>> GOOD AFTERNOON, EVERYBODY.

WELCOME TO CLINICAL CENTER GRAND

ROUNDS.

TODAY OUR SPEAKER'S GOING TO

PRECEPT ABOUT BEHCET'S DISEASE

AN ENEIGHT ENIGMA REVICEITED.

SPEAKING FIRST AND

DR. CAILIN HENDERSON SIBLEY, ON

AUTOINFLAMMATION AND THEN

DR. ELAINE REMMERS, WILL SPEAK.

FIRST LET ME TELL YOU ABOUT

DR. SIBLEY, SHE EARNED A B. S.

DEGREE AT THE CALIFORNIA

INSTITUTE OF TECHNOLOGY AND THE

MD DEGREE AT THE DAVID

GEFFEN SCHOOL OF UCLA, INTERNAL

RESIDENCY AT UNIVERSITY OF

CALIFORNIA SAN FRANCISCO WHERE

SHE COMPLETED HER FELLOW IN

RHEUMATOLOGY.

SHE IS THE CANDIDATE FOR MASTER

OF HEALTH SCIENCES DEGREE IN

CLINICAL RESEARCH, WHICH IS

OFFERED AS A COLLABORATION

BETWEEN THE CLINICAL CENTER ASK

DUKE UNIVERSITY MEDICAL CENTER.

DR. SIBLEY, WAS THE LAWRENCE

SHILLMAN RESEARCH TRANSLATIONAL

SCHOLAR AT NIAMS TWA 2008-2011.

CURRENTLY SHE IS THE ACTING

RHEUMATOLOGY FELLOWSHIP PROGRAM

DIRECTOR FOR NIAMS.

AND HER RESEARCH FOCUSES ON THE

ROLE OF INTERLEUKIN ONE AND

MONOGENIC AND GENETICALLY

COMPLEX DISEASES.

OUR SECOND SPEAKER DR. REMMERSS,

EARNED A BS DEGREE AND Ph.D.

IN MICROBIOLOGY FROM THE

UNIVERSITY OF MARYLAND.

AFTER SERVING AS A POST DOCTORAL

RESEARCH ASSOCIATE IN

BIOCHEMISTRY AT THE STATE

UNIVERSITY OF NEW YORK AT STONY

BROOK, DR. REMMERS CAME TO THE

NIHfC-lb IN 1986 AS A FELLOW ALSO IN

THE NATIONAL INSTITUTE OF

ARTHRITIS AND MUSK LOW SKELETAL

IS SKIN DISEASE.

HE WAS A STAFF SCIENTIST FROM

1994 AND MOVED TO HER CURRENT

POSITION IN 2010.

DR. REMMERS IS A MEMBER OF THE

AMERICAN ASSOCIATION OF

RHEUMATOLOGYST AND THE

ADVANCEMENT OF SCIENCE AND THE

AMERICAN SOCIETY OF HUMAN

GENETICS AND HER RESEARCH

FOCUSES ON THE GENIC BASIS OF

SUSEPTIBILITY TO INFLAMMATORY

ARTHRITIS AND OTHER AUTOIMMUNE

AND AUTOINFLAMMATORY DISEASES

AND NOW DR. SIBLEY.

[ APPLAUSE ]

>> THEIR YOU VERY MUCH

DR. GALLAN.

SO DISCLOSURES TO ALL

MEDICATIONS I WILL SPEAK ABOUT

TODAY ARE NOT FDA APPROVED AS

THERE ARE NO FDA APPROVED

MEDICATIONS, THEY'RE ALL OFF THE

TABLE.

BUT THE MAIN OBJECTIVE TODAY,

WE'RE GOING TO RECOGNIZE THE

CLINICAL MANIFESTATIONS OF

BEHCET'S DISEASE AND TWO TO

UNDERSTAND THAT DIFFERENTS MAKE

THIS FROM PATIENTS BETWEEN THE

UNITED STATES AND AREAS MORE

TYPICAL ETHNIC BACKGROUNDS AND

THREE, TO DISCUSS SOME OF THE

APPROACHES WE'RE USING TO

UNDERSTAND THE PATHOGENESIS OF

DISEASE.

SO WE KNOW THAT BEHCET'S DISEASE

IS A VERY OLD DISEASE AND WAS

DESCRIBED AS EARLY AS ABOUT 400

B. C. BY HIP--HIPPOCRATES, AND

IT WAS DISCOVERED THAT IT WAS

DEFLUXIONS ABOUT THE GENITAL

PARTS, WATER OPERATING GLOBALLY

THAT WILL MES OF A CHRONIC

CHARACTER AND WHICH DESTROYED

THE SIGHT OF MANY PERSONS AND

LARGE PERPETTIC LESIONS.

IT WAS LATER, MANY YEARS LATER,

THAT A GREEK PHYSICIAN DESCRIBED

THE SAME CONTELATION OF SYMPTOMS

IN THE FRENCH LITERATURE AND

SEVERAL YEARS LATER A TURKISH

PHYSICIAN DESCRIBED THESE IN THE

GERMAN LITERATURE WHICH AT THE

TIME WAS THE SCIENTIFIC LANGUAGE

WHICH THEN BECAME ADOPTED BY THE

MEDICAL COMMUNITY AND HENS THE

NAME BEHCET'S DISEASE ALTHOUGH

THERE IS CONTROVERSY ABOUT THE

TERMINOLOGY AND SOME MAY SAY

ADAM MONTIAS DISEASE.

WE KNOW IT HAS A--AN ETHNIC

PREDOMINANCE FOR PATIENTS WITH

BACKGROUND ALONG THE SILK ROAD

AND THIS WAS AN ANCIENT TRADING

ROUTE WHICH CONNECTED THE FAR

EAST IN EUROPE WHEREBY SILKS,

SUCCESS TILES, SPICES

WERE--TEXTILES, AND SPICES WERE

TRADED AND IT WAS THOUGHT THAT

MANY DISEASES WERE BROUGHT IN

THROUGH THIS ROUTE.

AND WE KNOW THE LARGEST

CONTRIBUTOR TO BEHCET'S DISEASE

IS HLAB51 AND DR. REMMERS, WILL

SPEAK OF THIS MUCH MORE BUT YOU

CAN SEE THAT THE PREVALENCE OF

HLAB51 IN THIS FIGURE IN RED FOR

THE HIGHEST PREVALENCE IS FOUND

ALONG AREAS FROM THE SILK ROUTE

AND THIS CORRESPONDS AS WELL TO

THE CLINICAL PREVALENCE OF

DISEASE.

SO IN TURKEY WHERE THERE'S A

HIGH PREVALENCE OF B51, THE

PREVALENCE OF DISEASE IS 370 PER

HUNDRED THOUSAND AND IRAN WAS

RELATIVELY HIGH, 80 PER 100,000,

HOWEVER IN THE UNITED STATES

WHERE THE PREVALENCE OF B51 IS

MUCH LESS, WE SEE MOST RECENTLY

5.2 PER HUNDRED THOUSAND PEOPLE

ARE AFFECTED BY BEHCET'S

DISEASE, SO THIS IS QUITE RARE.

THE DIAGNOSE OF BEHCET'S IS

BASED PURELY ON CRIPICAL

CRITERIA SO THERE ARE NO

LABORATORY MARKERS OR ANY

PATHOLOGIC TESTS THAT CAN HELP

US WITH THE DIAGNOSIS.

TO MAKE THESE INITIAL CRITERIA

WERE DESIGNED BY A GROUP OF

EXPERT PHYSICIANS WHO CAME WITH

THE CONSENSUS STATEMENT FOR THE

CRITERIA OF DISEASE AND THESE

ARE TERMED INTERNATIONAL

CRITERIA.

SO TO MEET THE CRITERIA,

PATIENTS MUST HAVE RECURRENT

ORAL ULCERS DEFINED BY AT LEAST

THREE PER YEAR, AND THEN TWO OF

THE FOLLOWING, EITHER RECURRENT

GENITAL ULCERS, TYPICAL LESIONS

WHICH WILL BE UV ITIS OR RETINAL

VASC LIGHTIS AND TYPICAL SKIN

LESIONS AND THESE ARE POPULAR

POSTULAR LESIONS OR

ACNEIFORM LESIONS AND A POSITIVE

PATHERGY TEST AND WHEN THE

PATIENTS MEET THESE CRITERIA

WHICH IS THE GOLD STANDARD WHICH

IS EXPERT OPINION, THEY'RE 95%

SENSITIVE AND 98 SPECIFIC FOR

THE DIAGNOSE OF THE DISEASE.

