Genetics, autoantibodies and clinical features in understanding and predicting rheumatoid arthritis

Hele tekst

(1)Genetics, autoantibodies and clinical features in understanding and predicting rheumatoid arthritis Helm-van Mil, A.H.M. van der. Citation Helm-van Mil, A. H. M. van der. (2006, October 26). Genetics, autoantibodies and clinical features in understanding and predicting rheumatoid arthritis. Retrieved from https://hdl.handle.net/1887/4929 Version:. Corrected Publisher’s Version. License:. Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden. Downloaded from:. https://hdl.handle.net/1887/4929. Note: To cite this publication please use the final published version (if applicable)..

(2) #HAPTER¬. 5NDERSTANDING¬THE¬GENETIC¬CONTRIBUTION TO¬RHEUMATOID¬ARTHRITIS. !(-¬VAN¬DER¬(ELM¬ ¬VAN¬-IL *:¬7ESOLY 47*¬(UIZINGA #URR¬/PIN¬2HEUMATOL¬ .

(3) !"342!#4. 0URPOSE¬OF¬REVIEW¬)DENTIl¬CATION¬OF¬THE¬GENETIC¬VARIANTS¬THAT¬MEDIATE¬RISK¬FOR¬SUSCEP TIBILITY¬ AND¬ SEVERITY¬ OF¬ 2HEUMATOID¬ !RTHRITIS¬ 2! ¬ WILL¬ ALLOW¬ DEVELOPMENT¬ OF¬ NEW¬ DRUG TARGETS¬AS¬WELL¬AS¬INCREASE¬THE¬ABILITY¬TO¬PREDICT¬DISEASE¬COURSE¬4ECHNICAL¬AND¬METHODOLOGI CAL¬PROGRESS¬HAS¬FUELLED¬THE¬PROGRESS¬IN¬THIS¬l¬ELD 2ECENT¬ l¬NDINGS 4HE¬ SECOND¬ RISK¬ FACTOR¬ FOR¬ 2!¬ WAS¬ IDENTIl¬ED

(4) ¬ THE¬ 040.¬ POLYMOR PHISM¬4HIS¬GENETIC¬VARIANT¬REGULATES¬THE¬THRESHOLD¬OF¬4 CELL¬ACTIVATION¬)NTRIGUINGLY¬THIS¬ VARIANT¬IS¬A¬RISK¬FACTOR¬FOR¬DIABETES¬AS¬WELL¬-OREOVER¬IT¬WAS¬SHOWN¬THAT¬MULTIPLE¬GENETIC¬ VARIANTS¬IN¬ONE¬PATHWAY¬BOTH¬IN¬A¬TRANSCRIPTION¬FACTOR

(5) ¬25.8 ¬AS¬IN¬THE¬TRANSCRIPTION FACTOR¬BINDING¬SITE¬OF¬25.8¬IN¬THE¬3,#!¬GENE ¬CAN¬EACH¬CONFER¬VERY¬SMALL¬RISKS¬BUT¬ BY¬GENE GENE¬INTERACTIONS¬CAN¬CONFER¬A¬ FOLD¬RISK¬TO¬2!¬0HENOTYPE GENOTYPE¬INTERACTIONS WERE¬ DESCRIBED¬ BY¬ THE¬ ENHANCED¬ PREVALENCE¬ OF¬ AN¬ 2! SPECIl¬C¬ AUTOANTIBODY¬ ANTI ##0¬ ANTIBODIES ¬IN¬2!¬PATIENTS¬THAT¬HARBOUR¬THE¬2! ASSOCIATED¬(,!¬CLASS¬))¬GENES

(6) ¬THE¬SHARED EPITOPE¬ALLELES¬!N¬ENVIRONMENTAL¬RISK¬FACTOR¬FOR¬2!

(7) ¬SMOKING¬WAS¬DEMONSTRATED¬TO¬CONFER ITS¬RISK¬ESPECIALLY¬IN¬2!¬PATIENTS¬THAT¬HAVE¬BOTH¬THE¬SHARED¬EPITOPE¬ALLELES¬AS¬THE¬2! SPE CIl¬C¬ANTI ##0¬ANTIBODIES #HAPTER¬. 3UMMARY¬4WO¬NEW¬PATHWAYS¬4 CELL¬2ECEPTOR¬SIGNALLING¬AND¬A¬HAEMATOPOIETIC SPECIl¬C¬. . SIGNAL¬ TRANSDUCTION¬ PATHWAY ¬ HAVE¬ BEEN¬ DISCOVERED¬ THAT¬ ALLOW¬ FUTURE¬ PHARMACOLOGICAL INTERVENTIONS¬4HE¬DESCRIPTION¬OF¬THE¬NEW¬GENETIC¬RISK¬FACTORS¬AND¬THE¬INTERACTION¬WITH¬EN VIRONMENTAL¬TRIGGERS¬AS¬WELL¬AS¬PHENOTYPIC¬FEATURES¬IS¬GRADUALLY¬EXPANDING¬OUR¬PROGNOSTIC¬ ABILITIES¬TO¬PREDICT¬DISEASE¬SUSCEPTIBILITY¬AND¬COURSE.

