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¬. 2El¬NING¬THE¬COMPLEX¬RHEUMATOID¬ARTHRITIS¬ PHENOTYPE¬BASED¬ON¬SPECIl¬CITY¬OF¬THE¬ (,! $2"¬SHARED¬EPITOPE¬FOR¬ANTIBODIES TO¬CITRULLINATED¬PROTEINS. 47*¬(UIZINGA #)¬!MOS !(-¬VAN¬DER¬(ELM¬ ¬VAN¬-IL 7¬#HEN &!¬VAN¬'AALEN $¬*AWAHEER '-4¬3CHREUDER -¬7ENER &#¬"REEDVELD .¬!HMAD 2&¬,UM 220¬DE¬6RIES 0+¬'REGERSEN 2%-¬4OES ,!¬#RISWELL !RTHRITIS¬2HEUM¬ .

(3) !"342!#4. /BJECTIVE 4HE¬MAIN¬GENETIC¬RISK¬FACTOR¬FOR¬RHEUMATOID¬ARTHRITIS¬2!

(4) ¬THE¬(,!¬REGION

(5) ¬HAS BEEN¬KNOWN¬FOR¬¬YEARS¬0REVIOUS¬RESEARCH¬HAS¬DEMONSTRATED

(6) ¬WITHIN¬THE¬2!¬POPULATION

(7) AN¬ASSOCIATION¬BETWEEN¬(,! $2"¬ALLELES¬CARRYING¬THE¬SHARED¬EPITOPE¬3% ¬AND¬ANTIBODIES DIRECTED¬ AGAINST¬ CYCLIC¬ CITRULLINATED¬ PEPTIDES¬ ANTI ##0¬ ANTIBODIES ¬ 7E¬ UNDERTOOK¬ THIS STUDY¬TO¬MAKE¬THE¬l¬RST¬COMPARISON¬OF¬3%¬ALLELE¬FREQUENCIES¬IN¬THE¬HEALTHY¬POPULATION¬WITH¬ THOSE¬IN¬2!¬PATIENTS¬WHO¬DO¬OR¬DO¬NOT¬HARBOR¬ANTI ##0¬ANTIBODIES -ETHODS (,! $2"¬ TYPING¬ WAS¬ PERFORMED¬ IN¬ ¬ 2!¬ PATIENTS¬ FROM¬ THE¬ ,EIDEN¬ %ARLY¬ !RTHRITIS¬ #LINIC¬ THE¬ ,EIDEN¬ %!#¬ A¬ $UTCH¬ POPULATION BASED¬ INCEPTION¬ COHORT¬ IN¬ WHICH¬ DISEASE¬ COURSE¬ WAS¬ FOLLOWED¬ UP¬ OVER¬ TIME

(8) ¬ IN¬ ¬ HEALTHY¬ $UTCH¬ CONTROLS

(9) ¬ AND¬ IN¬ ¬ AFFECTED¬ MEMBERS¬ OF¬ ¬ 53¬ MULTIPLEX¬ SIBPAIR ¬ FAMILIES¬ OF¬ #AUCASIAN¬ ORIGIN¬ FROM¬ THE .ORTH¬!MERICAN¬2!¬#ONSORTIUM¬.!2!# ¬WITH¬WELL ESTABLISHED¬DISEASE¬AND¬FULl¬LLING¬THE !MERICAN¬#OLLEGE¬OF¬2HEUMATOLOGY¬CLASSIl¬CATION¬CRITERIA¬FOR¬2!¬4HE¬PRESENCE¬OF¬ANTI ##0 ANTIBODIES¬WAS¬DETERMINED¬BY¬ENZYME LINKED¬IMMUNOSORBENT¬ASSAY 2ESULTS &OR¬THE¬,EIDEN¬%!#

(10) ¬THE¬ODDS¬RATIO¬/2 ¬DESCRIBING¬THE¬ASSOCIATION¬OF¬¬COPIES OF¬THE¬3%¬ALLELE¬WITH¬ANTI ##0¬POSITIVITY¬USING¬NO¬COPIES¬OF¬THE¬3%¬ALLELE¬IN¬THE¬HEALTHY #HAPTER¬. CONTROL¬GROUP¬AS¬THE¬REFERENT ¬WAS¬¬0¬¬

(11) ¬WHILE¬THE¬/2¬FOR¬¬3%¬ALLELE¬WAS¬¬ 0. . 0¬¬ ¬.O¬ASSOCIATION¬WITH¬THE¬3%¬WAS¬OBSERVED¬IN¬THE¬$UTCH¬ANTI ##0 NEGATIVE¬2! 0 PATIENTS¬&OR¬THE¬.!2!#¬FAMILIES

