Genetics, autoantibodies and clinical features in understanding and predicting rheumatoid arthritis
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(2) #HAPTER¬. 4HE¬2!'%¬'3¬POLYMORPHISM¬IS¬NOT ASSOCIATED¬WITH¬RHEUMATOID¬ARTHRITIS INDEPENDENT¬OF¬(,! $2" . --#¬3TEENVOORDEN !(-¬VAN¬DER¬(ELM¬ ¬VAN¬-IL '¬3TOEKEN 2!¬"ANK 220¬DE6RIES 47*¬(UIZINGA *¬DE¬'ROOT 2HEUMATOLOGY¬/XFORD ¬ .
(3)
(4) .O¬ASSOCIATION¬BETWEEN¬2!'%¬'3¬3.0¬AND¬2!. 4HE¬RECEPTOR¬FOR¬ADVANCED¬GLYCATION¬ENDPRODUCTS¬2!'% ¬HAS¬BEEN¬SHOWN¬TO¬PLAY¬A¬ROLE IN¬SEVERAL¬PATHOLOGIES¬INCLUDING¬2HEUMATOID¬!RTHRITIS¬2! ¬ ¬2!'%¬BINDING¬OF¬LIGANDS¬ UPREGULATED¬IN¬2!¬SYNOVIAL¬TISSUE
(5) ¬m¬UID¬AND¬SERUM
(6) ¬CAN¬LEAD¬TO¬INCREASED¬CELL¬ACTIVATION
(7) INCLUDING¬MIGRATION
(8) ¬HYPERPLASIA¬AND¬INCREASED¬CYTOKINE¬PRODUCTION¬3EVERAL¬ANIMAL¬STUD IES¬HAVE¬DESCRIBED¬A¬POSSIBLE¬ROLE¬FOR¬2!'%¬IN¬THE¬ONSET¬AND¬SEVERITY¬OF¬ARTHRITIS¬)N¬THESE ANIMAL¬ STUDIES
(9) ¬ BLOCKADE¬ OF¬ THE¬ RECEPTOR¬ SHOWED¬ SUPPRESSION¬ OF¬ ARTHRITIS
(10) ¬ WHILE¬ ADMIN ISTRATION¬OF¬2!'%¬LIGANDS¬INDUCED¬ARTHRITIS¬IN¬HEALTHY¬MICE¬
(11) ¬)N¬ADDITION
(12) ¬INCREASED¬ LEVELS¬OF¬2!'%¬LIGANDS¬HAVE¬BEEN¬FOUND¬IN¬2!¬PATIENTS¬AND¬CORRELATE¬WITH¬DISEASE¬SEVERITY¬ 0REVIOUS¬ STUDIES¬ INDICATED¬ THAT¬ A¬ GAIN¬ OF¬ FUNCTION¬ MUTATION¬ OF¬ 2!'%¬ CORRELATES¬ WITH¬ 2!¬,INKAGE¬OF¬2!'%¬WITH¬THE¬(,! $2" $1¬REGION
(13) ¬A¬REGION¬KNOWN¬TO¬ASSOCIATE¬WITH¬ 2!¬SUSCEPTIBILITY¬AND¬SEVERITY
(14) ¬COULD¬ACCOUNT¬FOR¬THIS¬CORRELATION¬4O¬DISSECT¬THE¬POSSIBLE CONFOUNDING¬EFFECTS¬OF¬THE¬(,! $2"¬REGION¬FOR¬THE¬POSSIBLE¬ASSOCIATION¬OF¬2!'%¬WITH 2!