SO SPEAKING SOME OF THE CLINICAL

MANIFESTATIONS, FIRST IS ORAL

ULCERS, SO THESE ULCERS CAN

OCCUR ONE AT A TIME, THEY CAN

OCCUR SEVERAL AT A TIME, THEY

CAN FILL THE ENTIRE MOUTH AT

TIMES AS WELL, THEY CAN OCCUR

REALLY ANYWHERE IN THE MOUTH,

THE PICTURE WE SEE HERE ALONG

THE LIPS AND AS WELL AS ALONG

THE TONGUE THEY THIS CAN BE IN

THE HARD PALLET, SOFT PALLET AND

GUMS AND THEY TYPICALLY HE'LL

WITHOUT A--HEAL WITHOUT A SCAR.

SO IN LOOKING AT THESE, THEY'RE

DIFFERENT THAN THOSE YOU MIGHT

SEE FROM HSV, ALTHOUGH MANY

FALSE-NEGATIVES CAN OCCUR AND

THIS CONTRAST, TO THE GENITAL

ULCERS WHICH TYPICALLY HAPPEN

ONE OR TWO AT A TIME CAN BE VERY

DEEP TOwwvb„V„E

IT'S NOT UNCOMMON FOR THERE TO

BE ONE OR TWO ULCERS AT THE

BEGINNING OF DISEASE FOR THAT

ROUGH ATOM NEVER REOCCUR SO THIS

IS QUITE DIFFERENT FROM THE ORAL

ULCERS.

I SHOULD ALSO NOTE THAT

NONINFECTIOUS ORAL ULCERS ARE

QUITE COMMON IN THE POPULATION.

ABOUT 10% HAVE ABSCESS

ULCERATIONS AND THIS IS REALLY

OF NO CLINICAL CONSEQUENCE.

YOU SEE A LOT OF PATIENT WHO IS

COME WITH ORAL ULCERS AND YOU

NEED A LOT MORE TO MEET THIS

DIAGNOSIS.

IN TERMS OF EYE DISEASE, THE

MOST CLASSIC FEATURES ARE

RETINAL VASC LIGHTIS.

SO PICTURE HERE ON THE SIGHT A

NORMAL OF A RETINA AND THE

FLUORESCING ANGIO AND ON THE

VISIT A PATIENT WHO HAS ACTIVE

VITRIITEIS, ACTIVATION

THROUGHOUT THE GLOBE AND YOU SEE

HAZINESS THROUGHOUT THE GLOBE

AND THAT'S BECAUSE IT'S FILLED

WITH INFLAMMATORY CELLS.

ANOTHER DESCRIPTION HERE IS THE

POSTERIOR UVITEIS, SO

INFLAMMATION WITHIN THE BACK OF

THE EYE, WITHIN THE RETINA AND

THAT CAN LEAD TO RETINAL

SCARRING SO THE SCOTTON SPOTS

HERE, PATIENT K'S GET RETINAL

VASC LIGHTIS--VASCULITEIS AND

THAT'S OBSERVED WITH THE

CLOUDINESS HERE WHICH IS

VASCULAR LEAKAGE FROM THE VEINS

AND IT'S IMPORTANT TO KNOW THAT

EYE DISEASE IS ONE OF THE MOST

FEARED COMPLICATIONS IN BEHCET'S

AND CAN COME ON AGGRESSIVELY AND

LEAD TO BLINDNESS RELATIVELY

QUICKLY AND THIS IS FROM THE

POSTERIOR INVOLVEMENT YOU CAN

SEE IN THESE PATIENTS.

ANOTHER CLASSIC FEATURE IS A

HIPOPIAN UVITEIS AND THIS IS DUE

TO AGGRESSIVE ANTERIOR UVITEIS

SO PATIENT WITHIN THE FRONT OF

THE EYE AND WHEN THERE'S ENOUGH

INFLAMMATION, THE LIGHT K'S

LAYER OUT AS A LAYER OF POSES IS

VISUALIZED IN THE PHOTO.

ANOTHER CLASSIC FEATURE IN

BEHCET'S IS THE PATH O GBAY

TEST, AND THIS IS WHERE THE SKIN

IS PRICKED WITH A NEEDLE AND 42

TO 72 HOURS LATER A POSTULE

FORMS WE TYPICALLY PRICK MORE

THAN ONE SITE TO SEE THE YIELD.

THERE'S SOME SUGGESTION THAT

NORMAL FLORA MAY BE NECESSARY

FOR THE PATHERGY TEST.

IN PATIENTS WITH MIDDLE EASTERN

BACKGROUNDS UP TO 15% HAVE A

POSITIVE PATHERGY TEST WHICH IS

NORMAL.

IN TERMS OF SKIN DISEASE THIS

CAN MANIFEST EITHER NODULES,

ACNEUROECTODERMALLA FORM LESIONS

OR POSTULES IN HER INNER THYS IT

CAN BE--THIGHS, IT CAN BE

DIFFICULT TO TOM PAIR THESE TO

NORMAL OR COMMON ACNE, AND IT

CAN BE HELPFUL IF THEY SHOWED IN

LESS TYPICAL REGIONS BUT STILL

THERE'S A GOOD AMOUNT OF

OVERLAP.

AND FINALLY, WELL, NOT ONE OF

THE CLASSIFICATION CRITERIA,

VASCULAR DISEASE IS A HALLMARK

OF BEHCET'S DISEASE AND THERE'S

CONTROVERSY WHETHER THIS IS VASC

LOPATHY, SO VASCULITEIS OR

BEHCET'S.

SO LARGE VAIN TO DEEP VEIN

THROMBOSIS, CAPILLARY TO ARTERY

WHICH IS CAN CAUSE ONE OF THE

MOST COMMON ISSUES IN BEHCET'S

WHICH CAN CAUSE PULMONARY

ANEURYSM WHICH PATIENTS WITH

BLEED AND DIE WITHIN MINUTES.

MOSTLY IT'S SUPERFICIAL

THROMBOPH LEBITIS, YOU CAN FINE

THE AREAS AX ROUND THE VESSELS

AND OFTEN TIMES PATIENTS WILL

DEVELOP POSTULES, AND YOU CAN

SEE THEM AS THEY'RE TRACING

ALONG THIS AREA HERE.

IN TERMS OF TREATMENT OPTIONS,

AZATHIOPRINE IS ONE OF THE BEST

STUDIES.

THIS IS A STUDY OF

AZATHIOPRINE VERSES PLACEBO.

ONLY THREE PATIENTS WHO TREATED

WITH THE DRUG, FOUGHT IT, NO & 

IN THE PLACEBO, NO PATIENTS

DEVELOPED LESIONS COMPARED TO 22

PATIENTS ON PLACEBO.

SO THIS IS ACTUALLY PRETTY GOOD

DATA AND ANOTHER WAY OF LOOKING

AT THIS IS YOU DEMONSTRATION

NEED IT TO TREAT TWO PATIENTS TO

PREVENT ONE EPISODE OF EYE

DISEASE OR FOUR PATIENTS TO

PREVENT A RECURRENCE OF EYE

DISEASE.

SIMILARLY, UVITEIS IS IN THREE%

OF THE PATIENTS VERSES 30 % OF

PLACEBO AND THERE'S ALSO A

SIGNATURES 95 REDUCTION IN ORAL

ULCERSERS AND GENITAL, GENITAL

ULCERS ALTHOUGH THEY DID NOT

APPEAR TO EFFECT POSTULAR

LESIONS OR RETINAL

LOCATIONINNITEIS.

--SO IN THIS RANDOMIZED TRIAL

AUTOMATICKIZED STUDY, THERE'S A

DIFFERENT EFFECT IN WOMEN

COMPARED TO MEN.

IN WOMEN THERE ARE DECREASED

GENITAL ULCERS AND DECREASED

ARTHRITIS WHEREAS IN MEN,

SIGNIFICANT ARTHRITIS ALEAN.

--ALONE.

THERE ARE MANY OTHER MEDICATIONS

THAT ARE USED IN BEHCETS AND

OFTEN TIMES WE TREAT BASED ON

THE DISEASE, THE ORGANIZATIONS

GANNA MANIFESTATION, THE

CYCLOSPORIN HAS BEEN SHOWN TO BE

EFFECTIVE FOR EYE DISEASE, FROM

MUC O CUTANEOUS DISEASE AND

HOWEVER, NOT FOR ARTHRITIS.

