON
WHAT--DEPENDING UPON YOUR GENO
TYPE AT THESE 20 GENES, SO IT'S
STILL VERY PRECLINICAL, IT'S
VERY PRECLINICAL BUT IT'S
GETTING THERE FOR PREDICTIVE
POWER.
WE MIGHT ANTICIPATE THAT FOR
ALCOHOL HEPATITIS THERE WILL BE
SIMILARLY, THERE WILL BE EFFORTS
TO CONSTRUCT POLYGENIC SCORES
FOR IT.
AND SO WHAT ABOUT THAT POLYGENIC
CONTRIBUTION TO ALCOHOL
HEPATITIS, THESE VARIANTS THAT
ARE NOT GENOME WIDE SIGNIFICANT
BUT THAT ARE RESPONSIBLE IN AN
ACUTE PLOT FOR THE SLIGHT LAMDA
VALUE INFLATION TAKEN--THEY WE
OBSERVED, SO YOU HAVE EXPECTED
P-VALUES AND OBSERVED P-VALUES
AND THERE'S SLIGHT EXCESS DUE TO
POLYGENIC CONTRIBUTION OF GENES
THAT ARE STILL SUBTHRESHOLD IN A
GWAS, SO WE LOOKED AT THAT
POLYGENIC CONTRIBUTION AND PING
DID IT IN A CLEVER WAY WHICH WAS
TO TAKE ALL THE GENES AND RANK
ORDER THEM AND THEN COMPARE THEM
TO THE RANK ORDER OF PRECOMPILED
LISTS, PRECURATED LISTS OF GENES
SO FOR EXAMPLE, ALL THESE WIKI
PATHWAYS, PRECOMPILED LISTS OR A
LIST THAT MIGHT BE COMPOSED OF
THE TOP GENES IN THE GWAS
CATALOG AND YOU LOOK FOR
ENRICHMENT AT THE EXTREMES OF
THE P-VALUES AND SO WHAT WE
OBSERVED WAS THIS THAT FIRST OF
ALL THERE ARE GLYCEROL LIPID
GENES WHICH ARE SIGNIFICANTLY
IMPLICATED AND THIS WHOLE
PATHWAY, THE 69 GENE WICKY
PATHWAY THAT IS A MASTER
REGULATOR OF FATTY ACID
BIOSYNTHESIS IS IMPLICATED BUT
FURTHER MORE, THERE'S THEN
THIS--THERE ARE THEN THESE
INFLAMMATORY GENES WHICH
BASICALLY DO NOT PLAY SUCH A
ROLE IN CIRRHOSIS.
THESE INFLAMMATORY GENES
INCLUDING THIS VITAMIN D
SENSITIVE CALCIUM SIGNALING AND
THIS BEING VERY IMPORTANT, IT'S
BEEN KNOWN FOR A LONG TIME THAT
VITAMIN D WAS CONNECTED TO
INFLAMMATION AND THIS IS
DRUGGABLE OF COURSE, AND THEN
ALSO LOOKING AT THE GWAS CATALOG
AT THE GENES THAT ARE SIMPLY
LABELED INFLAMMATION GENES.
AND SO YOU SEE THIS ENRICHMENT
WHICH GOES UP TO 40% FOR THE
VITAMIN D SENSITIVE CALCIUM
SIGNALING YEENS.
NOW ON THE OTHER HAND ISSUES
WA'S NEGATIVE, WELL, WE DON'T
HAVE TOO MUCH OF A ROLE FOR
GENES THAT ARE INVOLVED IN
ALCOHOL USE DISORDER OR
DRINKING, EITHER NOT SIGNIFICANT
IN THE CASE OF ALCOHOL
DEPENDENCE GENES OR VERY--IT'S
OVER HERE ON TOP OF IT ABOUT
VERY MARGINALLY SIGNIFICANT AND
THAT'S BECAUSE OUR CONTROLS WERE
ALSO HEAVY DRINKERS, SO WE'VE
ALREADY CONTROLLED FOR DRINKING.