(15) ¬WE¬INVESTIGATED¬THE¬CORRELATION¬OF¬A¬GAIN¬OF¬FUNCTION¬MUTATION¬IN¬2!'%
(16) ¬TO¬(,! $2" ALLELES¬AND¬2! ¬ CONSECUTIVE¬ 2!¬ PATIENTS¬ OF¬ THE¬ ,EIDEN¬ %ARLY¬ !RTHRITIS¬ #LINIC
(17) ¬ AN¬ INCEPTION¬ COHORT¬ FOR¬PATIENTS¬WITH¬RECENT¬ONSET¬ARTHRITIS¬ ¬MEAN¬AGE¬¬¢¬¬YEARS¬3$
(18) ¬¬FEMALE ¬AND¬ ¬ NON 2!¬ CONTROLS¬ OF¬ THE¬ SAME¬ COHORT¬ MEAN¬ AGE¬ ¬ ¢¬ ¬ 3$
(19) ¬ ¬ FEMALE ¬ WERE¬ IN CLUDED¬IN¬THE¬ANALYSIS¬!LL¬2!¬PATIENTS¬FULl¬LLED¬THE¬¬CRITERIA¬OF¬THE¬!MERICAN¬#OLLEGE OF¬ 2HEUMATOLOGY¬ 4HE¬ STUDY¬ WAS¬ APPROVED¬ BY¬ THE¬ LOCAL¬ %THICS¬ #OMMITTEE¬ AND¬ WRITTEN INFORMED¬CONSENTS¬WERE¬OBTAINED¬FROM¬ALL¬PATIENTS¬AND¬CONTROLS¬ACCORDING¬THE¬DECLARATION OF¬(ELSINKI¬(,!¬GENOTYPING¬WAS¬AVAILABLE¬FOR¬ALL¬PATIENTS¬AND¬CONTROLS¬AND¬IN¬ADDITION¬FOR¬ TYPING¬OF¬THE¬2!'%¬'3¬POLYMORPHISM¬A¬0#2¬WAS¬PERFORMED
(20) ¬FOLLOWED¬BY¬AN¬OVERNIGHT¬ DIGESTION¬WITH¬!LU )¬4HE¬3¬POLYMORPHISM¬RESULTED¬IN¬THE¬FORMATION¬OF¬AN¬EXTRA !LU) RESTRICTION¬SITE !¬PREVIOUS¬REPORT¬BY¬(OFFMAN¬ET¬AL¬ ¬DESCRIBED¬THAT¬THE¬2!'%¬3¬POLYMORPHISM¬COR RELATED¬WITH¬SUSCEPTIBILITY¬FOR¬RHEUMATOID¬ARTHRITIS¬(OWEVER
(21) ¬2!'%¬IS¬IN¬STRONG¬LINKAGE DISEQUILIBRIUM¬ WITH¬ (,! $2¬
(22) ¬ PARTICULARLY¬ (,! ALLELES¬ ENCODING¬ A¬ COMMON¬ @SHARED EPITOPE¬WITHIN¬THE¬(,! $2"¬ALLELE¬)N¬THE¬POPULATION¬STUDIED¬BY¬(OFFMAN¬ET¬AL
(23) ¬A¬LINK AGE¬WAS¬FOUND¬WITH¬$2 ¬AND¬AFTER¬CORRECTION¬FOR¬THIS¬ALLELE
(24) ¬THE¬CORRELATION¬BETWEEN¬ THE¬ 2!'%¬ 3¬ POLYMORPHISM¬ AND¬ SUSCEPTIBILITY¬ FOR¬ 2!¬ WAS¬ LOST¬ 4HESE¬ DATA¬ WERE¬ NOT CONCLUSIVE
(25) ¬SINCE¬THE¬NUMBER¬OF¬PATIENTS¬AND¬CONTROLS¬POSITIVE¬FOR¬THE¬2!'%¬3¬POLYMOR PHISM¬WERE¬VERY¬LOW¬¬OUT¬OF¬¬AND¬¬OUT¬OF¬¬RESPECTIVELY ¬(ERE
(26) ¬WE¬IDENTIl¬ED¬¬OUT¬ OF¬¬2!¬PATIENTS¬AND¬¬OUT¬OF¬¬CONTROLS¬HARBOURING¬THE¬2!'%¬3¬POLYMORPHISM 7E¬FOUND¬AN¬ASSOCIATION¬BETWEEN¬THE¬2!'%¬3¬POLYMORPHISM¬AND¬2!¬WITHOUT¬CORREC TION¬FOR¬(,!¬ALLELES¬(OWEVER
(27) ¬IN¬PATIENTS
(28) ¬2!'%¬3¬WAS¬IN¬LINKAGE¬DEl¬NED¬AS¬0 ¬ WITH¬ $2" ¬ ODDS¬ RATIO¬ /2 ¬ ¬ 0 ¬ )N¬ CONTROLS¬ 2!'%¬ 3¬ WAS¬ IN¬ LINKAGE. .