IN RHEUMATOLOGY WE DON'T TEND TO

USE CYCLOSPORIN AS MUCH BECAUSE

THE SIDE EFFECTS SO PATIENTS GET

NEUROPATHY OR RENAL DISEASE, SO

EFKAS SCHEEYE DISEASE IS USED

RATHER FREQUENTLY.

TNF INHIBITORS, ARE ALSO STUDIED

FOR THE DISEASE AND ARTHRITIS.

IN EYE DISEASE, THEY'RE ONLY

OPEN LABEL STUDIES SUPPORTING

THE USE OF TNF INHIBITORS AND

MUCH OF THE USAGE IS BASED ON

UVITEIS AND OTHER DISEASES.

BUT IT IS COMMONLY USED.

INTERFERON ALPHA WORKS WELL FOR

THE DISEASE, AND THERE'S

EVIDENCE OF OPEN LABEL STUDIES

FOR EYE DISEASE, BUT THIS IS

ALSO VERY DIFFICULT MEDICATION

TO TAKE, PATIENTS WILL GET FLU

LIKE SYMPTOMS, THEY'LL FEEL

TIRED AND OFTEN TIMES QUITE

DIFFICULT TO CONTINUE TAKE

THANKSGIVING MEDICATION BUT IT

DOES WORK.

SIMILAR, SOPHISTICATED LID MID

IS AFFECT INDEED SUBCUTANEOUS

DISEASE, NOT EYE DISEASE BUT WE

WORRY ABOUT NEUROPATHY AND AND

HERO GENERATEDISSITY.

AND FINALLY, WE HAVE BEEN NO

ABDOMEN ORDER OF MICRONSIZED

STUDIES OR REALLY EVEN OPEN

LABEL STUDIES SHOWING EFFICACY

OF STEROIDS IN THE DISEASE.

CERTAINLY HAVE BEEN CASE REPORTS

AND ONE RANDOMIZED TRIAL

AUTOMATICKIZED STUDY OF STEROIDS

IN BEHCET'S WHICH DID NOT SHOW

AN IMPROVEMENT IN ORULCKERS OR

ARTHRITIS, INTERESTINGLY.

SO IN DISCUSSING THE CLINICAL

MANIFESTATION, OR THE DIAGNOSTIC

CRITERIA, I TOLD YOU THEY'RE

BASED ON CLINICAL CRITERIA, SO

HOW WELL DID THESE APPLY TO OUR

PATIENTS.

IF YOU LOOK AT THE TEST

CHARACTERISTICS, SO VERY GOOD

SENSITIVITY AND SPECIFICITY,

95%.

98% AND PREVALENCEY OF DISEASE

IN OUR POPULATION, WHICH IS .2

PER HUNDRED THOUSAND, AND LOOK

IN THE PATIENTS WHO FULFILL FULL

CRITERIA WITH THE CHANCE THEY

HAVE DISEASE, THOSE NUMBERS COME

OUT TO ONLY .2% WHICH IS

ACTUALLY QUITE HUMBLING IF YOU

THINK ABOUT IT.

THIS IS THE CRITERIA WE HAVE TO

DIAGNOSE DISEASE AND BASED ON

THESE CRITERIA, MANY OF THESE

PATIENTS WILL NOT HAVE DISEASE.

I THINK THERE ARE A COUPLE OF

POINTS, ONE I THINK IS BEHCET'S

IS UNDERDIAGNOSED IN THE UNITED

STATES BECAUSE IT'S A RARE

DISEASE AND PEOPLE AREN'T

TERRIBLY FAMILIAR WITH IT BUT

IT'S A BIT BETTER THAN FIVE

HELPED THOUSAND, THE NUMBER WILL

BE LOW AND I THINK REALLY SHOWS

US THAT WHAT WE'RE SEE NOTHING

AMERICA WITH SUCH A LO

PREVALENCE OF DISEASE HAS TO BE

HETEROGENEOUS DISEASE AND TO ME,

UNDERSCORES THE IMPORTANCE FOR

UNDERSTANDING THIS DISEASE ON A

PATHOGENIC LEVEL SO QUEY IMPROVE

OUR CLINICAL

CHARACTERIDESSATIONS AND LOOK

FOR NEW TREATMENT TARGETS THAT

MAY HELP OUR PATIENTS IN THE

FUTURE.

AND SO IN ORDER TO ADDRESS THIS

ISSUE, WE BEGAN A COLLABORATION

AND INVESTIGATORS AT NYU WHO

HAVE ANOTHER LARGE COHORT OF

BEHCET'S PATIENTS AND THE

UNIVERSITY OF ISOTOPE TAN BIEWL,

THESE ARE COLLABORATORS THAT

WORKED WITH, AND THE GOAL WAS TO

BETTER CLASSIFY DISEASE

CLINICALLY AND PATHOLOGICALLY

AMONGST OUR SITES SO WE HAD

PRESPESSIFIED MATERIAL FOR ORGAN

MANIFESTATION, WE ALSO GAVE

VALIDATED DISEASE MEASURES TO

SEQUENTIAL AMERICAN PATIENTS AND

EVERY OTHER PATIENT IN TURKEY

AND THEN FINALLY WE COLLECTED

PATIENT SAMPLES IN ISTAN BIEWL

BOTH BLOOD AND TISSUE SAMPLES,

TO STUDY SIMILARLY THAT WHAT

WE'RE DOING IN THE UNITED

STATES.

WHAT DID WE FIND?

FOR MANY OF THEM THE

MANIFESTATIONS ARE SIMILAR.

SO AGE APPEAR SIMILAR, MUC O CUE

TANIOUS DISEASE ARE SIMILAR,

THERE ARE IN SWEARS--AREAS THAT

ARE CLEARLY QUITE DIFFERENT.

FIRST IS THAT WE'RE SEEING A LOT

LESS MEN IN THE UNITED STATES

COMPARED TO TURKEY.

WE'RE SEEING A LOT MORE

NEUROLOGIC DISEASE AND THIS IS

WORK THAT FRANK ANDERSON HAS

BEEN WORKING WITH US ON AND THIS

IS WHITE MATTER CHANGES ON MRI

OR DURAL SIGN OF THROMBOSIS,

SEEING QUITE A BIT MORE FROM NYH

AND NYU AND QUITE A LOT MORE GI

RULESRATIVE DISEASE IN PATIENTS

COMPARED TO TURKEY AND WE SEE

MORE THAN 40% OF OUR PATIENTS

HAVE GI ULCERS ON OUR EVALUATION

AND THIS WAS COMPARED TO NO

PATIENTS AT ALL IN TURKEY.

SO QUITE INTERESTING AND WE'RE

INTERESTED IN PURSUING THIS

FURTHER AND THIS HAS BEEN IN

COLLABORATION, AND SEVERAL

FELLOWS.

WE ALSO SEE THAT WE ARE USING

LESS CULT RASEEN IN THE UNITED

STATES AND MORE PREDNISONE.

THE OTHER USE OF OTHER DISEASE

MODIFYING DRUGS AND OTHER

SUPPRESS ANTS ARE PRETTY SIMILAR

AMONG SITES.

WE THEN LOOKED AT DISEASE

ACTIVITY AND COMPARE THAD

BETWEEN OUR--COMPARED THAT TO

OUR SITES.

WE THERE ARE TWO VALIDATED

PATIENT DISEASE ACTIVITY OF

MEASUREMENTS OF BEHCET'S AND THE

BEHCET'S ACTIVITY SCALE.

THERE'S ALSO A VALIDATED QUALITY

OF LIFE MEASURE, CALLED THE

BEHCET'S DISEASE QUALITY OF LIFE

SCORE AND WE FOUND THAT ACTUALLY

IN THE UNITED STATES, WE HAD

HIGHER DISEASE ACTIVITY MEASURED

BY THE BDCAS, AND THE SAS, FOR

HIGHER MEANING WORSE IN OUR IN

OUR SITES THAN IN ISOTOPE TAN

BIEWL.

AND OUR--ISOTOPE TAN BIEWL AND

OUR THIS DID NOT NOT REACH

STATISTICAL SIGNIFICANCE.

THEN PERFORMED A LENIER

REGRESSION MODEL TO UNDERSTAND

WHAT FACTORS MAY BE CONTRIBUTING

TO THESE DIFFERENCES IN SCORE

SYMPATHETIC NERVOUS SYSTEM AND

WE FOUND SOME OF THESE SCORES

WERE WORSE IN WOMEN AND IN OLDER

PATIENTS SOME THERE WAS WITH

RELATION TO THE ETHNIC

BACKGROUND.