(8) 5NDERSTANDING¬THE¬GENETIC¬CONTRIBUTION¬TO¬2!. ).42/$5#4)/.. 4HE¬COMPLETION¬OF¬HUMAN¬GENOME¬SEQUENCING¬AND¬THE¬TECHNOLOGICAL¬REVOLUTION¬IN¬GE NOTYPING¬IS¬DRIVING¬PROJECTS¬THAT¬AIM¬TO¬UNDERSTAND¬THE¬GENETIC¬CONTRIBUTION¬TO¬VIRTUALLY¬ EVERY¬COMMON¬DISEASE¬BY¬IDENTIFYING¬SEQUENCE¬VARIANTS¬ASSOCIATED¬WITH¬THESE¬DISORDERS 4HE¬MOTIVATION¬TO¬STUDY¬THE¬GENETIC¬CONTRIBUTION¬IS¬TWO FOLD¬&IRST

(9) ¬IDENTIl¬CATION¬OF¬NEW CRITICAL¬PATHWAYS¬IN¬DISEASE¬PATHOGENESIS¬LEADS¬TO¬THE¬IDENTIl¬CATION¬OF¬NEW¬DRUG¬TARGETS¬ LEADING¬TO¬MORE¬OPTIMAL¬TREATMENTS¬3ECOND

(10) ¬THE¬INCREASED¬UNDERSTANDING¬OF¬PATHOGENESIS¬ WILL¬ LEAD¬ TO¬ BETTER¬ AND¬ MORE¬ FOCUSSED¬ TREATMENT¬ PROTOCOLS¬ 4HE¬ CURRENT¬ CLINICAL¬ PREDIC TION¬MODELS¬HAVE¬INSUFl¬CIENT¬POWER¬TO¬PROVIDE¬PATIENTS¬WITH¬INDIVIDUALIZED¬TREATMENTS 'IVEN¬THE¬FACT¬THAT¬THE¬EFl¬CACY¬OF¬TREATMENTS¬IS¬PROVEN¬AT¬THE¬GROUP¬LEVEL¬BY¬RANDOMIZED¬ CONTROLLED¬ CLINICAL¬ TRIALS

(11) ¬ MANY¬ PATIENTS¬ ARE¬ OVER ¬ OR¬ UNDER¬ TREATED¬ )T¬ IS¬ HOPED¬ FOR¬ THAT PREDICTION¬ OF¬ DISEASE¬ OUTCOME¬ BY¬ GENETIC¬ RISK¬ FACTORS¬ MAY¬ LEAD¬ TO¬ MORE¬ INDIVIDUALIZED¬ TREATMENT¬PROTOCOLS &OR¬RHEUMATOID¬ARTHRITIS¬2! ¬HISTORICALLY¬SOUND¬EPIDEMIOLOGICAL¬DATA¬THE¬DIFFERENT¬PREVA LENCE¬OF¬2!¬IN¬VARIOUS¬POPULATIONS

(12) ¬MIGRATION¬STUDIES

(13) ¬FAMILIAL¬CLUSTERING¬AND¬TWIN¬STUD IES ¬ DEMONSTRATED¬ THE¬ GENETIC¬ CONTRIBUTION¬ TO¬ SUSCEPTIBILITY¬ OF¬ 2!¬ ¬ 4HE¬ COMPARISON¬ BETWEEN¬THE¬CONCORDANCE¬RATES¬IN¬MONOZYGOTIC¬TWINS¬AND¬THE¬PREVALENCE¬IN¬THE¬RESPECTIVE POPULATIONS¬REVEALED¬THAT¬ABOUT¬¬OF¬THE¬VARIATION¬IN¬OCCURRENCE¬OF¬DISEASE¬IS¬CAUSED¬BY GENETIC¬FACTORS¬ ¬-OREOVER¬LARGE¬INITIATIVES¬FROM¬*APAN

(14) ¬%UROPE

(15) ¬5NITED¬+INGDOM¬AND¬ THE¬53!¬ARE¬PRESENT¬IN¬WHICH¬MULTICASE¬FAMILIES¬ARE¬AVAILABLE¬AND¬GENOME¬WIDE¬SEARCHES ARE¬BEING¬PERFORMED¬&INALLY

(16) ¬BOTH¬THE¬RESOURCES¬LARGE¬INCEPTION¬COHORTS ¬AND¬THE¬TOOLS¬ WELL¬DEVELOPED¬DISEASE¬ACTIVITY¬MEASUREMENTS¬AND¬OUTCOME¬MEASUREMENTS ¬ARE¬AVAILABLE IN¬THE¬l¬ELD¬OF¬ARTHRITIS¬TO¬TAKE¬MAXIMUM¬ADVANTAGE¬OF¬THE¬AUTOMATED¬GENOTYPING¬TECH NOLOGIES¬WHICH¬ENABLE¬THE¬SYSTEMATIC¬ASCERTAINMENT¬OF¬SEQUENCE¬VARIANTS

(17) ¬IN¬THE¬FORM¬OF¬ SINGLE NUCLEOTIDE¬POLYMORPHISMS¬3.0S

(18) ¬FOR¬THE¬GENOMES¬OF¬LARGE¬NUMBERS¬OF¬INDIVIDU ALS¬$URING¬THE¬LAST¬TWO¬YEARS¬THIS¬HAS¬LED¬TO¬REMARKABLE¬PROGRESS¬IN¬UNDERSTANDING¬THE¬ GENETIC¬CONTRIBUTION¬TO¬2!¬4HIS¬REVIEW¬IS¬DIVIDED¬IN¬FOUR¬SECTIONS s¬. 0ROGRESS¬FOLLOWING¬LINKAGE¬DATA. s¬. 0ROGRESS¬FROM¬CANDIDATE¬GENES¬FROM¬PREVIOUSLY¬IDENTIl¬ED¬LINKAGE¬REGIONS¬IN¬2!. s¬. 0ROGRESS¬FROM¬CANDIDATE¬GENES. s¬. 0ROGRESS¬ON¬PHENOTYPIC GENOTYPIC¬INTERACTIONS. 02/'2%33¬&/,,/7).'¬,).+!'%¬$!4!. &OR¬THE¬PAN %UROPEAN

(19) ¬THE¬*APANESE

(20) ¬THE¬.ORTH¬!MERICAN¬2HEUMATOID¬!RTHRITIS¬AND¬THE¬ 5+¬CONSORTIUM

(21) ¬GENOME¬SCANS¬HAVE¬PREVIOUSLY¬BEEN¬PERFORMED¬WITH¬AN¬AVERAGE¬MARKER¬. .