BUT SO FAR, THE GWAS THAT HAVE
BEEN PERFORMED ON ALCOHOL
CIRRHOSIS AND RELATED PHENOTYPES
HAVE NOT REVEALED THOSE ALCOHOL
RELATED GENES, THAT'S PROBABLY
COMING WITH LARGER GWAS.
NOW FOLLOWING UP ON THIS FINDING
ON A NUMBER OF GENES THAT ARE
INVOLVED IN ALCOHOL CIRRHOSIS,
ARE THE 1S THAT WOULD BE
INTRINSIC TO THE HEPATOCYTES
BECAUSE THEY'RE INVOLVED IN
LIPID FORMATION FIRST.
WE THEN MADE INDUCED HEPATOCYTE
TYPE LIKE CELLS FROM THE
SAME--FROM THE VERY PATIENT WHO
IS HAVE ALCOHOL CIRRHOSIS AND
WHO WOULD HAVE THE COMPLETE
POLYGENIC CONTRIBUTION TO
ALCOHOL CIRRHOSIS.
THIS WAS DONE COLLABORATIVELY
WITH KUNOS SANYALL, AND WHAT WE
WERE ABLE TO SHOW IS THAT THE
IHLCs SPONTANEOUSLY ACCUMULATE
FAT AND THEY SHOW METABOLIC
TRANSCREPT ORDER OF MICRONSIC
ANDOXIDATIVE STRESS DIFFERENCES
AS WAS--AS WE PUBLISHED ABOUT 2
WEEKS AGO IN NATURE
COMMUNICATIONS.
SO HERE'S THE PROCESS BY WHICH
THE IHLCs, HEPATOCYTE LIKE
CELLS ARE MADE.
WE START WITH PERIPHERAL BLOOD,
WE PURIFY THE CD4 POSITIVE
T-CELLS, THOSE T-CELLS ARE
TRANSFECTED WITH THE 4 PRO
POTENCY GENES THAT
[INDISCERNIBLE] DISCOVERED AND
THEN THAT TAKES ABOUT A MONTH,
OUT TO ABOUT HERE, YOU HAVE
IPSCs AND THEN OVER ABOUT 2
MONTHS THEY'RE FORMED INTO
IHLCs USING A DIFFERENTIATION
METHOD OF ACADA.
YOU CAN SEE IT HERE WHERE THEY
START OFF WITH CLUMPS OF CELLS,
YOU END UP WITH A BETTER
MICROGRAPH OF THIS, BUT IT
WOULDN'T SHOW IN THIS ROOM,
ANYWAY, YOU WIND UP WITH NICE
CUBOIDAL LIKE CELLS,LES LOOK FOR
MUCH LEAK A PEP AT O SIGHT AND
THESE ARE CELLS WHICH NO LONGER
EXPRESS THE FLUR O POTENCY
MARKER, SESA4 WHICH THE IPSCs
DO, BUT THE MATURE, THESE MATURE
CELLS ARE SEMIMATURE CELLS
EXPRESS HEPATOCYTE
CHARACTERISTIC GENES SUCH AS
HNF4 AND ALBUT MIN.
AND IT DOESN'T MATTER IF THEY
ARE HEALTHY IHLCsS OR CONTROL
IHLCs, WHEN THEY'RE MATURE,
THEY EXPRESS SIMILAR LEVELS OF
THE HNF 4 OR THE ALBUMIN.
I'M KIND OF CONDITIONED TO HIT
THIS KEYBOARD, INTERESTING, NOT
VERY INTERESTING TO YOU, BUT TO
ME.
[LAUGHTER]
SO HERE'S THE FAC THAT THE
AC-IHLC SPONTANEOUSLY ACCUMULATE
FAT.
AND YOU CAN'T SEE THE
MICROGRAPHS BUT WE'RE USING HERE
3 DIFFERENT LIPID STAINS IN THE
ALCOHOL CIRRHOSIS IHLCs
ARE--WITH WE QUANTITATE IT ARE
ACCUMULATING WAY MORE OF THESE
LIPID TAINS THAN ARE THE HEALTHY
IHLCs.