SO THIS WAS CONFUSING BECAUSE

THE BELIEF IN THE FIELD,

PATIENTS, YOUNG MEN FROM CLASSIC

ETHNIC BACKGROUNDS TEND TO HAVE

DISEASE AND THIS IS BASED PARTLY

ON SOME LONG-TERM MORBIDITY AND

MORTALITY DATA THAT'S AVAILABLE

FROM THE UNIVERSITY OFI STAN

BIEWL--ISTANBUL WHERE THEY DID A

VERMEN INFECTED VIEW OF 380

PATIENTS.

AND FOUND THAT OF THE PATIENT

WHO IS DIED, 42, VAST MAJORITY

WERE MEN AND THEY TENDED TO BE

QUITE YOUNG AND MORE OVER, THE

MOST DREADED COMPLICATIONS OF

UVITEIS, VASC LOOR DISEASE AND

VASC LOOR DISEASE AND NEUROLOGIC

DISEASE OCCUR MUCH MORE COMMONLY

IN MEN.

SO THERE'S CLEARLY A DISCONNECT

BETWEEN WHAT'S BOTHERS PATIENTS

AND WHAT'S CAUSING LONG-TERM

MORBIDITY AND MORTALITY WHICH

WE'RE INTERESTED IN

UNDERSTANDING MORE.

WHICH BRINGS US TO WHAT WE KNOW

TO BE CAUSING DISEASE.

SO IT'S APPEARING MORE AND MORE

CLEAR THAT DISEASE MAY BE

DIFFERENT IN CERTAINTY

SUBPOPULATIONS, DIFFERENT IN

OTHER GROUPS, AND SO, REALLY,

MAKES IT NECESSARY TO TRY TO

UNDERSTAND A BIT MORE WHAT MAY

BE CAUSING DISEASE SO WE CAN

BETTER CLASSIFY OUR PATIENTS AND

BETTER TREAT OUR PATIENTS.

ONE THOUGHT FROM QUITE A WHILE

BACK IS THAT THERE MAY BE

INFECTIOUS CAUSE OR TRIG THEY'RE

MAY BE LEADING TO THE DISEASE.

SO THIS IS A STUDY WE DID IN

COLLABORATION WITH JULIE

SEGRE AND WE TOOK THE ORAL

BIOPSIES IN PATIENTS WITH

BEHCET'S WITH ULCERS AND

SEQUENCE THE RNA FROM THESE

SAMPLES.

AND WE FOUND THAT IN BOTH

PATIENTS AND CONTROLS IT

APPEARED THE MOST COMMON

ORGANISM WAS STRENGTH O CAUCUS

WHICH WASN'T SURPRISING AND

FOLLOWED BY A VARIETY OF

ANAROBES BUT THERE WASN'T A

SINGLE ORGANISM IN PATIENTS THAT

WASN'T FOUND IN CONTROLS AND

THERE WASN'T A CLEAR--SO THIS IS

LOOKING AT ANALYSIS AND THIS IS

DONE THROUGH GROUPING, THE IDEA

BEING THAT THE SAMPLES ARE

COMPARED TO OTHER SAMPLES FOR

THE MOST AMOUNT OF SIMILARITIES

AND THIS HAS BEEN MAPPED.

SO WE LOOKED HERE, HIGHLIGHTED

IN GREEN, ARE THE--ARE THE

CONTROLS WHICH DON'T APPEAR TO

CLUSTER TOGETHER.

WE LOOKED AT UNAFFECTED OR--I'M

SORRY ULCER SITES AND THOSE DID

NOT APPEAR TO CLUSTER TOGETHER

AND BEHCET'S PATIENTS, THEY

DIDN'T CLUSTER TOGETHER, SO

BASED ON THIS WE REALLY DIDN'T

SEE A CLUSTERING PATTERN THAT

MAY BE RESPONSIBLE FOR DISEASE.

--NHGRI TO DESCRIBE PATIENT WHO

IS HAVE PERIODIC EPISODES OF

INFLAILATION AND WE THOUGHT THIS

MAY BE SEEMINGLY UNPROVOKE BUD

WE'RE UNDERSTANDING THAT THERE

ARE TRIGGERS WHETHER THAT BE

INFECTIOUS MECHANICAL, TRIGGERS

THAT MAY CONTRIBUTE TOO DISEASE

AND A LACK OF HIGH TIGHTER

AUTOANTIBODIES OR ANTIGEN

SPECIFIC T-CELLS, MANY OF THESE

DISEASES HAVE A PRIMEAR

ILLEGALSLY NUTRAPHILIC BI

OPPOSITE SCHEIMPORTANTLY MANY OF

THEM RESPOND TO BLOCKADE

CLINICALLY.

THE BEHCET'S IS LIKE THIS, IT'S

EPISODIC ININATE AND YOU ARE

TODAY WE DON'T HAVE ANY

AUTOANTIS OR SPECIFIC T-CELLS TO

BE RESPONSIBLE FOR DISEASE.

SO WE'RE IN THE PROCESS OF--WE

HAVE SEVERAL STUDIES THAT ARE

ONGOING TO UNDERSTAND THE

PATHOPHYSIOLOGY, PARTICULARLY

FROM A STANDPOINT OF

AUTOINFLAMMATION, SO WE'VE

COLLECTED PERIPHERAL BLOOD

CELLS, AS WELL AS TISSUE

BIOPSIES, AND WE ARE IN THE

PROCESS OF DOING A VARIETY OF

GENE EXPRESSION ANALYSIS BUT ONE

IS LOOKING AT RNASEQUENCING,

WITH THE TISSUE IS BLOOD TO LOOK

AT PATTERNS OF--PATHWAYS OF

RECOGNITION WHICH ARE IMPLICATE

INDEED AUTOINFLAMMATORY DISEASES

AS WELL AS PATHWAYS OF

INFLAMMATION IN GENERAL.

WE ALSO HAVE A VERY EXTENSIVE

STUDY UNDERWAY WITH CELL

PHONOTYPING AND CYTOKINE

STAINING OF PURPLE CELLS AND

TISSUES AND THIS IS WITH ERTA,

ROBIN GARRISON IN COLLABBUATION

WITH DANNY AT NIAD, SO WE HOPE

TO HAVE ANSWERS TO THIS SOON.

ANOTHER APPROACH THAT CAN BE

TAKEN AND UNDERSTAND THE ROLE OF

INFLAMMATION IN DISEASES OR IN

BEHCET'S DISEASE IS TO TEST THIS

CLINICALLY SO WE HAVE AN ONGOING

STUDY, TO TEST ANAKIN RA, WHICH

IS AN IL-ONE BLOCKER IN BEHCET'S

DISEASE AND WE PLAN TO ENROLL 20

PATIENTS IN THIS STUDY, THEY'LL

BE TREATED FOR THREE MONTHS WITH

ANAKINRA AND THEY REMONTHS TO

MEET THE KRIST TERRIA.

AND IT IF THEY DO RESPOND AND

HAVE NO ULCERS FOR TWO MONTHS,

THEY WILL CONTINUE TO

ANAKINRA VERSES PLACEBO FTHEY

SHOW NO IMPROVEMENT THEY'LL BE

WITHDRAWN, IF THEY SHOW SOME BUT

NOT COMPLETE, THEY'LL BE OFTEN

LABELED THERAPY SO WE ACTUALLY

ENROLL ROLLED OUR FIRST PATIENTS

AND SO FAR SHE'S DOG PRETTY WELL

THAT WE'LL BE INTERESTING TO SEE

HOW THIS PROGRESSES AS WE GET

MORE PATIENTS.

SO TO SUMMARIZE, YOU KNOW THAT

BEHCET'S IS A MULTISYSTEM

DISORDER WITH PREDOMINANCE FROM

THE MIDDLE EAST.

DIAGNOSTIC CRITERIA ARE CLINICAL

AND THAT'S ORAL ULCERS PLUS THE

GENITAL ULCERS, SKIN DISEASE, OR

EYE DISEASE.

DISEASE CHARACTERISTICS DIFFER

IN TURKEY COMPARED TO THE UNITED

STATES AND WE BELIEVE THAT

AUTOINFLAMMATORY PATHWAYS MAY BE

RELEVANT TO DISEASE AND FINALLY

REALLY BELIEVE THAT WE NEED TO

BETTER UNDERSTAND THIS DISEASE

ON A PATHOGENESIS LEVEL SO THAT

WE CAN IMPROVE CLINICAL

CHARACTERIZATIONS AND

INVESTIGATE TREATMENT TARGETS.