(22) SPACING¬RANGING¬FROM¬¬TO¬¬CENTIMORGANS¬C- ¬4HE¬&RENCH¬GROUP¬PUBLISHED¬LAST¬YEAR¬A¬ SCAN¬WITH¬A¬MEAN¬MARKER¬SPACING¬OF¬¬C-

(23) ¬RESULTING¬IN¬AN¬AVERAGE¬DISTANCE¬BETWEEN¬ANY 2!¬SUSCEPTIBILITY¬GENE¬AND¬ITS¬NEAREST¬MARKER¬OF¬¬C-¬ ¬¬NON (,!¬REGIONS¬SHOWED SUGGESTIVE¬ EVIDENCE¬ FOR¬ LINKAGE¬ 0 0 ¬ ¬ .INE¬ OF¬ THESE¬ OVERLAPPED¬ WITH¬ REGIONS¬ SUG GESTED¬IN¬OTHER¬PUBLISHED¬2!¬GENOME¬SCANS¬)N¬ORDER¬TO¬PROVIDE¬AN¬ESTIMATE¬WHAT¬THE¬ERROR¬ RATE¬OF¬THIS¬APPROACH¬IS

(24) ¬AN¬ASSESSMENT¬OF¬THE¬SIGNIl¬CANCE¬OF¬THE¬NUMBER¬OF¬REGIONS¬WITH¬ SUGGESTIVE¬EVIDENCE¬FOR¬LINKAGE¬WAS¬OBTAINED¬BY¬USING¬

(25) ¬COMPUTER¬SIMULATIONS¬WITH THE¬NULL¬HYPOTHESIS¬OF¬ABSENCE¬OF¬ANY¬TRUE¬2!¬GENE¬REGION¬4HE¬PROBABILITY¬OF¬OBSERVING¬ ¬NON (,!¬PEAKS¬BY¬CHANCE¬WAS¬

(26) ¬WHICH¬PROVIDED¬CONVINCING¬EVIDENCE¬THAT¬THESE PEAKS¬CONTAINED¬AT¬LEAST¬¬TRUE¬NON (,!¬2!¬GENE¬REGION¬3INCE¬A¬MEAN¬¢¬3$¬OF¬ABOUT¬¬¢¬ ¬FALSE POSITIVE¬PEAKS¬WERE¬EXPECTED

(27) ¬THE¬NUMBER¬OF¬TRUE¬2!¬LINKAGE¬PEAKS¬WAS¬ESTIMATED TO¬BE¬¬¢¬ 4HE¬5+¬GROUP¬EXPLORED¬THE¬UTILITY¬OF¬3.0S¬FOR¬LINKAGE¬ANALYSIS¬!¬WHOLE GENOME¬SCREEN OF¬¬FAMILIES¬WITH¬MULTIPLE¬CASES¬OF¬2!¬WAS¬PERFORMED¬USING¬

(28) ¬GENOMEWIDE¬3.0S¬ ¬4HE¬3.0¬ANALYSIS¬DETECTED¬(,! $2"

(29) ¬THE¬MAJOR¬2!¬SUSCEPTIBILITY¬LOCUS¬0 0¬¬

(30) WITH¬ A¬ LINKAGE¬ INTERVAL¬ OF¬ ¬ C-

(31) ¬ COMPARED¬ WITH¬ A¬ C-¬ LINKAGE¬ INTERVAL¬ DETECTED¬ BY THE¬ PREVIOUSLY¬ PUBLISHED¬ C-¬ MICROSATELLITE¬ SCAN¬ IN¬ THE¬ SAME¬ COHORT¬ -OREOVER

(32) ¬ FOUR #HAPTER¬. ADDITIONAL¬LOCI¬WERE¬DETECTED¬AT¬A¬NOMINAL¬SIGNIl¬CANCE¬LEVEL¬0 0¬¬ ¬IN¬THE¬3.0¬LINKAGE ANALYSIS¬4HE¬AUTHORS¬CONCLUDED¬THAT¬A¬DENSE¬3.0¬MAP¬WAS¬VERY¬SUITABLE¬FOR¬PERFORMING LINKAGE¬ANALYSIS¬IN¬2!¬4HIS¬APPROACH¬ALLOWED¬LOCI¬TO¬BE¬DEl¬NED¬MORE¬PRECISELY. . 02/'2%33¬&2/-¬#!.$)$!4%¬'%.%3¬&2/-¬02%6)/53,9¬)$%.4)&)%$ ,).+!'%¬2%')/.3¬).¬2!. 4HE¬ *APANESE¬ CONSORTIUM¬ ¬ SET¬ OUT¬ BY¬ DENSELY¬ MAPPING¬ CANDIDATE¬ REGIONS¬ THAT¬ WERE¬ ORIGINALLY¬DEl¬NED¬BY¬WHOLE¬GENOME¬SCANS¬&OR¬THE¬PREVIOUSLY¬DEl¬NED¬P¬REGION

(33) ¬THE¬ *APANESE¬INVESTIGATORS¬REASONED¬THAT¬THE¬UNIQUE¬SPECIl¬CITY¬OF¬ANTI ##0¬ANTIBODIES¬FOR¬2! MIGHT¬BE¬CAUSED¬BY¬DIFFERENTIAL¬CITRINULLATION¬CAUSED¬BY¬MUTATIONS¬IN¬ENZYMES¬INVOLVED¬ IN¬CITRINULLATION¬4HE¬P¬GENE¬REGION¬CONTAINED¬ALL¬THE¬KNOWN¬GENES¬THAT¬ENCODE¬PEP TIDYLARGININE¬ DEIMINASES¬ CITRULLINATING¬ 0!$ ¬ ENZYMES