(29) #HAPTER¬. n. n. n n. CONTROLS¬3 . !SSOCIATION¬BETWEEN¬2!'% AND¬$2¬IN¬CONTROLS. CONTROLS¬3 . PATIENTS¬3 . . PATIENTS¬3 . . . . . . . . . . . . . . . . $2" . $2" . 3. 3. 0ATIENTS. !SSOCIATION¬BETWEEN¬2!'% AND¬$2¬IN¬PATIENTS. 3¬ ¬ ¬VS¬3 ¬. 3 ¬ ¬VS¬3 ¬. 3 ¬ ¬VS¬3 ¬. 3 ¬ ¬VS¬3 ¬. $2" ¬VS¬$2" . 2!'%¬3 ¬VS¬2!'%¬3. #OMPARISON. $2" . 2!'%¬3. CONTROLS¬ . PATIENTS¬ . . . . . . . . . . . 3. CONTROLS¬ ¬ . PATIENTS¬ . . . . . . . . . . $2" . #ONTROLS. $2" . . 3. . . . . 0ATIENTS. ¬ . ¬ . ¬ . ¬ . ¬ . ¬ . ¬ . ¬ . /2¬#). . . . . #ONTROLS. . . . . . . . . 0. ,INKAGE¬DISEQUILIBRIUM¬IN¬CONTROLS . ,INKAGE¬DISEQUILIBRIUM¬IN¬PATIENTS . $2¬ASSOCIATED¬IN¬2!'% . $2¬ASSOCIATED¬IN¬2!'% . 2!'%¬ASSOCIATED¬IN¬$2 . 2!'%¬ASSOCIATED¬IN¬$2 . $2¬ASSOCIATED . 2!'%¬ASSOCIATED . 4EST. 4ABLE¬ &REQUENCIES¬OF¬PATIENTS¬AND¬CONTROLS¬POSITIVE¬OR¬NEGATIVE¬FOR¬2!'%¬3¬OR¬(,! $2" ¬AND¬STATISTIC¬CALCULATION¬BY¬THE¬METHOD¬DESCRIBED¬BY 3VEJGAARD¬ET¬AL. .