THESE STUDIES WERE DONE IN

COLLABORATION WITH MANY, MANY,

PEOPLE AS WAS NECESSARY TO DO

THIS PROPERLY AND THESE ARE SOME

OF THE MANY PEOPLE INVOLVED IN

THESE STUDIES, THANK YOU.?–
7

[ APPLAUSE ]

CAPTIONS RETURN SHORTLY

>> THE BUT ALSO INTERACTIVE

EFFECTS MAY BE CONTRIBUTING,

INTERACTIVE EFFECTS AMONG THE

MULTIPLE GENETIC RISK FACTORS

AND ALSO INTERACTIVE AFFECTS

BETWEEN GENERATEDET AND I CAN

NONGENETIC RISK FACTORS AND

THOSE ACCOUNTED BE THINGS LIKE

INFECTIONS THAT MIGHT TRIPPINGER

THE DISEASE OR LEAD TO GREATER

INCIDENCE OF THE PREVALENCE OF

THE DISEASE AS WELL AS

ENVIRONMENTAL EXPOSURES.

MOST COMMON DISEASES ARE COMPLEX

OR POLYGENIC AND THE VAST

MAJORITY OF THE DISEASE

ASSOCIATED VALID AND RELIABLE

YAPTS THAT HAVE--VALID AND

RELIABLE YAPTS THAT HAVE

BEEN--VARIANTS THAT ARE ALSO

COMMON AND INDIVIDUALLY HAVE

ONLY SMALL EFFECTS ON DISEASE

RISK.

AND THEREFORE THOSE ARE NOT

USEFUL FOR DIAGNOSTIC OR

PROGNOSTIC PURPOSES.

SO WHY DO WE WANT TO SPEND THE

EFFORT TO IDENTIFY GENETIC

FACTORS WITH SUCH SMALL EFFECTS

THAT UNDERLIE THESE COMPLEX

GENETIC DISEASES AND THE REASONS

ARE THAT WE HOPE THAT THEY WILL

ALLOW US TO SHED NEW LIGHT ON

DISEASE PATHOGENESIS, PROVIDE

POTENTIAL TARGETS FOR EFFECTIVE

TREATMENT, SCREENING AND

PREVENTION AND TO INCREASE OUR

UNDERSTANDING OF WHY PATIENTS

RESPOND AND WHY OTHERS DO NOT TO

VARIOUS TREATMENTS.

SO LET'S MOVE ON TO BEHCET'S

DISEASE.

THE STRONGEST EVIDENCE THAT WE

HAVE FOR GENETIC CONTRIBUTION TO

THE DISEASE IS THAT DISEASE RISK

IS INCREASED IN RELATIVES OF AN

AFFECTED INDIVIDUAL.

AND SO FOR INSTANCE, IN SIBLINGS

OF AN AFFECTED INDIVIDUAL,

THERE'S A 10-50 FOLD INCREASE

COMPARE WIDE THE RISK--COMPARED

WITH THE RISK IN THE GENERAL

POPULATION.

WE ALSO SEE THIS MARK THAT

CAILIN ALREADY DESCRIBED, ALONG

THE SILK ROUTES COULD WHICH

COULD BE DUE TO DISSEMINATION OF

GENERATEDETICT FACTORS AND AS

SHE MENTIONED THE HIGHEST

PREVALENCE IS IN TURKEY, IRAN

AND JAPAN AND IT'S BEEN

ESTIMATED NEARLY AS HIGH AS FOUR

IN A THOUSAND IN TURKEY.

AND SHE ALSO DESCRIBED HLAB51 IS

INCREASED WITH MULTIPLE CITIES

BUT IT ONLY ACCOUNTS FOR LESS

THAN 20% OF THE GENETIC RISKS

THAT WE SEE.

SO WE CAN'T LOOK IN FAMILIES

WITH LINKAGE ANALYSIS AS

STANDARD METHODOLOGY THAT'S BEEN

USED FOR MENDELIAN INHERITED

DISEASES TO FIND THE GENETIC

FACTORS FOR COMPLEX--COMPLEXLY

INHERITED GENETIC DISEASES SO

WHAT WE TURN TO ARE GENOME WIDE

ASSOCIATION STUDIES TO IDENTIFY

THESE FACTORS, THEY REQUIRE

LARGE COLLECTIONS OF UNRELATED

CASES AND CONTROLS IN ORDER TO

FIND STATISTICALLY SIGNIFICANCE

ASSOCIATIONS OF THESE FACTORS

THAT HAVE RELATIVELY SMALL

EFFECTIVE SIZES AND WE GENOTYPE

VERY LARGE NUMBERS OF GENETIC

MARKERS, AND THE MOST COMMONLY

USE TED MARKERS, SINGLE

NUCLEOTIDE POLYMORPHISM.

WE TEST FOR ASSOCIATION OF

MARKERS WITH DISEASE BY

ESSENTIALLY LOOKING FOR

INCREASED PREVALENCE OF OF

MARKER ALLELES IN CASES COMPARED

TO CONTROLS.

AND THEN ONCE WE FIND SOME OF

THOSE, WE FINE MAP THEM BY

ADDITIONAL GENO TYPING

ADDITIONAL MARKERS TO DISEASE

ASSOCIATED GENOMIC REGIONS AND

THE GENE OR GENES THAT ARE IN

LINKAGE THAT THE EQUILIBRIUM

WITH THE ASSOCIATED MARKER.

ASSOCIATES DON'T GIVE US

NECESSARILY THE CAUSAL VARIANT.

WE FIND THE VARIANTS THAT ARE

ASSOCIATED THAT MAY BE LINKAGE

THE EQUILIBRIUM WITH THE CAUSAL

VARIANT.

AND THEN IT'S IMPORTANT TO

REPLICATE AN INDEPENDENT SAMPLE

COLLECTIONS TO REALLY FEEL

CERTAIN ABOUT THOSE GENETIC

EFFECTS.

SO I WILL QUICKLY DESCRIBE THE

BEHCET'S DISEASE GWAS HERE AND

THEN TELL YOU ABOUT SOME OF OUR

NEW INFORMATION THAT'S COMING

OUT FROM THE STUDIES.

SO, THE SAMPLES WERE COLLECTED

BY AMET GHOUL AND HIS COLLEAGUES

AT ISTANBUL UNIVERSITY AND

THEY'RE CONSECUTIVE CASES

MEANING BEHCET'S DISEASE GWAS

CRITERIA, THE PATIENTS WERE FROM

THROUGHOUT TURKEY AND WE

CAREFULLY MATCHED GEOGRAPHICALLY

THE CONTROLS TO THE CASES TO

AVOID STRATIFICATION.

AND WE DETERMINED THE SNP

GENOTYPES USING A COMMERCIALLY

AVAILABLE TRIP FOR GENOTYPING

THAT INTERROGATES MORE THAN

300,000 SNPS, AS A TIME AND

AFTER STRINGENT QUALITY CONTROLS

THE FINAL NUMBER OF SNPs IN

THE ANALYSIS IS 311,459 SNPs,

AND 1215 CASES AND 1278

CONTROLS.

AND IF WE LOOK AT THE GENOME

WIDE ASSOCIATION PLOT HERE, THIS

IS JUST A PLOT ALONG THE--ON THE

Y AXIS SHOWING MINUS LUG OF THE

P-VALUES,A CORDING TO THE--FOR

EACH SNP ACROSS THE GENOME AND

THIS IS COLOR BY COLOR, EACH

CHROMOSOME AND THE SNPs ARE

JUST LINED UP AND YOU SEE THE

ASSOCIATIONS BY THE MARKERS THAT

EXTEND UP WARD, AND THE

STRONGEST ASSOCIATION HERE IS

CLEARLY IN THE MHC, THAT'S THE

SKYSCRAPEROT MANHATTAN PLOT.

IF WE JUST FOCUS IN ON THE CLASS

ONE REGION OF THE MHC, YOU CAN

SEE THAT THE STRONGEST

ASSOCIATED SNPs, ONES WITH THE

SMALLEST P-VALUES ARE ALIGNED

HERE WITH THE HLAB LOCUST AND

PRESUMABLY THESE ASSOCIATIONS

ARE DUE TO LINKAGE OF THE

EQUILIBRIUM OF THE SNPs, WITH

HLAB51, THE KNOWN

HLA ASSOCIATION FOR THIS

DISEASE.