(34) ¬ THE¬ 0!$¬ GENES¬ 0!$¬ TYPES¬ n IN¬A¬REGION¬OF¬¬MEGABASE¬-B ¬!¬CASE¬CONTROL¬STUDY¬USING¬IN¬¬2!¬PATIENTS¬AND¬ HEALTHY¬*APANESE¬CONTROLS¬IDENTIl¬ED¬AN¬ASSOCIATION¬BETWEEN¬HAPLOTYPES¬COMBINATIONS¬OF¬ 3.0S¬ON¬ONE¬CHROMOSOME¬THAT¬TEND¬TO¬INHERIT¬TOGETHER ¬OF¬THE¬GENE¬ENCODING¬0!$¬WITH INCREASED¬SUSCEPTIBILITY¬TO¬2!¬4HE¬DIFFERENCE¬BETWEEN¬TWO¬HAPLOTYPIC¬VARIANTS¬WAS¬FOUR 3.0S¬IN¬EXONS

(35) ¬WITH¬THREE¬SUBSEQUENT¬AMINO¬ACID¬SUBSTITUTIONS¬4HE¬2! SUSCEPTIBLE¬0!$¬ VARIANT¬WAS¬SHOWN¬TO¬PRODUCE¬A¬MORE¬STABLE¬TRANSCRIPT¬THAN¬THE¬NON SUSCEPTIBLE¬VARIANT

(36) ¬ IMPLYING¬AN¬INCREASED¬PRODUCTION¬OF¬0!$¬BY¬THE¬2! SUSCEPTIBLE¬VARIANT¬#IRCUMSTANTIAL¬ EVIDENCE¬FOR¬A¬ROLE¬OF¬0!$¬IN¬2!¬WAS¬THE¬DETECTION¬OF¬0!$¬IN¬SYNOVIAL¬TISSUE¬!LTHOUGH¬.

(37) 5NDERSTANDING¬THE¬GENETIC¬CONTRIBUTION¬TO¬2!. THIS¬OBSERVATION¬MAY¬PROVIDE¬INSIGHT¬IN¬THE¬GENERATION¬OF¬ANTI ##0¬ANTIBODIES¬WITH¬THE NOT¬YET¬PROVEN¬SUGGESTION ¬THAT¬ENHANCED¬PRODUCTION¬OF¬CITRINULLATED¬ANTIGENS¬LEADS¬TO¬A¬ HIGHER¬CHANCE¬OF¬DEVELOPING¬ANTI ##0¬ANTIBODIES

(38) ¬IT¬IS¬NOT¬KNOWN¬WHETHER¬THIS¬IS¬SPECIl¬C¬ FOR¬THE¬*APANESE¬POPULATION¬$ATA¬FROM¬BOTH¬&RANCE¬#AUCASIANS¬AS¬WELL¬AS¬#AUCASIANS¬FROM¬ THE¬ 5+¬ SHOWED¬ NO¬ ASSOCIATION¬ WITH¬ 0!$¬ HAPLOTYPES¬ AND¬ 2!¬

(39) ¬ -ORE¬ SPECIl¬C¬ DATA ON¬THE¬0!$¬ ¬GENE¬REVEALED¬THAT¬THIS¬GENE¬IS¬EXTREMELY¬VARIABLE¬AT¬LEAST¬IN¬THE¬WHITE #AUCASIAN¬POPULATION¬4HEREFORE¬THE¬JURY¬IS¬STILL¬OUT¬WHETHER¬THE¬OBSERVED¬ASSOCIATION¬IN THE¬ *APANESE¬ POPULATION¬ IS¬ SPECIl¬C¬ FOR¬ THIS¬ POPULATION¬ OR¬ WHETHER¬ ASSOCIATIONS¬ EXIST¬ IN¬ OTHER¬POPULATIONS¬AS¬WELL¬4HIS¬LAST¬OPTION¬IS¬IMPORTANT¬BECAUSE¬THIS¬MAY¬INDICATE¬THAT¬THE¬ AMOUNT¬OF¬CITRINULLATED¬ANTIGENS¬CAN¬BE¬A¬NEW¬TARGET¬FOR¬THERAPY 7ITH¬RESPECT¬TO¬THE¬PROGRESS¬ON¬THE¬P¬REGION¬IT¬IS¬NOT¬YET¬KNOWN¬WHAT¬PROPORTION¬OF¬ THIS¬LINKAGE¬PEAK¬CAN¬BE¬EXPLAINED¬BY¬0!$¬GENE¬VARIANTS¬!NOTHER¬CANDIDATE¬GENE¬IN¬THIS¬ REGION¬IS¬THE¬4.& RECEPTOR¬TYPE¬))¬GENE¬THAT¬HAS¬A¬POLYMORPHISM¬CAUSING¬THE¬AMINO¬ACID SUBSTITUTION¬-¬TO¬2¬AT¬POSITION¬¬)NITIALLY¬THE¬5+¬GROUP¬REPORTED¬AN¬ASSOCIATION¬BUT¬IN¬ &RENCH¬FAMILIES¬THIS¬ASSOCIATION¬BETWEEN¬DIFFERENT¬VARIANTS¬OF¬THE¬4.& 2))¬GENE¬COULD¬ONLY BE¬REPLICATED¬IN¬A¬SUBSET¬OF¬MULTICASE¬2!¬FAMILIES¬