(12) ¬LINKAGE¬AND¬ASSOCIATION¬ANALYSIS¬REVEALED¬THE¬3%¬TO¬BE ASSOCIATED¬ONLY¬WITH¬ANTI ##0 POSITIVE¬DISEASE¬AND¬NOT¬WITH¬ANTI ##0 NEGATIVE¬DISEASE¬ 3TRATIl¬ED¬ANALYSES¬INDICATED¬THAT¬ANTI ##0¬ANTIBODIES¬PRIMARILY¬MEDIATED¬ASSOCIATION¬OF¬ THE¬3%¬WITH¬JOINT¬DAMAGE¬OR¬DISEASE¬PERSISTENCE #ONCLUSION¬(,! $2"¬ALLELES¬ENCODING¬THE¬3%¬ARE¬SPECIl¬C¬FOR¬DISEASE¬CHARACTERIZED¬BY ANTIBODIES¬TO¬CITRULLINATED¬PEPTIDES

(13) ¬INDICATING¬THAT¬THESE¬ALLELES¬DO¬NOT¬ASSOCIATE¬WITH¬2!¬ AS¬SUCH

(14) ¬BUT¬RATHER¬WITH¬A¬PARTICULAR¬PHENOTYPE.

(15) 2El¬NING¬THE¬2!¬PHENOTYPE. ).42/$5#4)/.. !¬ DEl¬NITION¬ OF¬ THE¬ RHEUMATOID¬ ARTHRITIS¬ 2! ¬ PHENOTYPE¬ HAS¬ BEEN¬ DEVELOPED¬ THROUGH¬ CONSENSUS¬ PROCEDURES¬ 4HE¬ CURRENT¬ 2!¬ CLASSIl¬CATION¬ CRITERIA¬ WERE¬ DEVELOPED¬ BY¬ EXPERT¬ CLINICIANS¬WHO¬EXAMINED¬THE¬FEATURES¬OF¬hCLASSICv¬2!¬CASES¬AND¬ANALYZED¬THEIR¬SENSITIVITY AND¬ SPECIl¬CITY¬ USING¬ CLINICAL¬ JUDGMENT¬ AS¬ THE¬ GOLD¬ STANDARD¬ !S¬ IS¬ THE¬ CASE¬ WITH¬ MOST¬ COMPLEX¬DISORDERS¬DEl¬NED¬BY¬CONSENSUS¬CRITERIA

(16) ¬THERE¬IS¬LARGE¬VARIATION¬IN¬THE¬PHENOTYPE¬ $ESPITE¬THE¬PHENOTYPIC¬HETEROGENEITY¬ENCOMPASSED¬BY¬THIS¬DISEASE¬DEl¬NITION

(17) ¬THE¬GENETIC¬ CONTRIBUTION¬IS¬ESTIMATED¬TO¬BE¬ ¬

(18) ¬WITH¬THE¬(,!¬REGION¬HAVING¬THE¬LARGEST¬IMPACT¬ ON¬GENETIC¬RISK¬)N¬PARTICULAR

(19) ¬(,! $2"¬ALLELES¬ENCODING¬A¬COMMON¬AMINO¬ACID¬SEQUENCE THE¬SHARED¬EPITOPE¬3% ¬IN¬THE¬THIRD¬HYPERVARIABLE¬REGION¬OF¬THE¬$2"¬MOLECULE¬HAVE¬BEEN IDENTIl¬ED¬AS¬RISK¬ALLELES¬FOR¬2!¬ ¬4HE¬FUNCTIONAL¬SIGNIl¬CANCE¬IMPLIED¬BY¬THE¬LOCATION¬OF¬ THIS¬3%¬SEQUENCE¬ALONG¬THE¬RIM¬OF¬THE¬PEPTIDE BINDING¬GROOVE¬HAS¬STIMULATED¬EFFORTS¬TO¬ SEARCH¬FOR¬THE¬PUTATIVE¬2!¬ANTIGEN !¬CONSIDERABLE¬PROPORTION¬OF¬2!¬PATIENTS¬HAVE¬AUTOANTIBODY¬RESPONSES

(20) ¬ESPECIALLY¬RHEU MATOID¬FACTOR¬2& ¬-ORE¬RECENTLY

(21) ¬ANOTHER¬AUTOANTIBODY¬RESPONSE¬HAS¬RECEIVED¬MUCH¬AT TENTION¬4HESE¬ANTIBODIES¬ARE¬DIRECTED¬AGAINST¬CYCLIC¬CITRULLINATED¬PEPTIDES¬##0S ¬AND¬ARE HIGHLY¬SPECIl¬C¬FOR¬2!¬

(22) ¬)NTRIGUINGLY

(23) ¬THESE¬ANTIBODIES¬MAY¬BE¬DETECTED¬YEARS¬BEFORE¬ DISEASE¬ONSET¬

(24)

(25) ¬ARE¬STABLE¬OVER¬TIME¬

(26) ¬AND¬ARE¬ASSOCIATED¬WITH¬JOINT¬DESTRUCTION

(27) ¬THE HALLMARK¬OF¬2!¬

(28) 4HE¬ IMMUNE¬ RESPONSE¬ TO¬ CITRULLINATED¬ ANTIGENS¬ MAY¬ OCCUR¬ IN¬ THE¬ CONTEXT¬ OF¬ THE¬ 3%

(29) ¬ BECAUSE¬CONVERSION¬OF¬ARGININE¬TO¬CITRULLINE¬AT¬THE¬PEPTIDE¬SIDE CHAIN¬POSITION¬INTERACT ING¬WITH¬THE¬3%¬SIGNIl¬CANTLY¬INCREASES¬PEPTIDE MAJOR¬HISTOCOMPATIBILITY¬COMPLEX¬AFl¬NITY¬ AND¬LEADS¬TO¬THE¬ACTIVATION¬OF¬#$ POSITIVE¬4¬CELLS¬IN¬MICE¬TRANSGENIC¬FOR¬ONE¬OF¬THE¬3% ALLELES¬ ¬0REVIOUS¬RESEARCH¬HAS¬DEMONSTRATED