YOU ALSO NOTICE THERE'S AN

INDEPENDENT BUMP OVER HERE AND

ALL OF THESE MARKERS THAT ARE

ABOVE THIS GREEN LINE ARE

REACH--THE STANDARD OF GENOME

WIDE SIGNIFICANCE AND WE

WONDERED WHETHER THERE MIGHT BE

OTHER THINGS THEN HLA B51 IN

ORDER TO DETERMINE THAT, AND

WHETHER THE ASSOCIATIONS THAT WE

SEE IN THAT REGION ARE ALL

EXPLAINED BY THE HLAB51

ASSOCIATION, MIKE LUMBLE O AND

OUR GROUP, DETERMINED THE

B-TYPES OF 1190 OF THE CASES AND

1200 FETCH OF THE CONTROLS.

--1257 OF THE CONTROLS.

USING A REVERSE OLIGO TYPE

METHOD.

B51 IS FOUND IN 97% OF CASES,

WITH 29% CONTROL GIVES US AN OR

OF 3.49.

BUT HAVING THIS HLA-B-51 DATA WE

COULD LOOK FOR IT INDEPENDENT

ASSOCIATIONS BY PERFORMING

REGRESSION ANALYSIS,

CONDITIONING ON B51 AND THAT'S

SHOWN IN THIS FIGURE.

TO SIMPLIFY THE FIGURE HAVE

OMITTED THE SNPs THAT HAD LOW

ASSOCIATIONS, THE ONES WITH

P-VALUES THAT WERE GREATER THAN

10 TO THE MINUS FOUR AND SO THE

BLUE DOTS ARE THIS SNP

ASSOCIATIONS THAT ARE SHOW

INDEED THE PREVIOUS SLIDES, THE

PREVIOUS ASSOCIATION SLIDES AND

YOU CAN SEE B51 TYPE HERE IS

ACTUALLY STRONGER THAN ANY

INDIVIDUAL SNP WE SAW IN THIS

REGION.

BUT IF WE CORRECT FOR B51 IN

RED, CAN YOU SEE THE REVISED

ASSOCIATION FOR EACH OF THESE

SNPs, ALL OF THE SNPs IN

THIS REGION DROP WELL BELOW

GENOME WIDE SIGNIFICANCE WHEREAS

OVER HERE THEY DROP A LITTLE BUT

SOME OF THESE STILL MAINTAIN

GENOME WIDE SIGNIFICANCE ABOVE

THE SCREEN LINE.

AND WE DON'T KNOW WHAT THAT IS

YET BUT WE'RE VERY INTERESTED TO

FIND OUT FROM'S OTHER CLASS ONE

LOCI HERE THAT THERE MAY BE

ANOTHER FACTOR THAT IS ALSO

CONTRIBUTING.

SO GOING BACK TO THE GENOME WIDE

ASSOCIATION PLOTS, THE OTHER

ASSOCIATIONS DON'T REALLY MAKE

IT HERE.

WE CAN SEE THEY HAVE A

NUMBER--THESE INTERESTING

SIGNALS AND IN ORDER TO

INVESTIGATE THEM MORE

THOROUGHLY, WE FINE MAPPED EACH

OF THOSE REGIONS AND BY FINE

MAPPING JUST GENOTYPED

ADDITIONAL SNPs IN THE REGION,

FOUND THE SIGNIFICANT SNP AND

ASSOCIATE WIDE IN A CONTROL

COLLECTION AND PERFORMED

META-ANALYSIS.

AND IN TWO OF THOSE THREE

REGIONS, THEY SHOW STRONG

ASSOCIATIONS IN A META-ANALYSIS

INCLUDING OVER 2300 CASES IN

2600 CONTROLS ALTOGETHER AND SO

WE FELT LIKE THEE THESE ARE VERY

STRONGLY SUPPORTED.

NOW LET ME JUST GO BACK NOW AND

SUMMARIZE WHAT WE'VE GOT FOR

ASSOCIATION EVIDENCE FOR GENOME

WIDE ASSOCIATION FOR BEHCET'S

DISEASE LOCI, FIRST OF ALL WE

HAVE THE LH51 LOCUST WHICH

INCLUDES THE MOLECULE WITH AN

ODDS RATIO OF 3.49 AND WE DON'T

KNOW IF IT'S PLAYING A ROLE BY

ANTIGENS TO SEE THE CDEIGHT

POSITIVE T-CELLS FOR INSTANCE OR

WHETHER IT MIGHT HAVE A

PRESENTATION EMPTY PROCESS FOR

EXAMPLE--INDEPENDENT PROCESS FOR

EXAMPLE, ER STRESS AND THE

PROTEIN RESPONSE HAVE BEEN

SUGGESTED OR WHETHER, IT EVEN

COULD BE DUE TO ASSOCIATION WITH

ANOTHER LINKED GENE.

IL10 NONCODING VARIANT.

IL10 IS AN ANTIINFLAMMATORY

CYTOKINE.

WE HAVE ODDS RATIO OF 1.45.

WE'VE DONE FUNCTIONAL STUDIES

THAT SHOW THAT THE BEHCET'S

DISEASE ASSOCIATED NONCODING

VARIANT IS ASSOCIATED WITH LOW

GENE EXPRESSION AND LOW IL10

PRODUCTION BY LPS STIMULATED FOR

FULL BLOOD CELLS AND TLR LIGAND

STIMULATED MONOCYTES AND IT

MAKES SENSE THAT AN

UNDERPRODUCTION OF AN

ANTIINFLAMMATORY CYTOKINE MIGHT

BE ASSOCIATED WITH THE

PROPENSITY FOR INFLAMMATORY

DISEASE.

AND THEN THIRD LOCUST IS THE

IL23 RECEPTOR LOCUST.

IT'S A NONCODING VARIANT AND

IT'S A CYTOKINE RECEPTOR THAT'S

IMPORTANT IN THE TH17 PATHWAY

AND IT HAS AN ODDS RATIO OF 1.28

AND WE DON'T YET HAVE A FUNCTION

FOR THAT NONCODING VARIANT BUT

RESUMABLY IT'S ALSO ASSOCIATE

WIDE AN ALTERATION AND

EXPRESSION.

SO THAT'S A RATHER PALTRY LIST

OF VARIANTS FROM THE GENOME WIDE

ASSOCIATION AND WE FELT LIKE

THERE CLEARLY MUST BE OTHER

FACTORS THAT CONTRIBUTE TO THE

DISEASE ASK WONDERED IF THEY

COULD--THERE COULD BE ADDITIONAL

COMMON VALID AND

RELIABLEIABILITIES THAT WE

HADN'T YET DETECTED AND HOW

COULD WE DETECT THOSE.

SEVERAL REASONS, SEVERAL METHODS

WE COULD INCREASE SNP COVERAGE

ACROSS THE GENOME AND PICK UP

ADDITIONAL AND WE CAN REDUCE THE

GENETIC HETEROGENEITY AND

PERHAPS INCREASE POWER BY

LOOKING AT PHENOTYPIC SUBSETS.

WE COULD TEST OTHER GENETIC

MODELS, WE COULD LOOK FOR GENE

HELP GENE INTERACTS AND LOOK FOR

EFFECTS THAT WE'RE NOT LOOKING

UP BY SNPs INDIVIDUALLY AND

ALSO DO META-ANALYSIS OF

MULTIPLE LARGE GWAS' TO AFFECT

SMALLER SIZES.

THE SECOND POSSIBILITY IS THAT

THERE MAY BE RARE VARIANTS AND

RARE VARIANTS ARE NOT IDENTIFIED

BY GENOME WIDE ASSOCIATION

STUDIES BY NATURE OF THE

DISEASE, BUT WE'RE NOT GOING TO

TALK ABOUT THAT STUDY TODAY.

THAT'S THE FIRST METHODOLOGY

WHICH IS TO INCREASE COVERAGE

AND WE DID THAT BY GENOTYPE

IMPEWITATION, IT'S A STATISTICAL

TOOL THAT USES CORRELATION

BETWEEN MARKERS PRESENT IN A

REFERENCE SET TO GET GENOTYPES

IN EXPERIMENTAL DATA AND FOR

THIS EXAMPLE, WE HAVE A FEW

MARKERS FOR ONE INDIVIDUAL AND

FACAs WE CAN RECOGNIZE

THE--RECOGNIZE THESE

APPLICATIONS LO TYPES THAT ARE

MADE UP OF THESE MARKERS, THESE

ALLELES IN A REFERENCE

COLLECTION, AND THE TOP ONE IS

THIS PURPLE ONE HERE IN THE

REFERENCE COLLECTION IN THE

BOTTOM ONE IS THIS BLUE ONE.

THEN YOU CAN FILL IN THE

GENOTYPES OF THE MARKERS THAT

INTERVENE BETWEEN.