(40) ¬&INALLY¬BY¬TAKING¬ADVANTAGE¬OF¬THE SPECTRUM¬OF¬PHENOTYPES¬IN¬A¬LARGE¬INCEPTION¬COHORT¬FROM¬4HE¬.ETHERLANDS

(41) ¬IT¬WAS¬FOUND THAT¬EITHER¬IN¬2!¬PATIENT¬THAT¬DEVELOPED¬COMPLETE¬REMISSION¬OR¬IN¬THOSE¬WITH¬THE¬WORST PROGRESSION¬TO¬DESTRUCTIVE¬DISEASE¬AND¬IN¬HEALTHY¬CONTROLS¬THE¬GENOTYPE¬DISTRIBUTION¬WAS¬ EQUAL¬ ¬4HUS¬IN¬CONCLUSION¬IT¬IS¬MOST¬LIKELY¬THAT¬VARIANTS¬IN¬THE¬4.& 2))¬GENE¬ARE¬NOT¬ RELEVANT¬FOR¬SUSCEPTIBILITY¬OR¬SEVERITY¬OF¬2! 4HE¬(,!¬#LASS¬))¬MOLECULES¬ARE¬THE¬MOST¬POWERFUL¬RECOGNIZED¬GENETIC¬FACTORS¬FOR¬2!¬THAT CONTRIBUTES¬TO¬AT¬LEAST¬¬OF¬THE¬TOTAL¬GENETIC¬EFFECT¬4HE¬(,! $2"¬ALLELES¬

(42) ¬

(43).

(44) ¬

(45) ¬

(46) ¬

(47) ¬

(48) ¬ ¬SHARE¬A¬CONSERVED¬AMINO¬ACID¬SEQUENCE¬1+2!!

(49) 122!!¬OR¬222!! ¬AT¬POSITION¬ ¬IN¬THE¬THIRD¬HYPERVARIABLE¬REGION¬OF¬THE¬$2`¬CHAIN¬ 4HESE¬RESIDUES¬CONSTITUTE¬AN¬_ HELICAL¬DOMAIN¬FORMING¬ONE¬SIDE¬OF¬THE¬ANTIGEN¬PRESENTING¬ BINDING¬SITE¬4HE¬3HARED¬%PITOPE¬HYPOTHESIS¬POSTULATES¬THAT¬THE¬SHARED¬EPITOPE¬MOTIF¬ITSELF¬ IS¬DIRECTLY¬INVOLVED¬IN¬THE¬PATHOGENESIS¬OF¬2!¬BY¬ALLOWING¬THE¬PRESENTATION¬OF¬AN¬ARTHRITO GENIC¬PEPTIDE¬%XTENSIVE¬EVIDENCE¬EXISTS¬SHOWING¬ASSOCIATIONS¬BETWEEN¬THE¬SHARED¬EPITOPE ENCODING¬ALLELES¬AND¬SUSCEPTIBILITY¬TO¬2!¬AS¬WELL¬AS¬SEVERITY¬OF¬2!¬ ¬(OMOZYGOSITY FOR¬THE¬SHARED¬EPITOPE¬IS¬ASSOCIATED¬WITH¬A¬HIGHER¬RISK¬TO¬DEVELOP¬2!¬

(50) ¬AND¬WITH¬MORE SEVERE¬RADIOLOGICAL¬DESTRUCTION¬ ¬2EGIONAL¬DIFFERENCES¬IN¬(,!¬PREVALENCE¬AND¬ASSOCIA TION¬ WITH¬ 2!¬ EXIST¬ !SSOCIATIONS¬ BETWEEN¬ (,! $2" ¬ AND¬ ¬ AND¬ 2!¬ WERE¬ l¬RST DESCRIBED¬IN¬7ESTERN¬!MERICANS¬AND¬IN¬THE¬.ORTHERN¬%UROPE¬POPULATION¬(,! $2" WAS¬ASSOCIATED¬WITH¬2!¬IN¬.ATIVE¬!MERICANS¬ ¬AND¬ASSOCIATIONS¬WITH¬(,! $2" ¬ AND¬ ¬ WERE¬ REPORTED¬ IN¬ )NDIAN¬ AND¬ -EDITERRANEAN¬ PATIENTS¬

(51) ¬ /N¬ THE¬ OTHER¬ HAND¬NO¬ASSOCIATIONS¬WERE¬FOUND¬IN¬'REEKS¬ ¬%XTRA ARTICULAR¬MANIFESTATIONS¬OF¬2!¬SUCH¬ AS¬RHEUMATOID¬NODULES¬ARE¬DESCRIBED¬TO¬OCCUR¬MORE¬OFTEN¬IN¬SHARED¬EPITOPE¬POSITIVE¬PA. .

(52) TIENTS¬ ¬(OMOZYGOSITY¬FOR¬(,! $2" ¬AS¬WELL¬AS¬HOMOZYGOSITY¬FOR¬TWO¬DIFFERENT SHARED¬ EPITOPE¬ ENCODING¬ (,! $2"¬ ALLELES¬ CONFERRED¬ A¬ HIGHER¬ RISK¬ TO¬ DEVELOP¬ EXTRA AR TICULAR¬MANIFESTATIONS¬THAN¬HETEROZYGOSITY¬ ¬!¬RELATIONSHIP¬OF¬VASCULITIS¬WITH¬¬GENO TYPES¬CONTAINING¬A¬DOUBLE¬DOSE¬OF¬THE¬SHARED¬EPITOPE

(53) ¬SPECIl¬CALLY¬(,! $2"

(54). ¬AND¬ ¬HAS¬BEEN¬OBSERVED¬AS¬WELL¬ !LTHOUGH¬IT¬IS¬ACCEPTED¬THAT¬THE¬SHARED¬EPITOPE¬ENCODING¬(,! $2"¬ALLELES¬ARE¬ASSOCIATED WITH¬2!