AND HERE YOU SEE THAT THE
MITOCHONDRIA RESPIRATION OF
THESE CELLS WERE DISRUPPED.
WE WERE ANAL TO TAKE THESE
CELLS, PUT THEM IN AN INSTRUMENT
CALLED THE SEA HORSE WHICH
MEASURES OXYGEN COMSUMPTION
RIGHT, USE THESE SPECIFIC
INHIBITORS THAT LET US ACCESS
DIFFERENT PARTS OF THEOXIDATIVE
RESPIRATORY CHAIN, THESE
DIFFERENT INHIBITORS, YOU CAN
SEE THEM THERE, ANAMICEIN A AND
FCCP, AND ESTIMATE ALL THESE
DIFFERENT PARAMETERS AND THE
IMPORTANT THING IS THAT EXCEPT
FOR BASE--EXCEPT FOR THE
NONMITOCHONDRIA RESPIRRAATION
WHICH IS NOT MUCH DIFFERENT THAN
THE CASES AND CONTROLS THAT
THESE CELLS WHICH HAVE BEEN
GROWING INVITRO, AND OUTSIDE THE
BODY FOR ALL THESE MONTHS THAT
THESE CELLS ARE ALREADY AT BASE
LINE, DIFFERENT IN THE ZONE, YOU
CAN LOOK AT MAXIMAL RESPIRATION
OR SPARE CAPACITY OR WHATEVER
AND SEE THAT THE BLUE LINES ARE
ABOVE THE RED LINES AND FURTHER
MORE THE AC RESULTS ARE NOT ABLE
TO UTILIZE FATTY ACIDS AND
GLUTAMATE AND GLUTAMINE AS WELL,
AND FOR THIS THE IRREVERSIBLE
TRANSPORT INHIBITOR ANAMOCKSIER
ARE USED FOR FATTY ACIDS AND
THEN [INDISCERNIBLE] IS USED TO
ESTIMATE THE METABOLISM OF
GLUTAMATE.
AND WHAT WE SEE AGAIN IS THAT
THE DEPENDENCE OF THESE
AC AHLCs ON THE SUBSTRATES IS
MUCH LOWER THAN NORM AT IHLCs.
SO THEN 1 CAN FOLLOW THIS UP BY
THE YEERN LEVEL BY
TRANSCRIPTOMICS AND SO WHAT'S
DONE HERE IS TO DO SO CALLED RNA
SEQ, ON THE RNA FROM THE CELLS,
JUST BULK RNA SEQUENCING, THAT
LETS YOU MEASURE ABOUT 16,000
GENES AND TO LOOK AT THE
DIFFERENTIALLY EXPRESSED YEENS
BETWEEN CONTROL AND AND ALCOHOL
CIRRHOSIS, IHLCs AND WHAT YOU
SEE IS DOWN REGULATION IN THE ON
THE IHLCs ON A NUMBER OF
PATHWAYS INCLUDING IT, C CYCLE,
GLYCOLYSIS AND
GLUCONEOGENESIS,OXIDATIVE
PHOSPHORYLATION AND ELECTRON
TRANSPORT CHAIN AND VERY LARGE
OF THESE GENES IN THESE FORMERLY
PREDEFINED WIKIPATHWAYS.
AND THENOT OTHER HAND
UPREGULATED ARE APOPTOSIS AND
DNA DAMAGE AND ADIPOSE GENESIS,
AND SO IT REFLECTS WHAT YOU SEE
THROUGH A MICROSCOPE.
THE SICKENING OF CELLS AND THE
ACCUMULATION OF DROPLETS AND
FINALLY IT'S A POTENTIAL
PLATFORM FOR TESTING
THERAPEUTICS.
THIS IS A THERAPEUTIC RAM CALL
THAT'S ALREADY IN A PHASE 2 B
TRIAL, AND SHOWING POSITIVE
RESULTS IN METABOLIC ASSOCIATED
HEPATITIS, WHICH USE TO BE
CALLED SNASH AND FACTORED IN TO
SEE ARAMCHOL HAS A POETIC
TEBTIAL BENEFIT IN THESE
PATIENTS WHEN YOU GO FROM 5%
MASH RESOLVED TO 16.7% MASH
RESOLVED.