(30) .O¬ASSOCIATION¬BETWEEN¬2!'%¬'3¬3.0¬AND¬2!. WITH¬$2" ¬/2¬
(31) ¬0 ¬AND¬ ¬/2¬
(32) ¬0 ¬#ORRECTION¬FOR¬PRES ENCE¬OR¬ABSENCE¬OF¬THESE¬(,!¬ALLELES¬WAS¬DONE¬BY¬THE¬3VEJGAARD¬METHOD¬ ¬7HEN¬THE ASSOCIATION¬OF¬2!'%¬3¬WITH¬2!¬WAS¬CORRECTED¬FOR¬THE¬ABSENCE¬OR¬PRESENCE¬OF¬$2"
(33) ¬ THE¬ ASSOCIATION¬ BETWEEN¬ 2!'%¬ AND¬ 2!¬ REMAINED¬ PRESENT¬ #ONVERSELY
(34) ¬ AFTER¬ CORRECTION FOR¬THE¬PRESENCEABSENCE¬OF¬(,!¬$2" ¬THE¬ASSOCIATION¬BETWEEN¬2!'%¬3¬AND¬2!¬ WAS¬LOST¬4ABLE¬
(35) ¬INDICATING¬THAT¬2!'%¬IS¬NOT¬ASSOCIATED¬WITH¬2!¬INDEPENDENTLY¬OF¬(,!¬ $2" ¬IN¬THIS¬COHORT¬!LSO¬IN¬LOGISTIC¬REGRESSION¬ANALYSIS¬WITH¬$2" ¬AND¬2!'%¬ AS¬ POSSIBLE¬ EXPLANATORY¬ VARIABLES¬ AND¬ THE¬ PRESENCE¬ OF¬ 2!¬ AS¬ DEPENDENT¬ VARIABLE
(36) ¬ ONLY¬ $2" ¬WAS¬INDEPENDENTLY¬ASSOCIATED¬WITH¬2!¬/2¬
(37) ¬0 )N¬CONCLUSION
(38) ¬CONSIDERING¬THE¬SIZE¬OF¬OUR¬STUDY
(39) ¬IT¬IS¬UNLIKELY¬THAT¬THE¬2!'%¬3¬POLY MORPHISM¬IS¬ASSOCIATED¬WITH¬2!¬INDEPENDENTLY¬OF¬(,!¬$2" ¬. .
(40) 2%&%2%.#%3 ¬ ¬ ¬ ¬ ¬ ¬ ¬ ¬. ¬ ¬. ¬ ¬ ¬ ¬ ¬ ¬. #HAPTER¬. ¬ ¬. . 3CHMIDT¬!-
(41) ¬9AN¬3$
(42) ¬9AN¬3&
(43) ¬3TERN¬$-¬4HE¬MULTILIGAND¬RECEPTOR¬2!'%¬AS¬A¬PROGRESSION¬ FACTOR¬AMPLIFYING¬IMMUNE¬AND¬INm¬AMMATORY¬RESPONSES¬*¬#LIN¬)NVEST¬ (OFMANN¬-!
(44) ¬$RURY¬3
(45) ¬(UDSON¬")¬ET¬AL¬2!'%¬AND¬ARTHRITIS¬THE¬'3¬POLYMORPHISM AMPLIl¬ES¬THE¬INm¬AMMATORY¬RESPONSE¬'ENES¬)MMUN¬ 0ULLERITS¬2
(46) ¬*ONSSON¬)-
(47) ¬6ERDRENGH¬-¬ET¬AL¬(IGH¬MOBILITY¬GROUP¬BOX¬CHROMOSOMAL¬PRO TEIN¬
(48) ¬A¬$.!¬BINDING¬CYTOKINE
(49) ¬INDUCES¬ARTHRITIS¬!RTHRITIS¬2HEUM¬ &OELL¬$
(50) ¬+ANE¬$
(51) ¬"RESNIHAN¬"¬ET¬AL¬%XPRESSION¬OF¬THE¬PRO INm¬AMMATORY¬PROTEIN¬3!¬ %. 2!'% ¬IN¬RHEUMATOID¬AND¬PSORIATIC¬ARTHRITIS¬2HEUMATOLOGY¬/XFORD ¬ +OKKOLA¬2
(52) ¬3UNDBERG¬%
(53) ¬5LFGREN¬!+¬ET¬AL¬(IGH¬MOBILITY¬GROUP¬BOX¬CHROMOSOMAL¬PRO TEIN¬¬!¬NOVEL¬PROINm¬AMMATORY¬MEDIATOR¬IN¬SYNOVITIS¬!RTHRITIS¬2HEUM¬ 4AKAHASHI¬ -
(54) ¬ 3UZUKI¬ -
(55) ¬ +USHIDA¬ +¬ ET¬ AL¬ 2ELATIONSHIP¬ BETWEEN¬ PENTOSIDINE¬ LEVELS¬ IN SERUM¬AND¬URINE¬AND¬ACTIVITY¬IN¬RHEUMATOID¬ARTHRITIS¬"R¬*¬2HEUMATOL¬ VAN¬!KEN¬*
(56) ¬VAN¬"ILSEN¬*(
(57) ¬!LLAART¬#&¬ET¬AL¬4HE¬,EIDEN¬%ARLY¬!RTHRITIS¬#LINIC¬#LIN¬%XP¬ 2HEUMATOL¬3 3 0REVOST¬'
(58) ¬&AJARDY¬)
(59) ¬&ONTAINE¬0¬ET¬AL¬(UMAN¬2!'%¬',93%2¬DIMORPHISM¬AND¬(,!¬CLASS¬ ))¬$2" $1! $1"¬HAPLOTYPES¬IN¬TYPE¬¬DIABETES¬%UR¬*¬)MMUNOGENET¬ 3VEJGAARD¬!