(30) ¬WITHIN¬THE¬2!¬POPULATION

(31) ¬AN¬ASSOCIA TION¬ BETWEEN¬ (,!¬ ALLELES¬ AND¬ ANTI ##0¬ ANTIBODIES

(32) ¬ BUT¬ NO¬ COMPARISON¬ HAS¬ BEEN¬ MADE¬ BETWEEN¬THE¬(,!¬PROl¬LE¬IN¬THE¬HEALTHY¬POPULATION¬AND¬THAT¬IN¬2!¬PATIENTS¬WHO¬DO¬OR¬DO NOT¬ PRODUCE¬ ANTI ##0¬ ANTIBODIES¬

(33)

(34) ¬ 3UCH¬ A¬ COMPARISON¬ MAY¬ BE¬ IMPORTANT

(35) ¬ SINCE DIFFERENT¬GENETIC¬CONTRIBUTIONS¬ASSOCIATING¬WITH¬DIFFERENT¬PHENOTYPES¬POINT¬TO¬DIFFERENT ETIOPATHOLOGIES. 0!4)%.43¬!.$¬-%4(/$3. 0ATIENTS &OUR¬ HUNDRED¬ EIGHT¬ $UTCH¬ 2!¬ PATIENTS¬ WERE¬ PARTICIPANTS¬ IN¬ THE¬ ,EIDEN¬ %ARLY¬ !RTHRITIS¬ #LINIC¬ %!#

(36) ¬ A¬ POPULATION BASED¬ INCEPTION¬ COHORT¬ DESCRIBED¬ PREVIOUSLY¬ IN¬ DETAIL¬ ¬ !LL¬2!¬PATIENTS¬FULl¬LLED¬THE¬¬REVISED¬CRITERIA¬OF¬THE¬!MERICAN¬#OLLEGE¬OF¬2HEUMATOL OGY¬!#2¬FORMERLY

(37) ¬THE¬!MERICAN¬2HEUMATISM¬!SSOCIATION ¬ ¬AND¬WERE¬OF¬#AUCASIAN¬. .

(38) ORIGIN¬4HE¬STUDY¬PROTOCOL¬INCLUDED¬COLLECTION¬OF¬SEROLOGIC

(39) ¬RADIOGRAPHIC

(40) ¬AND¬CLINICAL¬DATA¬ UPON¬STUDY¬ENTRY¬AND¬YEARLY¬THEREAFTER¬)NFORMED¬PATIENT¬CONSENT¬WAS¬OBTAINED

(41) ¬AND¬THE LOCAL¬MEDICAL¬ETHICS¬COMMITTEE¬APPROVED¬THE¬STUDY¬2ADIOGRAPHS¬OF¬THE¬HANDS¬AND¬FEET¬ WERE¬OBTAINED¬FOR¬ALL¬%!#¬PATIENTS¬AT¬BASELINE¬AND¬AT¬EACH¬SUBSEQUENT¬ANNUAL¬VISIT¬AND WERE¬SCORED¬FOR¬DAMAGE¬USING¬THE¬MODIl¬ED¬3HARPVAN¬DER¬(EIJDE¬METHOD¬ ¬#ONTROLS¬ CONSISTED¬OF¬A¬RANDOM¬PANEL¬OF¬¬HEALTHY¬UNRELATED¬$UTCH¬INDIVIDUALS 0ATIENTS¬WITH¬2!¬WHO¬HAD¬CLINICAL¬REMISSION¬OF¬DISEASE¬WERE¬DEl¬NED¬AS¬FOLLOWS¬AT¬CO HORT¬ ENTRY¬ THEY¬ HAD¬ ¬ SYMMETRIC¬ ARTHRITIS¬ OF¬ THE¬ SMALL¬ JOINTS