(55) ¬A¬MORE¬CONTROVERSIAL¬ISSUE¬IS¬THE¬QUESTION¬WHETHER¬PREDISPOSITION¬TO¬2!¬IS¬ALSO¬ CONFERRED¬BY¬(,! $1¬ALLELES¬3UPPORT¬FOR¬A¬ROLE¬FOR¬(,! $1¬COMES¬FROM¬STUDIES¬IN¬MICE

(56) ¬AND¬HUMANS¬

(57) ¬4HE¬CONCERNING¬(,! $1¬ALLELES¬ARE¬THE¬$1¬AND¬$1¬HET ERODIMERS¬!S¬THEY¬BOTH¬ARE¬IN¬STRONG¬LINKAGE¬WITH¬SOME¬SHARED¬EPITOPE¬ALLELES

(58) ¬THE¬INDI VIDUAL¬CONTRIBUTION¬OF¬THE¬(,! $1¬ALLELES¬IS¬DIFl¬CULT¬TO¬DISCERN¬2ECENTLY¬THE¬(,!¬REGION¬ HAS¬BEEN¬l¬NE MAPPED¬ ¬4HE¬HIGHEST¬LINKAGE¬PEAK¬WAS¬LOCATED¬EXACTLY¬AT¬THE¬$2"¬LOCUS

(59) ¬ HOWEVER¬CONSIDERING¬THE¬WIDENESS¬OF¬THE¬LINKAGE¬PEAK¬HAPLOTYPE¬ASSOCIATIONS¬CANNOT¬BE¬ EXCLUDED¬ ¬4HEREFORE

(60) ¬NO¬DEl¬NITE¬EVIDENCE¬IS¬AVAILABLE¬PINPOINTING¬2!¬SUSCEPTIBILITY¬TO¬ EITHER¬(,! $2¬OR¬(,! $1¬ALLELES "ESIDES¬ THE¬ ABOVE MENTIONED¬ PREDISPOSIVE¬ EFFECTS¬ OF¬ (,! $2"¬ ALLELES

(61) ¬ THERE¬ ARE¬ ALSO¬ #HAPTER¬. REPORTS¬ON¬PROTECTIVE¬EFFECTS¬BY¬CERTAIN¬(,! $2"¬HAPLOTYPES¬4HESE¬HAPLOTYPES¬CONTAIN

(62) ¬. . INSTEAD¬OF¬THE¬SHARED¬EPITOPE

(63) ¬ANOTHER¬COMMON¬ANCHOR REGION¬CONSISTING¬OF¬THE¬AMINO ACIDS¬ $%2!!¬ 4HE¬ (,! $2"¬ ALLELES¬ THAT¬ EXPRESS¬ THE¬ $%2!!¬ SEQUENCE¬ $2"

(64) ¬.

(65) ¬

(66) ¬

(67) ¬

(68) ¬

(69) ¬ ¬HAVE¬BEEN¬SHOWN¬TO¬PROTECT¬AGAINST¬2!¬ (OWEVER

(70) ¬THESE¬STUDIES¬HAVE¬BEEN¬PERFORMED¬WITH¬RELATIVELY¬FEW¬2!¬PATIENTS¬CARRYING¬THE¬ $%2!!¬ HAPLOTYPE¬

(71) ¬ 4HERE¬ IS¬ ALSO¬ EVIDENCE¬ THAT¬ PATIENTS¬ CARRYING¬ THE¬ $%2!!¬ SE QUENCE¬HAVE¬LESS¬EROSIVE¬DISEASE¬

(72) ¬)T¬IS¬NOT¬KNOWN¬WHETHER¬THE¬EFFECT¬OF¬THE¬$%2!!¬ ENCODING¬(,! $2"¬ALLELES¬IS¬TRULY¬PROTECTIVE¬OR¬IS¬DUE¬TO¬THE¬EFFECT¬OF¬THE¬CONCOMITANT ABSENCE¬OF¬SHARED¬EPITOPE¬ENCODING¬(,! $2"¬ALLELES¬NON PREDISPOSITION ¬-ORE¬CLARITY¬ WILL¬ COME¬ FROM¬ CURRENTLY¬ PERFORMED¬ STUDIES¬ IN¬ WHICH¬ A¬ LARGE¬ NUMBER¬ OF¬ PATIENTS¬ WITH¬ EARLY¬2!¬HAVE¬BEEN¬FOLLOWED¬FOR¬¬YEARS¬!S¬IN¬THIS¬STUDY¬SUBGROUPS¬OF¬PATIENTS¬WITH¬THE¬ SAME¬AMOUNT¬OF¬SHARED¬EPITOPE¬ALLELES¬WERE¬COMPARED

(73) ¬THE¬EFFECTS¬OF¬$%2!!¬COULD¬BE¬DIF FERENTIATED¬FROM¬NON PREDISPOSITION¬)T¬WAS¬OBSERVED¬THAT¬THE¬$%2!!¬HAPLOTYPE¬CONFERRED A¬LOWER¬RISK¬TO¬DEVELOP¬2!¬AND¬WAS¬ASSOCIATED¬WITH¬A¬LOWER¬RATE¬OF¬JOINT¬DESTRUCTION. 02/'2%33¬&2/-¬#!.$)$!4%¬'%.%3¬&2/-¬02%6)/53,9¬)$%.4)&)%$ ,).+!'%¬2%')/.3¬).¬!54/)--5.%¬$)3%!3%¬).¬'%.%2!,. ,INKAGE¬DATA¬TO¬SELECT¬CANDIDATE¬GENES¬CAN¬BE¬ALTERNATIVELY¬USED¬BY¬SEARCHING¬FOR¬GENOMIC REGIONS¬THAT¬OVERLAP¬IN¬THE¬SCANS¬REPORTED¬FOR¬SEVERAL¬DISEASES¬SUCH¬AS¬ARTHRITIS

(74) ¬DIABETES

(75) ASTHMA

(76) ¬ATOPIC¬DERMATITIS

(77) ¬OSTEOPOROSIS

(78) ¬AND¬INm¬AMMATORY¬BOWEL¬DISEASE¬ ¬/NE¬OF¬THE¬.