SO WE THEN TOOK THAT ARAMCHOL
AND USED IT IN THE IHLCs AND
SAW THAT IT IMPROVED THE
MITOCHONDRIA PERFORMANCE IN A
POWERFUL WAY.
AND YOU CAN JUST SEE THE
DIFFERENCE BETWEEN THE RED BAR
AND THE GREEN BAR FOR THESE
DIFFERENT PARAMETERS FOR THE
MITOCHONDRIA FUNCTIONAL
RESPIRATION, ATP PRODUCTION,
SPARE RESPIRATORY CAPACITY AND
FACIAL RESTORATION, AND COULD
PROVE IN THE HEPATOCYTE AND
POTENTIALLY MIGHT HELP PATIENTS
AND HELP MORE PATIENTS BY THESE
DRUGS THAN OTHERS.
SO I WOULD LIKE TO CONCLUDE TO
SAY THAT ALCOHOL USE HAS USE
DISORDERS AND PSYCHIATRIC
DISEASES AND NEVERTHELESS, IT'S
A CLASSIC THEME BY ENVIRONMENT
INTERACTION DISORDER, AND THE
GENE EFFECTS ARE STRONGER IN
MEDICAL KIEWLS AND ISHT MEDIATE
PROCESSES BUT WE'VE LEARNED THAT
LARGE GWAS ON CRUDE PHENOTYPES
CAN DETECT UNKNOWN GENES AND
MANY MORE GENES OF SMALL EFFECT
AND THAT ARE LARGELY UNKNOWN.
ALCOHOL HAS POWERFUL EPIGENETIC
EFFECTS AS YOU WOULD EXPECT BUT
IT'S WONDERFUL TO SEE THIS
MAPPED OUT NOW WITH OUR POWERFUL
TECHNOLOGIES AND TO REALIZE THAT
THE AFFECTS ARE STRONGER IN SOME
PEOPLE THAN THIS OTHERS AND
NOBODY WANTS TO ACCELERATE THEIR
EPIGENETIC AGE BY 2 YEARS.
THE YEENS AFFAIRS TEAM
LEADERRERRING RISK OF AUD,
ALCOHOL CIRRHOSIS AND HEPATITIS
ARE OVERLAPPING BUT THEY ARE
DISTINCT OF THE THE HEPATITIS
GENES ARE MUCH MORE INVOLVED IN
INFLAMMATION BUT TILL METABOLIC
GENES ARE ALSO INVOFFED IN
ALCOHOL ASSOCIATED HEPATITIS.
INVITRO, THE INTRINSIC METABOLIC
VULNERABILITY IF HEPATOCYTES,
THE IHLCs THAT IS, DERIVED THE
PATIENTS OH IPSCs APPEARS TO
BE CONSERVED, I WILL JUST
CONCLUDE BY THANKING YOU ALL FOR
YOUR ATTENTION AND SPECIAL
THANKS TO THE ALCOHOL CIRRHOSIS
CONSORTIUM, MY 2 PIs FOR THAT,
AND THEN OUR NEW DATA ON ALCOHOL
HEPATITIS THAT STUDY REALLY
INVOLVING A NUMBER OF OUR STAFF
NANCY DIAZ, MEL SCHWANDT, AND
BONNIE MOVED TO [INDISCERNIBLE]
AND THE LAB IS LEADING IT.
OUR EPIGENETIC STUDIES ARE WITH
FALK, AND HIS GROUP AND MANY
OTHERS AND FINALLY THIS WORK ON
THE AUDIT C, A SPECIAL SHOUT OUT
TO GEIN, NY, MBAMALU AND THE
REST OF THE CENTER AT THE
CKRSHES AUGHTIT C TEAM.
THANK YOU VERY MUCH.
[ APPLAUSE ]
TOM?