(42) ¬ ¬ MORNING¬ STIFFNESS¬ OF¬ AT¬LEAST¬¬HOUR¬DURATION

(43) ¬ ¬A¬DIAGNOSIS¬OF¬DEl¬NITE¬OR¬PROBABLE¬2!¬ACCORDING¬TO¬THE¬!#2¬ CRITERIA

(44) ¬AND¬ ¬THEY¬HAD¬ACHIEVED¬LONG TERM¬AND¬COMPLETE¬REMISSION¬OF¬DISEASE¬NO¬SIGNS¬ OF¬ARTHRITIS¬IN¬THE¬ABSENCE¬OF¬DISEASE MODIFYING¬DRUGS ¬0ATIENTS¬WERE¬NOT¬INCLUDED¬IN¬THE REMISSION¬GROUP¬WHEN¬THEIR¬DISEASE¬HAD¬BEEN¬IN¬REMISSION¬FOR¬¬YEAR¬WITHOUT¬THE¬USE¬OF¬ DISEASE MODIFYING¬DRUGS¬!LL¬OTHER¬PATIENTS¬WERE¬CLASSIl¬ED¬AS¬HAVING¬PERSISTENT¬2! 4HE¬53¬SAMPLE¬CONSISTED¬OF¬MULTIPLEX¬SIBPAIR ¬FAMILIES¬OF¬#AUCASIAN¬ORIGIN¬FROM¬THE .ORTH¬!MERICAN¬2!¬#ONSORTIUM¬.!2!# ¬WITH¬WELL ESTABLISHED¬DISEASE¬AND¬FULl¬LLING¬THE !#2¬CLASSIl¬CATION¬CRITERIA

(45) ¬AS¬DESCRIBED¬PREVIOUSLY¬ ¬2ADIOGRAPHS¬OF¬THE¬HANDS¬AND¬FEET¬ OF¬ALL¬AFFECTED¬INDIVIDUALS¬WERE¬OBTAINED¬AT¬THE¬TIME¬OF¬STUDY¬ENTRY

(46) ¬UNLESS¬l¬LMS¬OBTAINED¬ #HAPTER¬. WITHIN¬ ¬ YEARS¬ PRIOR¬ TO¬ ENTRY¬ WERE¬ AVAILABLE¬ FOR¬ REVIEW¬ 4O¬ DOCUMENT¬ THE¬ PRESENCE¬ OF¬. . EROSIVE¬DISEASE

(47) ¬ALL¬RADIOGRAPHS¬WERE¬READ¬BY¬A¬SINGLE¬RADIOLOGIST¬WHO¬WAS¬BLINDED¬TO¬THE PATIENTS¬CLINICAL¬AND¬GENETIC¬INFORMATION 3EROLOGY¬AND¬GENOTYPING !NTI ##0¬TITERS¬WERE¬DETERMINED¬BASED¬ON¬A¬SECOND GENERATION¬ENZYME LINKED¬IMMUNO SORBENT¬ASSAY¬%,)3! ¬EITHER¬THE¬)MMUNOSCAN¬2!¬-ARK¬¬;%URO $IAGNOSTICA

(48) ¬!RNHEM

(49) ¬4HE .ETHERLANDS=

(50) ¬IN¬THE¬CASE¬OF¬THE¬,EIDEN¬%!#

(51) ¬OR¬AN¬%,)3!¬MANUFACTURED¬BY¬)NOVA¬$IAGNOS TICS¬;3AN¬$IEGO

(52) ¬#!=

(53) ¬IN¬THE¬CASE¬OF¬THE¬.!2!# ¬(,! $2"¬TYPING¬AND¬SUBTYPING¬WERE¬ PERFORMED¬ USING¬ POLYMERASE¬ CHAIN¬ REACTION BASED¬ METHODS¬ 4HE¬ FOLLOWING¬ ALLELES¬ WERE CLASSIl¬ED¬ AS¬ 3%¬ POSITIVE¬ $2"

(54) ¬

(55) ¬

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(58) ¬

(59) ¬

(60) ¬

(61).

(62) ¬

(63) ¬AND¬ ¬ ¬'ENOTYPING¬OF¬.!2!#¬FAMILIES¬FOR¬¬MICROSATELLITE¬MARKERS¬ ON¬ CHROMOSOME¬ ¬ WAS¬ PERFORMED¬ USING¬ MARKERS¬ FROM¬ THE¬ -ARSHl¬ELD¬ SET!¬ COMBO¬ LIST AVAILABLE¬ONLINE¬AT¬HTTPWWWMARSHl¬ELDCLINICORGRESEARCHGENETICSSETSCOMBOHTML WITH¬ADDITIONAL¬MARKERS¬IN¬THE¬(,!¬COMPLEX

(64) ¬AS¬DESCRIBED¬PREVIOUSLY¬ 3TATISTICAL¬ANALYSIS .ONPARAMETRIC¬ LINKAGE¬ ANALYSIS¬ WAS¬ PERFORMED¬ USING¬ THE¬ -ULTIPOINT¬ %NGINE¬ FOR¬ 2APID ,IKELIHOOD¬).FERENCE¬-%2,). ¬STATISTICAL¬PACKAGE¬ ¬!NALYSIS¬OF¬THE¬ANTI ##0 POSITIVE¬ FAMILIES¬¬AFFECTED¬MEMBERS¬IN¬¬FAMILIES¬COMPRISING¬¬SIBPAIRS ¬WAS¬RESTRICTED¬TO ANTI ##0 POSITIVE¬SIBLINGS¬IE

(65) ¬ANTI ##0 NEGATIVE¬SIBLINGS¬WERE¬EXCLUDED ¬!NALYSIS¬OF¬THE ANTI ##0 NEGATIVE¬FAMILIES¬¬AFFECTED¬MEMBERS¬IN¬¬FAMILIES¬COMPRISING¬¬SIBPAIRS ¬.