(79) 5NDERSTANDING¬THE¬GENETIC¬CONTRIBUTION¬TO¬2!. REGIONS¬IS¬THE¬QnQ¬REGION¬"Y¬VERY¬DENSE¬3.0¬MAPPING¬USING¬A¬SIMILAR¬STRATEGY¬ AS¬ THE¬ 0!$¬ IDENTIl¬CATION¬ IN¬ THE¬ *APANESE¬ POPULATION

(80) ¬ THE¬ *APANESE¬ GROUP¬ PERFORMED¬ LINKAGE¬DISEQUILIBRIUM¬,$ ¬MAPPING¬USING¬SINGLE¬NUCLEOTIDE¬POLYMORPHISMS¬3.0S ¬IN¬A CASE CONTROL¬APPROACH¬ ¬)N¬¬2!¬PATIENTS¬AND¬¬CONTROLS¬A¬RISK¬FOR¬2!¬OF¬¬WAS IDENTIl¬ED¬ FOR¬ A¬ RISK¬ ALLELE¬ IN¬ THE¬ ORGANIC¬ CATION¬ TRANSPORTER¬ GENE¬ 3,#!¬ 4HE¬ EXPRES SION¬OF¬3,#!¬IS¬SPECIl¬C¬TO¬HAEMATOLOGICAL¬AND¬IMMUNOLOGICAL¬TISSUES¬AND¬3,#!¬ IS¬ HIGHLY¬ EXPRESSED¬ IN¬ THE¬ INm¬AMMATORY¬ JOINTS¬ OF¬ MICE¬ WITH¬ COLLAGEN INDUCED¬ ARTHRITIS¬ )NTRIGUINGLY¬THE¬IDENTIl¬ED¬3.0¬AFFECTS¬THE¬TRANSCRIPTIONAL¬EFl¬CIENCY¬OF¬3,#!¬IN¬VITRO¬ BY¬ALTERING¬THE¬BINDING¬AFl¬NITY¬OF¬A¬HAEMATOPOIETIC¬TRANSCRIPTION¬FACTOR

(81) ¬CALLED¬25.8 .EXT¬3.0S¬IN¬THIS¬TRANSCRIPTION¬FACTOR¬WERE¬ANALYSED¬AS¬WELL¬!N¬ASSOCIATION¬WAS¬OBSERVED WITH¬THE¬MINOR¬ALLELE¬IN¬THE¬25.8 GENE¬CONFERRING¬A¬SMALL¬BUT¬SIGNIl¬CANT¬RISK¬ ¬IN¬ THE¬COMPARISON¬BETWEEN¬¬2!¬PATIENTS¬AND¬¬CONTROLS¬)NTRIGUINGLY

(82) ¬THE¬BIOLOGICAL DATA¬SUGGEST¬THAT¬THESE¬TWO¬3.0S¬WOULD¬HAVE¬A¬CUMULATIVE¬EFFECT¬GIVEN¬THAT¬A¬TRANSCRIPTION¬ FACTOR¬WITH¬LESS¬BINDING¬CAPACITY¬HAS¬TO¬BIND¬TO¬A¬DISRUPTED¬TRANSCRIPTION¬FACTOR¬BINDING¬ SITE

(83) ¬ THUS¬ RESULTING¬ IN¬ OVERALL¬ LOSS¬ OF¬ FUNCTION¬ )NDEED¬ IN¬ THE¬ ANALYSIS¬ OF¬ THE¬ DATA¬ FROM¬ INDIVIDUALS¬WHO¬WERE¬GENOTYPED¬FOR¬BOTH¬3.0S¬¬CASES¬AND¬¬CONTROLS

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(85) ¬WHEREAS¬THE GENOTYPE¬THAT¬WAS¬HOMOZYGOUS¬WITH¬RESPECT¬TO¬THE¬SUSCEPTIBLE¬ALLELE¬OF¬3,#! AND¬HET EROZYGOUS¬WITH¬RESPECT¬TO¬25.8 SHOWED¬A¬MODERATELY¬HIGH¬ODDS¬RATIO¬OF¬¬FOR¬DISEASE¬ 4HE¬DATA¬HAVE¬BEEN¬REPLICATED¬IN¬TWO¬OTHER¬DISEASES¬PSORIASIS¬AND¬3,% ¬AND¬STUDIES¬ARE UNDERWAY¬IN¬COHORTS¬OF¬2!¬PATIENTS¬OF¬DIFFERENT¬ETHNIC¬BACKGROUND¬4HIS¬IS¬A¬NICE¬EXAMPLE¬ HOW¬GENE GENE¬INTERACTIONS¬MAY¬EXPLAIN¬COMPLEX¬TRAITS¬WHILE¬AT¬THE¬SAME¬TIME¬THE¬CRUDE¬ /2¬OF¬THE¬GENE¬VARIANT¬FOR¬THE¬DISEASE¬IS¬QUITE¬LOW. 02/'2%33¬&2/-¬#!.$)$!4%¬'%.%3. 4HE¬METHODOLOGY¬OF¬SEARCHING¬GENES¬CAN¬BE¬DIVIDED¬IN¬THE¬UNBIASED¬APPROACH¬OF¬LINKAGE¬ ANALYSIS¬AND¬SUBSEQUENT¬l¬NE¬MAPPING¬)N¬THIS¬METHOD¬A¬LINKAGE¬HOT¬SPOT¬IS¬COVERED¬WITH¬ A¬ GRID¬ OF¬ MARKERS¬ IN¬ ORDER¬ TO¬ SEARCH¬ SYSTEMATICALLY¬ FOR¬ LINKAGE¬ DISEQUILIBRIUM¬ ,$