>> WELL WE DID HAVE A FEW
VIDEOCAST QUESTIONS.
WE DO HAVE A FEW
VIDEOCAST--FIEVER FIRST I WANT
TO SAY THANK YOU VERY MUCH FOR
THAT VERY THOUGHT PROVOKING AND
PRESENTATION ON GENOMICS AND
CELLULAR TOXICITIES ASSOCIATE
WIDE ALCOHOL USE, WHICH IS IF I
WILL SOBERING, ANYWAY.
SORRY ABOUT THAT, I'M HERE EVERY
THURSDAY.
WE DO HAVE A FEW QUESTIONS COME
IN.
ONE QUESTION IS AND I SHOWED
THIS TO YOU BEFORE HAND IS WHY
IS ALCOHOL NOT ILLEGAL?
>> WELL THE SIMPLE ANSWER IS WE
TRIED THAT AND THERE WERE 2
CONSTITUTIONAL AMENDMENTS
DEVOTED TO THE LEGALITY OF
ALCOHOLISM.
THE TEMPERANCE MOVEMENT WHICH
PRECEDED THE PROHIBITION
ACTUALLY HAD A LONG HISTORY MORE
THAN A CENTURY HISTORY IN THE
UNITED STATES AND YOU KNOW, IT
WAS MARKED BY ACTIVISTS,
MARCHING IN THE TREATS AND
ACTUALLY INNOVATING BARS AND
SMASHING ALCOHOL.
THERE ARE MANY DRY AREAS STILL
OF THE UNITED STATES.
MY HOME STATE OF TEXAS HAS
COUNTIES LIKE DEAF-SMITH COUNTY
WHERE 1 CANNOT BUY ALCOHOL AND
EVEN IN PLACES WHERE YOU CAN
PURCHASE ALCOHOL, YOU MAY NOT BE
ABLE TO DO SO ON A SUNDAY.
WE KNOW THAT SHORT OF MAKING
ALCOHOL ILLEGAL THAT JUST MAKING
IT MORE EXPENSIVE OR MORE
TYPICAL TO OBTAIN HAS ENORMOUS
EFFECTS SO I THINK THAT IT'S A
LOGICAL QUESTION TO ASK, BUT
THEN THE REALITY OF PROHIBITION
WAS THAT THERE WAS A COUNTER
MOVEMENT AND THAT COUNTER
MOVEMENT WAS VERY POWERFUL AND
IT WAS POWERFUL BECAUSE ALCOHOL
IS SUCH A WIDELY ENJOYED
SUBSTANCE BECAUSE THERE'S SUCH A
CULTURE OF ASSOCIATED WITH
ALCOHOL WHERE, YOU KNOW WHERE
WINE AND WHISKEY AND EVEN BEER,
EVEN BEER PLAY VERY IMPORTANT
PARTS IN PEOPLE'S LIVES AND
TRADITIONS.
AND SO IT'S A DIFFICULT THING TO
STAMP OUT.
AND WE NEVER WILL AND PROBABLY
WITHIN THE NEXT WEEK OR 2, I
WILL HAVE A GLASS OF WINE,
MYSELF.
BUT I LOVE THE QUESTION AND IT'S
CERTAINLY A VERY RELEVANT
QUESTION, ALSO IN TERMS OF THE
HARM REDUCTION MOVEMENT AND THE
TENDENCY TO LEGALIZE OTHER DRUGS
AND YOU KNOW WE'RE CERTAINLY
SEEN THAT CONVERSATION PLAY OUT
AND WE TALK ABOUT WHETHER THAT
CANNABIS SHOULD BE SCHEDULE 1,
SCHEDULE 3 OR COMPLETELY LEGAL
AS IT IS IN 26 STATES PRESENTLY.