(66) 2El¬NING¬THE¬2!¬PHENOTYPE. WAS¬RESTRICTED¬TO¬ANTI ##0 NEGATIVE¬PATIENTS¬AND¬THEIR¬SIBLINGS¬WITH¬NEGATIVE¬OR¬LOW¬TITERS¬ OF¬ANTI ##0¬ANTIBODIES¬

(67) ¬PROVIDED¬THAT¬AT¬LEAST¬¬SIBLING¬IN¬THE¬FAMILY¬HAD¬ANTI ##0 NEGATIVE¬DISEASE¬#HI SQUARE¬TESTS¬AND¬ODDS¬RATIOS¬/2S ¬WERE¬USED¬TO¬ASSESS¬THE¬STATISTICAL¬ SIGNIl¬CANCE¬AND¬MAGNITUDE¬OF¬ASSOCIATIONS¬FOR¬CATEGORICAL¬OUTCOMES 7ITH¬ REGARD¬ TO¬ THE¬ ISSUE¬ OF¬ MULTIPLE¬ TESTING

(68) ¬ STATISTICAL¬ SIGNIl¬CANCE¬ LEVELS¬ ACCOUNTED¬ FOR¬THE¬FACT¬THAT¬WE¬EXAMINED¬THE¬FOLLOWING¬¬HYPOTHESES¬IN¬THIS¬STUDY¬ ¬WHETHER¬THE¬ 3%¬ AND¬ ANTI ##0¬ ANTIBODIES¬ ARE¬ ASSOCIATED

(69) ¬ ¬ WHETHER¬ THE¬ 3%¬ AND¬ ANTI ##0¬ ANTIBODIES ARE¬ASSOCIATED¬DIFFERENTLY¬IN¬2!¬PATIENTS¬AND¬IN¬CONTROLS

(70) ¬ ¬WHETHER¬THE¬3%¬AND¬ANTI ##0¬ ANTIBODIES¬ARE¬ASSOCIATED¬WITH¬REMISSION

(71) ¬AND¬ ¬WHETHER¬THE¬3%¬AND¬ANTI ##0¬ANTIBODIES ARE¬ASSOCIATED¬WITH¬JOINT¬DESTRUCTION¬!LTHOUGH¬ONE¬MAY¬ARGUE¬THAT¬THESE¬¬HYPOTHESES¬ARE¬ PROBABLY¬NOT¬COMPLETELY¬INDEPENDENT¬BASED¬ON¬PREVIOUS¬DATA

(72) ¬WE¬CONSIDERED¬RESULTS¬TO¬BE STATISTICALLY¬SIGNIl¬CANT¬IF¬THE¬0 0 VALUES¬WERE¬LESS¬THAN¬OR¬EQUAL¬TO¬. 2%35,43. !S¬SHOWN¬IN 4ABLE¬

(73) ¬THE¬PRESENCE¬OF¬THE¬3%¬ALLELE¬WAS¬STRONGLY¬ASSOCIATED¬WITH¬ANTI ##0 POSITIVITY¬4HERE¬WAS¬ALSO¬EVIDENCE¬OF¬A¬DOSE¬EFFECT

(74) ¬WITH¬INCREASING¬COPIES¬OF¬THE¬3%¬ALLELE¬ BEING¬ASSOCIATED¬WITH¬INCREASING¬RISK¬FOR¬2!¬&OR¬THE¬,EIDEN¬%!#

(75) ¬THE¬/2¬DESCRIBING¬THE ASSOCIATION¬OF¬¬COPIES¬OF¬THE¬3%¬ALLELE¬WITH¬ANTI ##0¬POSITIVITY¬USING¬NO¬COPIES¬OF¬THE¬3% ALLELE¬IN¬THE¬HEALTHY¬CONTROL¬GROUP¬AS¬THE¬REFERENT ¬WAS¬¬0¬¬

(76) ¬WHILE¬THE¬/2¬FOR¬ 0 ¬3%¬ALLELE¬WAS¬¬0 0 ¬ ¬7HEN¬NO¬COPIES¬OF¬THE¬3%¬ALLELE¬IN¬THE¬%!#¬WAS¬USED¬AS¬ THE¬REFERENT

(77) ¬THE¬/2¬DESCRIBING¬THE¬ASSOCIATION¬OF¬¬COPIES¬OF¬THE¬3%¬ALLELE¬WITH¬ANTI ##0 POSITIVITY¬WAS¬¬0 0¬¬

(78) ¬WHILE¬THE¬/2¬FOR¬¬3%¬ALLELE¬WAS¬¬0 ¬ ¬)NTEREST INGLY

(79) ¬HOWEVER

(80) ¬NO¬ASSOCIATION¬WITH¬THE¬3%¬WAS¬OBSERVED¬IN¬THE¬$UTCH¬ANTI ##0 NEGATIVE¬ 2!¬PATIENTS¬FOR¬¬COPIES¬OF¬THE¬3%¬ALLELE¬VERSUS¬HEALTHY¬$UTCH¬CONTROLS