IF YOU'RE WORKING WITH

POPULATIONS THAT ARE IN THE

HAPMAP, DATA YOU CAN GO TO A

DATABASE AND GET THIS

INFORMATION.

THE TURKISH POPULATION IS NOT

REPRESENTED THERE SO WE DID--WE

MADE OUR OWN TURKISH REFERENCE

SET BY GENOTYPING 96 OF THE

CONTROLS ON A HIGH DENSITY SNP

CHIP WITH OVER A MILLION SNPs

ON IT.

AND WE USE THIS PREFERENCE TO

INPUT NEARLY AT HUNDRED THOUSAND

SNPs IN THE GENOME WIDE

ASSOCIATION STUDY SAMPLES AND

THAT HAD BEEN GENOTYPES FOR

APPROXIMATELY 300,000 SNPs,

WITHOUT DOING ANY ADDITIONAL

GENOTYPING AND NOW, IF WE LOOK

AT A NEW, DISEASE ASSOCIATION

PLOT, GWAS, WITH THE IMPUTED SNP

GENOTYPES, CAN YOU SEE THE

ORIGINAL LOCI THAT WE FOUND FROM

THE ORIGINAL ANALYSIS MHC IL10

AND 23 RECEPTOR SIGNALS ARE ALL

HERE, THE COMPLEX IN ONE THAT

DID NOT REPLICATE IS STILL HERE

BUT AS WELL WE SEE A NUMBER OF

ADDITIONAL SYMBOLS, THAT ARE OF

ANY THAT WE FOLLOWED UP WITH

FINE MAPPING AND REPLICATION IN

ADDITIONAL CASE CONTROL

COLLECTIONS AND THREE OF THESE

REACH GENOME WIDE SIGNIFICANCE

IN THE META-ANALYSIS OF THE

COMBINED SAMPLES THAT ARE SHOWN

IN THIS AREA HERE, YOU CAN SEE

ALL OF THESE HAVE SIGNIFICANT

HAVE P-VALUES THAT ARE LESS THAN

FIVE TIMES 10 TO THE MINUS

EIGHT.

INTERESTINGLY, COUPLE OF THESE,

THE TOP ONE, WE HAVE THREE LOCI,

CCR ONE, STAT FOUR AND KLRC

FOUR, AND THE CCR ONE LOCUST AND

THE KR-LRC FOUR LOCUST, HAVE

ODDS RATIOS THAT ARE LESS THAN

ONE AND SO THAT INDICATES THAT

THE ALLELE FREQUENCY WAS HIGHER

IN THE CONTROLS THAN IN THE

CASES AND SO,g@ow THE ALLELE IS

PROTECTED INSTEAD OF A RISK

ALLELE ARE PROTECTED IN THOSE

CASES.

AND LET'S GO AND LOOK AT EACH OF

THESE FURTHER.

TCR ONE IS A CCMOTIF, CHEMOKINE

RECEPTOR ONE AND A RECEPTOR AND

MCP THREE AND IMPORTANT FOR

RECRUITMENT OF IMMUNE EFFECTOR

CELLS TO SIGHTS OF INFLAMMATION,

THE VARIANTS WE FOUND ASSOCIATED

WITH DISEASE WAS NONCODING SO WE

LOOKED IN LIMP FOE PLAST

EXPRESSION DATABASES TO SEE IF

WE COULD SEE ANY EVIDENCE OF

EXPRESSION DIFFERENCE IN

INDIVIDUALS THAT CARRY THE--TCR

ONE ALSO MONOCYTES, AND

EXPRESSION IS HIGHER.

THEN WE DECIDED TO LOOK AT A

FUNCTIONAL ASSAY FOR CHEMO

TAXIS, YOU PUT THE CELLS OF

KNOWN GENOTYPE IN THE UPPER

CHAMBER AND PUT THE CHEMO KIND

ALPHA IN THE LOWER AND DETERMINE

THE DIFFERENCE IN CELL

MIGRATION, ACROSS THE MEMBRANE

HERE, AND WE FOUND THAT THE

INDIVIDUALS THAT CARRY THE

DISEASE PROTECTIVE ALLELE ALSO

HAVE GREATER CHEMO TAXIS IN THIS

ASSAY, SO THIS MIGHT HAVE BEEN

SURPRISING, YOU WOULD THINK THAT

MAYBE MORE CHEMO TAXIS WOULD BE

ASSOCIATE WIDE GREATER

INFLAMMATION BUT ON THE OTHER

HAND, MORE EFFICIENT CHEMO TAXIS

MIGHT ALLOW MORE EFFICIENT

RECRUITMENT AND MORE RAPID

PATHOGEN CLEARANCE AND THAT

COULD EXPLAIN HOW IT COULD BE

PROTECTIVE FOR BEHCET'S.

AND ACTIVATOR OF TRANSCRIPTION

FEBRUARY 4 IS A TRANSCRIPTION OF

INTERFERON-GAMMA PRODUCING THONE

CELLS AND SO WE AGAIN LOOK FOR

ASSOCIATIONS OF THE BEHCET

DISEASE ASSOCIATED SNP AND

INDIVIDUALS FROM--WITH

LYMPHOBLASTOID CELLS AND YOU CAN

SEE THERE'S A TREND FOR

ASSOCIATION WITH SIGNIFICANCE

WITH COMEGZ LEVELS FOR THE

DISEASE ASSOCIATED ALLELE WAS

EXPRESSED MORE HIGHLY IN THOSE

CELLS FOR THE DISEASE ASSOCIATED

ALLELE INTERESTINGLY THE STAT

FOUR HAD VARIANT ASSOCIATE WIDE

AUTOIMMUNE DISEASES AND THIS

VARIANT IS QUITE FAR, THE SAME

ENTRON BUT GENETICALLY QUITE FAR

FROM THE BEHCET DISEASE

ASSOCIATION, IF WE LOOK AT THIS,

THE ASSOCIATION OF THE

AUTOIMMUNE DISEASE, ASSOCIATED

LOCI THAT'S BEEN IDENTIFY INDEED

RHEUMATOID ARTHRITIS AND LUPUS

AND IT'S NOT ASSOCIATED AT ALL

WITH WISHET'S DISEASE, SO

PRESUMABLY THERE'S DIFFERENT

MECHANISM FOR INDUCTION OF THE

THATY ASSOCIATE OPPOSE TO THESE

OTHER AUTOIMMUNE DISEASE

ASSOCIATED LOCI.

AND THE THIRD LOCUST IS KILLER

SELECTIVE RECEPTOR CFOUR AND

THERE'S A CODING VARIANT.

IT'S DISPARAGING AND POSITION

104, CONVERTED TO A SIRRINE THAT

IS ASSOCIATE WIDE PROTECTION

THIS AGAIN A PROTECTION FROM

DISEASE AND THAT STRUCK US AS

VERY INTERESTING BECAUSE IF YOU

GO BACK TO THE MHC REGION HERE

THAT WE HAVE THE STRONGEST

DISEASE ASSOCIATION WITH, CAN

YOU SEE RIGHT NEXT DOOR TO HLA

B, IS THE MC A GENE WHICH IS A

KILLER CELL RECEPTOR LIGAND

THAT'S IN STRONG LB HAS VARIANTS

THAT ARE STRONG LB WITH HLAB AND

IT'S BEEN PROPOSED IN SOME CASES

THAT THE OF HLAB COULD BE DUE TO

THE VARIANCE IN THE Mc A GENE

BUT WHAT WE WANTED TO KNOW FIRST

OF ALL IS WHETHER OR NOT THERE

MIGHT BE AN INTERACTION BETWEEN

THE LIGAND AND THE RECEPTOR, A

GENETIC INTERACTION SEE WE COULD

TEST FOR THAT AND TO DO THAT, WE

LOOK AT EACH OF THE GENOTYPIC

GROUPS IN EITHER THE HLAB19151

NEGATIVE INDIVIDUALS OR B51

POSITIVE INDIVIDUALS IN THIS

SIDE OF THE GRAPH AND YOU CAN

SEE THE ODDS RATIO FOR BEHCET'S

DOESN'T CHANGE MUCH ACCORDING TO

THE KLRCFOUR GENOTYPE GOING

ACROSS HERE.

BUT IN THE INDIVIDUALS THAT HAVE

THE B51 ALLELE, GENOTYPE, YOU

CAN SEE THAT INTROR TECTIVE

ALLELES, ONE PROTECTIVE ALLELE

AND TWO PROTECTIVE ALLELES

PROGRESSIVELY INCREASE THE

RESIST--THE PROTECTION OR THE

REDUCE THE ODDS RATIO FOR

DISEASE.