(60) ¬2YDER¬,0¬(,!¬AND¬DISEASE¬ASSOCIATIONS¬DETECTING¬THE¬STRONGEST¬ASSOCIATION 4ISSUE¬!NTIGENS¬ .
(61)
GERELATEERDE DOCUMENTEN
$2"¬ TYPING¬ WAS¬ PERFORMED¬ IN¬ ¬ 2!¬ PATIENTS¬ FROM¬ THE¬ ,EIDEN¬ %ARLY¬ !RTHRITIS¬ #LINIC¬ THE¬ ,EIDEN¬ %!#¬ A¬ $UTCH¬ POPULATION BASED¬ INCEPTION¬ COHORT¬
$2¬IS¬ASSOCIATED¬WITH¬ANTI ##0 NEGATIVE¬ARTHRITIS¬AND¬NOT¬WITH¬ANTI ##0 POSITIVE¬ ARTHRITIS¬ 4HESE¬ DATA¬ SHOW¬ THAT¬ DISTINCT¬ GENETIC¬ RISK¬ FACTORS¬ ARE¬
¬BUT¬ STRATIl¬CATION¬ REVEALED¬ THAT¬ THE¬ INTERACTION¬ PRIMARILY¬ ASSOCIATES¬ WITH¬ THE¬ ANTI ##0¬
¬IT¬WAS¬OBSERVED¬BY¬TWO¬DIFFERENT¬ METHODS¬ LINKAGE¬ AND¬ ASSOCIATION¬ ANALYSIS ¬ THAT¬ THE¬ 3% ALLELES¬ ARE¬ ONLY¬ A¬ RISK¬ FACTOR¬ FOR¬ 2!¬ THAT¬ IS¬
WERE¬ PROMPTLY¬ TREATED¬ WITH¬ EITHER¬ METHOTREXATE¬ OR¬ SALAZOPYRINE¬ EARLY¬ TREATMENT ¬ 4HE¬
DIFFERENT¬ SAMPLES¬ WERE¬ OBTAINED¬ FROM¬ TWO¬ DIFFERENT¬ JOINTS¬ 4HE¬ DIFFERENCES¬ IN¬ INVASIVE NESS¬ WITHIN¬ THE¬ DIFFERENT¬ SAMPLES¬ OF¬ INDIVIDUAL¬ PATIENTS¬
)N¬CONCLUSION ¬THE¬PRESENT¬STUDY¬OBSERVED¬AFTER¬CORRECTION¬FOR¬DIFFERENCES¬IN¬DISEASE¬DURA TION¬ AND¬ AUTOANTIBODY¬ STATUS¬ AN¬ INCREASE¬ IN¬ VARIATION¬
MODELS¬ THAT¬ TAKE¬ INTO¬ ACCOUNT¬ BOTH¬ GENETIC¬ AND¬ CLINICAL¬ CHARACTERISTICS¬ WILL¬ HAVE¬ TO¬ BE EVALUATED¬ IN¬ PATIENT¬ GROUPS¬ WITH¬ UNDIFFERENTIATED¬