(81) ¬/2¬

(82) ¬0¬¬¬FOR¬ 0 ¬COPY¬OF¬THE¬3%¬ALLELE¬VERSUS¬HEALTHY¬$UTCH¬CONTROLS

(83) ¬/2¬

(84) ¬0 0 ¬

(85) ¬INDICATING¬THAT¬THE¬ 3%¬DOES¬NOT¬ASSOCIATE¬WITH¬2!¬AS¬SUCH

(86) ¬BUT¬RATHER¬WITH¬A¬DEl¬NED¬ANTI ##0¬PHENOTYPE¬ 4ABLE¬ $ISTRIBUTION¬OF¬3%¬AND¬ANTI ##0¬POSITIVITY. $UTCH¬%!#¬2!¬PATIENTS 3%. $UTCH¬CONTROLS N

(87) ¬NO¬. !NTI ##0¬POSITIVE¬N. !NTI ##0¬NEGATIVE¬N. .O¬. /2¬¬#). .O¬. /2¬¬#). . ¬. ¬. ¬ . ¬. ¬ . n. ¬. ¬. ¬ . ¬. ¬ . nn. ¬. ¬. . ¬. . 4HE¬FOLLOWING¬ALLELES¬WERE¬CLASSIl¬ED¬AS¬SHARED¬EPITOPE¬3% ¬POSITIVE¬$2"

(88) ¬

(89) ¬

(90) ¬.

(91) ¬

(92) ¬

(93) ¬

(94) ¬

(95) ¬

(96) ¬

(97) ¬AND¬ ¬ ¬%!#¬¬%ARLY¬!RTHRITIS¬#LINIC¬2!¬ RHEUMATOID¬ARTHRITIS¬##0¬¬CYCLIC¬CITRULLINATED¬PEPTIDE¬/2¬¬ODDS¬RATIO¬¬#)¬¬¬CONl¬DENCE¬ INTERVAL. .

(98) /THER¬AUTOANTIBODIES¬SUCH¬AS¬)G-¬2&¬HAVE¬BEEN¬REPORTED¬TO¬BE¬ASSOCIATED¬WITH¬THE¬3%¬ AS¬WELL¬(OWEVER

(99) ¬A¬COMPARISON¬OF¬THE¬DISTRIBUTION¬OF¬COPIES¬OF¬THE¬3%¬ALLELE¬AMONG¬2!¬ PATIENTS¬WHO¬WERE¬2&¬NEGATIVE¬AND¬ANTI ##0¬POSITIVE¬¬3% ¬PATIENTS

(100) ¬¬3% ¬PATIENTS

(101) ¬ ¬3% ¬PATIENTS ¬WITH¬THE¬DISTRIBUTION¬AMONG¬THOSE¬WHO¬WERE¬2&¬POSITIVE¬AND¬ANTI ##0 NEGATIVE¬¬3% ¬PATIENTS

(102) ¬¬3% ¬PATIENTS

(103) ¬¬3% ¬PATIENTS ¬YIELDED¬A¬STRIKINGLY¬SIGNIl¬ CANT¬DIFFERENCE¬0 0¬¬ ¬4HUS

(104) ¬THE¬3%¬APPEARS¬TO¬BE¬ASSOCIATED¬PRIMARILY¬WITH¬ANTI ##0¬ AUTOANTIBODIES

(105) ¬BUT¬NOT¬WITH¬2&¬AUTOANTIBODIES !NALYSIS¬OF¬.!2!#¬FAMILIES¬REVEALED¬A¬STRONG¬ASSOCIATION¬BETWEEN¬THE¬3%¬AND¬ANTI ##0 POSITIVITY¬3PECIl¬CALLY

(106) ¬THE¬/2¬DESCRIBING¬THE¬ASSOCIATION¬OF¬¬COPIES¬OF¬THE¬3%¬ALLELE¬WITH ANTI ##0¬POSITIVITY¬WAS¬¬0 0 ¬

(107) ¬AND¬THE¬/2¬FOR¬¬3%¬ALLELE¬WAS¬¬0 ¬

(108) ¬ BOTH¬RELATIVE¬TO¬.!2!#¬PATIENTS¬WITH¬NO¬COPIES¬OF¬THE¬3%¬ALLELE 2ESULTS¬ OF¬ NONPARAMETRIC¬ LINKAGE¬ ANALYSIS¬ IN¬ .!2!#¬ FAMILIES¬ HIGHLIGHTED¬ THE¬ STRONG RELATIONSHIP¬BETWEEN¬THE¬(,!¬REGION¬AND¬ANTI ##0¬POSITIVITY¬&IGURE¬¬SHOWS¬THE¬LINKAGE¬ ANALYSIS¬ FOR¬ ¬ MICROSATELLITE¬ MARKERS¬ ON¬ CHROMOSOME¬ ¬ AMONG¬ ¬ AFFECTED¬ MEMBERS OF¬¬FAMILIES¬!MONG¬THE¬¬ANTI ##0 POSITIVE¬FAMILIES