(86) ¬ THE¬ NON RANDOM¬ASSOCIATION¬OF¬GENES¬ACROSS¬THE¬GENOME ¬AND¬HAPLOTYPES¬.EXT¬THE¬ORIGINAL¬ REGION¬IS¬NARROWED¬AND¬THE¬DISEASE¬GENE¬IS¬IDENTIl¬ED¬&OR¬MULTIFACTORIAL¬DISEASES¬LIKE¬2!¬ THE¬POWER¬TO¬DETECT¬A¬RISK¬GENE¬FOR¬A¬COMMON¬DISEASE¬WITH¬A¬RELATIVE¬RISK¬OF¬TWO¬BY¬,$ MAPPING¬NECESSITATES¬DATA¬ON¬TRANSMISSION¬IN¬¬AFFECTED¬AND¬¬NON AFFECTED¬'IVEN¬ THE¬FACT¬THAT¬THESE¬NUMBERS¬ARE¬NOT¬AVAILABLE¬THE¬CHOICE¬OF¬A¬CANDIDATE¬GENE¬HAS¬SUBJEC TIVE¬ELEMENTS¬BECAUSE¬THE¬GENES¬THAT¬ARE¬INTUITIVELY¬LOGICAL¬WILL¬BE¬TESTED¬l¬RST¬SEE¬ABOVE MENTIONED¬ EXAMPLES¬ OF¬ 0!$¬ AND¬ 4.& 2))¬ AS¬ CANDIDATE¬ GENES ¬ !¬ LESS¬ BIASED¬ APPROACH IS¬IN¬GENOME WIDE¬ASSOCIATION¬STUDIES¬0ATIENTS¬AND¬CONTROLS¬ARE¬UNRELATED¬AND¬THEREFORE. .

(87) MORE¬RECOMBINATIONS¬HAVE¬TAKEN¬PLACE

(88) ¬LEADING¬TOO¬MUCH¬SMALLER¬REGIONS¬IN¬WHICH¬NON RANDOM¬ASSOCIATION¬OF¬GENES¬IS¬PRESENT¬4HUS¬A¬POSITIVE¬RESULT¬IS¬LESS¬LIKELY¬TO¬BE¬CAUSED¬ BY¬LINKAGE¬OF¬RECOMBINING¬NEIGHBORING¬GENES¬THAT¬EXPLAIN¬THE¬OBSERVED¬LINKAGE¬PATTERN 4HE¬OBVIOUS¬CURSE¬IS¬THAT¬SELECTION¬OF¬CANDIDATE¬GENES¬IS¬BIASED¬BY¬LIMITED¬KNOWLEDGE¬!N INTERESTING¬ALTERNATIVE¬WAS¬EXPLORED¬BY¬"EGOVICH¬ET¬AL¬ ¬WHO¬TESTED¬THE¬ASSOCIATION¬OF¬ 3.0S¬WITH¬PUTATIVE¬FUNCTIONAL¬CONSEQUENCES¬IN¬DIFFERENT¬SETS¬OF¬PATIENTS¬AND¬CONTROLS¬4HIS¬ YIELDED¬A¬LARGE¬NUMBER¬OF¬PUTATIVE¬FUNCTIONAL¬POLYMORPHISMS¬DISTRIBUTED¬DIFFERENTLY¬IN¬ PATIENTS¬AND¬CONTROLS¬)N¬A¬SECOND¬SET¬OF¬¬PATIENTS¬AND¬¬CONTROLS

(89) ¬ALL¬FROM¬#AUCASIAN¬ ORIGIN

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(93) ¬REAL POSITIVES¬MAY¬BE¬FALSELY¬EXCLUDED¬IF¬RISK¬IS¬ONLY¬CONFERRED¬ #HAPTER¬. IN¬THE¬CONTEXT¬OF¬GENE GENE¬INTERACTIONS¬SUCH¬AS¬THE¬25.8¬PATHWAY¬GENES¬. . 0ROGRESS¬FROM¬OTHER¬CANDIDATE¬GENES¬THAT¬WERE¬SELECTED¬BY¬PRESUMED¬IMPORTANCE¬IS¬STILL PRELIMINARY¬/N¬THE¬TELOMERIC¬PORTION¬OF¬THE¬(,!¬REGION¬IS¬A¬GENE¬LOCATED¬WHICH¬IS¬CALLED hINHIBITOR¬OF¬.& KAPPA¬" LIKE¬GENEv¬OR¬) KAPPA ",¬)N¬SPITE¬OF¬INITIAL¬REPORTS¬OF¬A¬POSITIVE¬ ASSOCIATION¬OF¬A¬3.0¬LOCATED¬AT¬n

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(95) ¬,ARD¬ET¬AL¬WERE¬NOT¬ABLE¬TO¬l¬ND¬THIS¬ASSOCIATION¬IN¬ INCIDENT¬CASES¬OF¬2!

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(97) ¬CURRENTLY¬THE¬RELATION¬BETWEEN¬THE¬DIFFERENT¬HAPLOTYPES¬AND¬SUSCEPTIBILITY TO¬2!¬IS¬STILL¬UNCLEAR¬&OR¬THE¬ASSOCIATION¬OF¬),¬HAPLOTYPES¬GENE GENE¬INTERACTIONS¬HAVE BEEN¬SUGGESTED¬BY¬THE¬OBSERVATION¬THAT¬THE¬ASSOCIATION¬OF¬),¬GENOTYPES¬IS¬ONLY¬PRESENT¬ IN¬FEMALE¬PATIENTS¬AND¬NOT¬IN¬MALE¬PATIENTS¬ ¬&INALLY¬),¬HAPLOTYPES¬WERE¬ASSOCIATED WITH¬TREATMENT¬RESPONSES¬TO¬4.& BLOCKING¬AGENTS¬ .

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