SO WE'VE SEEN THAT, WE'RE SEEING
THAT WITH CANNABIS, WE'RE SEEING
IT WITH PSYCHEDELIC DRUGS, WHERE
THEY'VE BEEN MADE LEGAL IN A
COUPLE OF STATES AND WE'RE
LIKELY TO SEE THIS EXPERIMENT
PLAY OUT OVER THE NEXT FEW YEARS
AND AS THE EXPERIMENT PLAYS OUT,
IT'S VERY PREDICTABLE THAT A
CONSEQUENCE MAY BE THAT PEOPLE
WILL ENJOY THESE DRUGS BUT THAT
MANY PEOPLE WILL BECOME VICTIMS
OF THESE DRUGS.
SO I WOULD LOVE THE QUESTION, I
LOVE WHAT'S BEHIND IT.
>> THANK YOU.
I HAVE ANOTHER QUESTION, DOES
ANYBODY HAVE ANY QUESTIONS, WE
WILL TAKE THEM FROM THE AUDIENCE
OTHERWISE I WILL KEEP GOING
HERE.
ANOTHER VIEWER WRITES IN, PLEASE
DISCUSS THE GUT MICROBI OTA AND
THE EFFECTS OF THE ENVIRONMENT
AND WITH THE STUDY.
>> GREAT QUESTION.
SO THE CLINICAL CENTER, AND
COLLABORATIVELY WITH CLINICAL
TRUSTEES PERSONNEL INCLUDING
NANCY [INDISCERNIBLE] WHO IS
RETIRED NOW, WE DID A
LONGITUDINAL MICROBIOME STUDY IN
AUD, AND THIS IS A DNA
SEQUENCING, LOOKING AT THE
MICROBIOME OF AUD PATIENTS ON
ADMISSION AND THEN FOLLOWING
THEM ACROSS TIME WHEN THEY COME
INTO THE HOSPITAL, THEY'RE VERY
DISBIOTIC, THE SO CALLED
DIVERSITY INDEX, THE DIVERSITY
OF ORGANISMS THAT ARE IN THE
MICROBIOME ARE VASTLY PRODUCED
TO WHAT WILL HAPPEN OVER JUST A
COUPLE OF WEEKS OF ABSTINENCE
AND RESUSMGZ OF NORMAL NUTRITION
AND IT'S KNOWN THAT THE GUT
MICROBIOME PLAYS A CRITICAL ROLE
IN SOME OF THE ALCOHOL
ASSOCIATED DECS, ESPECIALLY
LIVER DISEASE, RON THURM AN
DECADES AGO SHOWED IF YOU
ACTUALLY ELIMINATE THE GUT
MICROBIOME YOU CAN LARGELY
PREDICT, YOU CAN LARGELY PREVENT
LIVER DISEASE IN LIFE, SO,
THE--WHEN YOU LOOK AT WHAT COMES
FROM THE GUT, FACTORS LIKE TUMOR
NECROSIS FACTOR AND OTHERS, YOU
REALIZE THAT AND REALIZE THE
IMPORTANT ROLE OF INFLAMMATION,
THE GUT MICROBIOME IS PLAYING A
CRITICAL ROLE IN THAT AND
ALCOHOL STRONGLY PERTURBS IN THE
GUT MICROBIOME.
>> THANK YOU.
I ACTUALLY HAVE A QUESTION ABOUT
THE AUDIT C PROJECT WHICH IS
OBVIOUSLY VERY POWERFUL AND
SENSITIVE TO IDENTIFYING THOSE
AT RISK.
I THINK 1 OF THE QUESTIONS AND
THIS S UP A LOT IS THE KREENING
THAT WE DO IS LIKE WHAT DO YOU
DO WITH THE RESULTS,
SPECIFICALLY FOR THE PATIENT.
I SUPPOSE A PATIENT WHO SCORES A
12 PROBABLY HAS ENOUGH INSIGHT
TO REALIZE HE OR SHE HAS ISSUES
WITH ALCOHOL USE BEFORE BUT FOR
THE 1S THAT CAME UP WITH, WERE
MORE LIKE TOWARD THE 5 AND 6
RANGE AND HOW DO YOU COUNSEL
THOSE PATIENTS ON OUR SYSTEMS
AND PROGRAMS IN PLACE FOR THAT,
FOR THOSE TYPE PATIENTS.