(109) ¬THE¬MAXIMUM¬LOGARITHM¬OF¬ ODDS¬ ,/$ ¬ SCORE¬ IN¬ THE¬ REGION¬ WAS¬

(110) ¬ IN¬ CONTRAST¬ TO¬ THE¬ MAXIMUM¬ ,/$¬ SCORE¬ OF¬ ¬AMONG¬THE¬¬ANTI ##0 NEGATIVE¬FAMILIES¬!NTI ##0 NEGATIVE¬FAMILIES¬WERE¬DEl¬NED #HAPTER¬. BY¬ANTI ##0 NEGATIVE¬PATIENTS¬AND¬THEIR¬SIBLINGS¬WITH¬NEGATIVE¬OR¬LOW¬TITERS¬OF¬ANTI ##0¬. . ANTIBODIES¬

(111) ¬PROVIDED¬THAT¬AT¬LEAST¬¬SIBLING¬IN¬THE¬FAMILY¬HAD¬ANTI ##0 NEGATIVE¬DIS EASE¬ 4HEREFORE

(112) ¬ SENSITIVITY¬ ANALYSES¬ EMPLOYING¬ STRICTER¬ DEl¬NITIONS¬ OF¬ ANTI ##0 NEGATIVE¬ FAMILIES¬ EG

(113) ¬ ALL¬ AFFECTED¬ INDIVIDUALS¬ WITHIN¬ A¬ FAMILY¬ MUST¬ BE¬ ANTI ##0¬ NEGATIVE ¬ WERE PERFORMED

(114) ¬ AND¬ THESE¬ REVEALED¬ A¬ SIMILAR¬ PATTERN¬ DATA¬ NOT¬ SHOWN ¬ 4HE¬ LEVEL¬ OF¬ ¬ WAS CHOSEN¬DUE¬TO¬THE¬FACT¬THAT¬TITERS¬IN¬THE¬RANGE¬OF¬ ¬ARE¬CONSIDERED¬INTERMEDIATE¬BASED¬ ON¬ANALYSES¬OF¬SENSITIVITY¬VERSUS¬SPECIl¬CITY¬

(115) ¬. &IGURE¬¬2ESULTS¬OF¬NONPARAMETRIC¬LINKAGE¬ANALYSIS¬OF¬CHROMOSOME¬¬IN¬ANTI ##0 POSITIVE¬AND¬ANTI ##0 NEGATIVE¬#AUCASIAN¬MULTIPLEX¬FAMILIES¬WITH¬WELL ESTABLISHED RHEUMATOID¬ARTHRITIS 4HE¬¬CURVES¬CORRESPOND¬TO¬ANTI ##0 POSITIVE¬FAMILIES¬¬AFFECTED MEMBERS¬OF¬¬FAMILIES ¬AND¬ANTI ##0 NEGATIVE¬FAMILIES¬¬AFFECTED¬MEMBERS¬OF¬¬FAMILIES ,/$¬¬LOGARITHM¬OF¬ODDS.

(116) 2El¬NING¬THE¬2!¬PHENOTYPE. &IGURE¬¬0ROGRESSION¬OF¬JOINT¬DAMAGE¬IN¬3HARPVAN¬DER¬(EIJDE¬UNITS ¬ACCORDING¬TO¬ THE¬PRESENCE¬OF¬THE¬3%¬AND¬ANTI ##0¬ANTIBODIES¬¬PATIENTS¬WERE¬ANTI ##0¬POSITIVE¬AND¬3% POSITIVE

(117) ¬¬WERE¬ANTI ##0¬POSITIVE¬AND¬3%¬NEGATIVE

(118) ¬¬WERE¬ANTI ##0¬NEGATIVE¬AND¬3%¬POSITIVE

(119) ¬AND ¬WERE¬ANTI ##0¬NEGATIVE¬AND¬3%¬NEGATIVE¬2ADIOGRAPHS¬OF¬THE¬HANDS¬AND¬FEET¬WERE¬OBTAINED¬AT¬ BASELINE¬AND¬AT¬EACH¬SUBSEQUENT¬ANNUAL¬VISIT¬AND¬WERE¬SCORED¬FOR¬DAMAGE¬USING¬THE¬MODIl¬ED¬3HARP VAN¬DER¬(EIJDE¬METHOD¬3HOWN¬ARE¬MEAN¬¢¬3%-. 4HE¬PROSPECTIVE¬DESIGN¬OF¬THE¬%!#¬COHORT¬ALLOWED¬US¬TO¬EXAMINE¬THE¬RELATIVE¬CONTRIBU TIONS¬OF¬ANTI ##0¬STATUS¬AND¬THE¬3%¬TO¬THE¬RATE¬OF¬JOINT¬DESTRUCTION¬&IGURE¬ ¬,ARGE¬DIFFER ENCES¬WERE¬OBSERVED¬BETWEEN¬ANTI ##0 POSITIVE¬AND¬ANTI ##0 NEGATIVE¬PATIENTS¬.O¬AP PARENT¬ASSOCIATION¬WAS¬OBSERVED¬BETWEEN¬3%¬POSITIVITY¬AND¬PROGRESSION¬OF¬JOINT¬DAMAGE¬IN¬ ANTI ##0 NEGATIVE¬PATIENTS¬)N¬CONTRAST

(120) ¬RADIOGRAPHIC¬SEVERITY¬SCORES¬WERE¬HIGHER¬AMONG ANTI ##0 POSITIVE¬PATIENTS¬WHO¬WERE¬3%¬POSITIVE¬THAN¬AMONG¬THOSE¬WHO¬WERE¬3%¬NEGATIVE¬ 3IMILAR¬RESULTS¬WERE¬OBSERVED¬FOR¬THE¬SECOND¬HALLMARK¬OF¬2!