AND THAT WAS VERY INTERESTING

BECAUSE IT LOOKS LIKE A PRETTY

GOOD EXAMPLE OF AN INTERACTION

WE SEE THE EFFECT OF

PREDOMINANTLY IN THE B51

INDIVIDUALS AND WE LOOKED IN THE

LITERATURE AND FOUND THAT

THIS--THERE'S A BD PROTECTIVE

HAPLOTYPE THAT CONTAINS

THIS--THERE'S+caŽ A HAPLOTYPE, A

GENETIC HAPLOTYPE THAT CONTAINS

THIS, BD ASSOCIATED KLRC VARIANT

THAT IS ASSOCIATE WIDE REDUCED

PERIPHERAL BLOOD LEUKOCYTE

CYTOTOXICITY AND THIS AFFECT

WAS--AS I SAID PREDOMINANTLY IN

P51 POSITIVE INDIVIDUALS.

NOW LET'S GO TO LOOKING AT

ANALYSIS OF UVITEIS SUBSET IN

ORDER TO REDUCE GENETIC

HETEROGENEITY.

WE TRIED FIRST THE REGULAR

ASSOCIATION STUDY, AND DIDN'T

SEE ANYTHING ADDITIONAL THAT WE

HAD KNOWN ABOUT AND SO, WE THEN

LOOKED AT GENETIC--DIFFERENT

GENETIC MODELS AND IF WE SPECIFY

A RECESSIVE MODEL, NOW WE SEE,

BESIDES THE MHC HERE, A NEW

LOCUST THAT WE HADN'T SEEN

BEFORE THAT NEARLY REACHES

GENOME WIDE SIGNIFICANCE, THIS

IS ERAP ONE AND ERAP TWO, AND

GENOME WIDE SIGNIFICANCE HAS TO

BE MORE STRINGENT BECAUSE OF

ADDITIONAL MODELS AND WHAT ARE

ERAP ONE AND ERAP TWO, THERE ARE

ER ASSOCIATED PEP SID ACES THAT

ARE RESPONSIBLE FOR TRIMMING

PEPTIDES ON TO MHC CLASS ONE

MOLECULES.

SO WE DID THE FINE MAPPING AND

META-ANALYSIS AND SO FORTH, AND

FOUND THAT A CODING VARIANT,

RGENERATEDDINE 725 GLUTEA MIN

BEHCET'S DISEASE, ASSOCIATE WIDE

BEHCET'S DISEASE IN THE SUBSET

AND YOU CAN SEE WE HAVE A NICE

P-VALUE HERE FOR 4.7 TIMES 10 TO

THE MINUS 11 WITH AN OUDS RATIO

OF GREATER THAN FOUR.

WELL, WE SAID, WELL, IS THIS

REALLY LIMITED TO THE UVITEIS

SUBSET AND WE WENT BACK TO THE

COMPLETE CASE CONTROL

POPULATION, CAN STILL SEE THE

ASSOCIATION WITH AN ODDS--LOWER

ODDS RATIO AND LITTLE BIT LESS

SIGNIFICANT PVALUE.

INTERESTINGLY, ERAP ONE R725 Q

HAS BEEN ASSOCIATE WIDE TWO

OTHER DISEASES THAT HAVE A

STRONG MHC CLASS ONE

ASSOCIATION.

SOPHISTICATED RICEIS, AND

ANKYLOSING SPONDYLITIS BUT WITH

REVERSE DISEASE RISK.

AND, FURTHER MORE, THAT STRONG,

STRONG GENE-GENE INTERACTION VS

BEEN DESCRIBED BETWEEN ERAUGHT

ONE AND MHC, THAT'S HLAC SIX AND

HLAB 27 AND ANKYLOSING

SPONDYLITIS, SO THAT LED US TO

ASK THE SAME QUESTION, DO WE SEE

AN INTERACTION BETWEEN THESE

LOCI AND WE DO.

THIS AFFECT AGAIN IS

PREDOMINANTLY LIMITED TO THE HLA

B51 POSITIVE INDIVIDUALS, AND

YOU SEE WE DON'T SEE MUCH

DIFFERENCE IN EFFECT HERE, WITH

THE HOMOZYGOTES AND THE

HETEROZYGOTES BECAUSE THIS IS

RECESSIVELY ACTING ALLELE AND

THE RECESSIVE ALLELE ON THE B-51

IN THE B51 INDIVIDUAL SYSTEM

ASSOCIATED WITH AN ODDS RATIO

FOR BV OF LIKE 67 HALF.

SO THIS STRONG INTERACTION

SUGGESTS THAT PROCESSING AND

PRESENTATION BY B51 DO PLAY A

ROLL IN BEHCET'S DISEASE

SUSEPTIBILITY.

SO NOW I'M COMING TO MY

CONCLUSIONS, HERE WE HAVE THE

CURRENT LIST OF GENETIC LOCI

WITH VARIANTS ASSOCIATE WIDE

SUSEPTIBILITY OF THE BEHCET'S

DISEASE, HLAB51, IL10, IL23

RECEPTOR, CCRONE, STAT FOUR,

KLRCFOUR AND ERAP ONE.

INTERESTINGLY, THESE GENETIC

RISK FACTORS TONED SUPPORT A

ROLE OF THE ADAPTIVE IMMUNE

SYSTEM MORE SO THAN INNATE

IMMUNITY.

THIS WAS SURPRISING TO US

BECAUSE WE SORT OF THOUGHT THAT

THE--AS CAILINSPACES PRESENTED,

THE DISEASE HAS

AUTOINFLAMMATION, BUT IT'S QUITE

POSSIBLE THAT THE VALID AND VARIANTS THAT

WE FIND BY GENOME WIDE

ASSOCIATION VARIANTS ARE COMMON

VARIANTS THAT MIGHT BE MORE

LIKELY TO PLAY A ROLE IN THIS

THE ADAPTIVE IMMUNE SYSTEM

BECAUSE OF THE PRESSURE OF

SELECTION THAT'S BEEN ON THAT

IMMUNE SYSTEM AND THAT

THE--MAYBE WE WOULD FIND THAT

THE AUTOINFLAMMATORY DISEASES

HAVE--DON'T HAVE THOSE COMMON

VARIANTS AND INSTEAD, IN OUR

FUTURE WORK WE PLAN TO LOOK FOR

DISEASE ASSOCIATED ARRA VALID

AND RELIABLEIANTS AND JUST TO

FINISH UP HERE, WE FOUND

INTERESTING GENE-GENE

INTERACTIVE EFFECTS THAT MAY BE

TELLS US SOMETHING ABOUT THE

DISEASE, WE HAVE ERAP ONE AND

B51 ASSOCIATION THAT MAY TELL US

THAT ANTIGEN PRESENTATION REALLY

IS AN IMPORTANT COMPONENT TO THE

DISEASE.

THE AND THEN WE HAVE THIS KLRC

FOUR AND HLAB51 ASSOCIATION

PRESUMABLY THROUGH THE RECEPTORS

LIGAND MYC A THAT MAY BE TELLING

US SOMETHING ABOUT THE KILLER

RECEPTOR INTERACTIONS, LIGAND

INTERACTIONS.

INTERESTINGLY, THE GENETIC,

THESE GENETIC SIMILARITIES AMONG

PSORIASIS, AND ANKYULOSEIS AND

BEHCET'S DISEASE, ARE LONGER, WE

HAVE THE MHC CLASS ONE

ASSOCIATION THAT WAS NOT KNOWN

BEFORE AND IL23 RECEPTOR

ASSOCIATION BUT WE ALSO

IDENTIFIED ERAP ONE AND

CONTRIBUTING TO ALL THREE

DISEASES AND THAT IMPORTANT

INTERACTION BETWEEN MHC CLASS

ONE IN ALL THREE DISEASES.

SO THE IDEA HERE IS THAT THE

GENETIC SIMILARITIES IN THESE

DISEASES MAY PROVIDE CLUES FOR

SHARED PATHOGENESIS AND SHARED

TREATMENT OPTIONS AMONGST THESE

DISEASES.

I'D LIKE TO ACKNOWLEDGE

COWORKERS.

AND TAKES A LOT OF PEOPLE TO DO

THESE KINDS OF STUDIES AND ALSO

ACKNOWLEDGE THE NIH CLINICAL

RESEARCH CENTER WHERE WE'RE

DOING ALL THIS WORK AND THANK

YOU ALL FOR LISTENING.