NYEAH, EXCELLENT QUESTION, TOM,
YOU KNOW I THINK THAT THE
INFORMATION IS REALLY FOR THE
PRIMARY CARE TEAM.
THE PHYSICIAN MAY BE WELL AWARE
ALREADY OF PATIENT'S HEAVY
DRINKING OR ALCOHOL USE
DISORDER, THE PATIENT MAY HAVE
EVEN ALREADY BEEN TREATED FOR
ALCOHOL USE DISORDER.
THE PATIENT THEMSELVES MAY NOT
HAVE THE FULL INSIGHT INTO THE
INTERACTIONS BETWEEN THE ALCOHOL
AND DRUGS THAT THEY MAY BE
TAKING OR WHY IT IS THAT THEY
HAVE SYMPTOMS LIKE ANXIETY,
DEPRESSION, OR WHY THEIR SEIZURE
THRESHOLD MIGHT BE LOWERED,
THERE ARE MANY INSIGHTS THAT THE
PHYSICIAN MIGHT HAVE, THE
PATIENT MIGHT NOT, MANY PATIENTS
DON'T KNOW THAT THERE'S A
DANGEROUS INTERACTION FOR
EXAMPLE BETWEEN TYLENOL AND
ALCOHOL AND THEY SHOULD, AND A
PHYSICIAN SHOULD BE ASKING ABOUT
THAT BECAUSE TYLENOL IS A DRUG
THAT IS PROBABLY SOLD IN
HUNDREDS OF MILLIONS IF NOT
BILLIONS OF DOSES IN THIS
COUNTRY AND IF YOU JUST LOOK AT
THE RESULTS FROM LAB CHEMISTRIES
OR HEMEATOLOGY REPORTS THAT MAY
COME BACK ON TO THE CHART, VERY
OFTEN TIMES TO INTERPRET THESE
RESULTS CORRECTLY AND CAREFULLY,
YOU MEDE TO KNOW ABOUT THE HEAVY
DRINKING OF A PERSON.
I MEAN THERE'S A REASON WHY THE
C-REACTIVE PROTEIN LEVEL, MAY BE
HIGH.
IT'S NOT JUST RANDOM, THEYA MAY
NOT HAVE AN AUTOIMMUNE DISORDER,
IT MAY BE THAT THEY ARE A PERSON
WHO HAS A LOT OF ALCOHOL
ASSOCIATED INFLAMMATION AND
THERE'S ALSO A GREAT NEED FOR
MANY PEOPLE WHO HAVE BEEN
DRINKING HEAV AND WHO ARE
NUTRITIONALLY DEFICIENT TO HAVE
VITAMIN SUPPLEMENTATION
INCLUDING THYMA MIN SO THEY DO
NOT DEVELOP [INDISCERNIBLE]
COUGH SYNDROME.
SO THERE'S A VARIETY OF REASONS
THAT THE AUDIT C SHOULD EVEN BE
THE SO CALLED FIFTH VITAL SIGN.
I DON'T KNOW IF I WOULD GO THAT
FAR BUT I THINK THAT EVERY
PHYSICIAN, EVERY HEALTH SYSTEM
SHOULD BE INQUIRING ABOUT
ALCOHOL IN THE SAME WAY THAT
THEY INQUIRE ABOUT PAIN OR THAT
THEY INQUIRE--THEY WANT TO KNOW
WHAT BLOOD PRESSURE AND A PULSE
AND A PULSE AND A TEMPERATURE
ARE IN A PERSON.
THIS IS NOT SOMETHING THAT YOU
NEED TO REPEAT OVER AND OVER,
BUT MISSION TO HAVE THAT
INFORMATION IS EXTREMELY
POWERFUL.
I THINK.
NIT'S POWER EMPLOY THANK YOU
VERY MUCH.
I THINK WE HAVE TIME FOR 1 MORE
QUESTION.
LET'S SEE, WHAT IS THE--WHAT ARE
THE NEXT STEPS IN AUD GENETICS
RESEARCH AND DO YOU THINK
POLYGENIC RISK FACTORS ARE
OFFERING PROMISING CONCLUSIONS?
>> CAN YOU REPEAT THAT?
>> YEAH.
WHAT ARE THE NEXT STEPS IN AUD
GENETICS RESEARCH AND DO YOU
THINK POLYGENIC RISK SCORES ARE
OFFERING PROMISING CONCLUSIONS?
>> YES.
OF COURSE THE NEXT STEP MIGHT BE
TO GET RID OF ME, BUT LET'S NOT
GO THERE.
I THINK THAT THEY'RE VERY USEFUL
IN A COUPLE WAYS.
ONE THING IS TO LOOK AT THE
INTERACTION OF EXPOSURES WITH
VULNERABILITY, SO IN THE OLD
DAYS, WE WOULD GET A FAMILY
HISTORY OR WE WOULD GET A FAMILY
HISTORY SCORE, AND SO NOW IS THE
POLYGENIC SCORE THAT'S BECOMING
MORE AND MORE POWERFUL, YOU KNOW
NOT JUST THE PERSON IS THE SON
OR DAUGHTER OF SOMEONE WHO MAY
HAVE ALCOHOL USE DISORDER OR
SOME OTHER VULNERABLE, BUT YOU
HAVE THE INFORMATION ON THE
GENES THAT THEY CARRY AND THAT'S
AS THE POLYGENIC SCORES GET MORE
POWERFUL, THEY'RE NOT YET VERY
POWERFUL AND SO, THAT'S CLEARLY
1 USE.
ANOTHER USE MIGHT BE COUNSELING
USE, YOU MIGHT USE THE POLYGENIC
CORE SCORES TO COUNCIL PEOPLE AS
TO THEIR VULNERABLE, A LOT OF
PEOPLE WHO COME FROM A FAMILY,
WHERE THERE MAY BE A LOT OF
ALCOHOL USE DISORDER OR ARE WELL
AWARE THAT THEY HAVE A
VULNERABILITY AND IT CAN ALSO BE
USED TO--FOR MEN DEALIAN
RANDOMIZATION TO STRATIFY PEOPLE
IN OUR STUDIES.
SO IF YOU HAVE A STUDY WHICH IS
A--WE'RE INVESTIGATE A TREATMENT
MODALITY TO KNOW THAT OVER HERE,
YOU HAVE PATIENTS WHO HAVE A
STRONG VULNERABILITY TO AUD AND
OVER THERE, THAT YOU HAVE SOME
PATIENTS WHO HAVE AUD BECAUSE
THEY JUST DECIDED TO START
DRINKING NOT THAT THEY HAD THE
STRONG VULNERABILITY, THE NUANCE
THERE IS THAT IT'S NOT JUST A
POLYGENIC SCORE FOR AUD, THAT 1
WOULD HAVE, 1 WOULD HAVE A
POLYGENIC CORE FOR RISK TAKING,
FOR NEGATIVE EMOTIONALITY, FOR
MANY OTHER PHENOTYPES THAT ARE
RELATED TO AUD AND SO YOU CAN
BEGIN TO ACTUALLY PARSE
INDIVIDUALITY IN NEW WAYS AND WE
WANT AS MUCH INFORMATION AS WE
CAN IN GENERAL IN MEDICINE, WE
WANT TO KNOW IF THE PERSON IS
MALE OR FEMALE, WE WANT TO KNOW
IF THEY'RE YOUNG OR OLD, SO
HERE'S ANOTHER PIECE OF
INFORMATION THAT WE CAN GIVE TO
CLINICIANS AND ALSO TO
INVESTIGATORS.
>> THANK YOU VERY MUCH.
AND THAT SORT OF TAKES US RIGHT
UP TO THE HOUR.
DR. GOLDMAN, THANK YOU FOR YOUR
OUTSTANDING PRESENTATIONS AND
YOUR EXTRAORDINARY BODY OF WORK
APPRECIATE IT. 1445 01:00:47,844 [ APPLAUSE ]