(121) ¬CHRONIC¬INm¬AMMATION¬4HE PRESENCE¬OF¬ANTI ##0¬ANTIBODIES¬YIELDED¬AN¬/2¬OF¬¬0¬¬ ¬FOR¬PERSISTENT¬DISEASE¬ 0 COMPARED¬WITH¬2!¬PATIENTS¬WHO¬HAD¬CLINICAL¬REMISSION¬OF¬THEIR¬DISEASE¬)N¬STRATIl¬ED¬ANALY SES¬OF¬THE¬.!2!#¬POPULATION

(122) ¬THE¬NUMBER¬OF¬COPIES¬OF¬THE¬3%¬ALLELE¬WAS¬ASSOCIATED¬WITH THE¬PRESENCE¬OF¬EROSIVE¬DISEASE¬AMONG¬PATIENTS¬WITH¬ANTI ##0 POSITIVE¬DISEASE¬0 0 ¬

(123) BUT¬NOT¬AMONG¬THOSE¬WITH¬ANTI ##0 NEGATIVE¬DISEASE. $)3#533)/.. $El¬NING¬THE¬PHENOTYPE¬FOR¬MULTIFACTORIAL¬DISEASES¬OFTEN¬OCCURS¬THROUGH¬CONSENSUS¬PRO CEDURES¬ 4HE¬ CURRENT¬ 2!¬ CLASSIl¬CATION¬ CRITERIA¬ WERE¬ DEVELOPED¬ BY¬ EXPERT¬ CLINICIANS¬ WHO EXAMINED¬THE¬FEATURES¬OF¬hCLASSICv¬2!¬CASES¬AND¬ANALYZED¬THEIR¬SENSITIVITY¬AND¬SPECIl¬CITY¬ USING¬CLINICAL¬JUDGMENT¬AS¬THE¬GOLD¬STANDARD¬)T¬IS¬ANTICIPATED¬THAT¬PHENOTYPE¬DEl¬NITIONS. .

(124) BASED¬ON¬SPECIl¬C¬BIOLOGIC¬CHARACTERISTICS¬SUCH¬AS¬ANTI ##0¬ANTIBODY¬PRODUCTION¬WILL¬FA CILITATE¬THE¬SEARCH¬FOR¬GENETIC¬RISK¬FACTORS

(125) ¬LEADING¬TO¬GREATER¬UNDERSTANDING¬OF¬UNDERLYING DISEASE¬MECHANISMS )T¬HAS¬BEEN¬PREVIOUSLY¬REPORTED¬THAT¬THE¬3%¬CORRELATES¬STRONGLY¬WITH¬ANOTHER¬AUTOANTIBODY

(126) 2&¬ ¬'IVEN¬THE¬FACT¬THAT¬2&¬IS¬LESS¬SPECIl¬C¬FOR¬2!¬THAN¬ANTI ##0

(127) ¬IT¬IS¬NOT¬SURPRISING¬THAT¬ THE¬3%¬WAS¬MORE¬STRONGLY¬ASSOCIATED¬WITH¬ANTI ##0¬THAN¬WITH¬2&¬)NDEED

(128) ¬COMPARISON¬OF¬ THE¬DISTRIBUTION¬OF¬COPIES¬OF¬THE¬3%¬ALLELE¬AMONG¬2& NEGATIVE

(129) ¬ANTI ##0 POSITIVE¬PATIENTS WITH¬THE¬DISTRIBUTION¬OF¬COPIES¬OF¬THE¬3%¬ALLELE¬AMONG¬2& POSITIVE

(130) ¬ANTI ##0 NEGATIVE¬PA TIENTS¬REVEALED¬A¬MUCH¬STRONGER¬ASSOCIATION¬OF¬THE¬3%¬WITH¬ANTI ##0¬ANTIBODIES¬!LTHOUGH ANTI ##0¬AUTOANTIBODY¬TITERS¬WERE¬NOT¬AVAILABLE¬FOR¬THE¬HEALTHY¬CONTROLS¬IN¬THE¬CURRENT¬ STUDY

(131) ¬MANY¬PREVIOUS¬STUDIES¬HAVE¬DOCUMENTED¬THE¬ABSENCE¬OF¬ANTI ##0¬ANTIBODY¬PRODUC TION¬AMONG¬HEALTHY¬INDIVIDUALS¬

(132) ¬&URTHER

(133) ¬PREVIOUS¬RESEARCH¬INDICATES¬THAT¬A¬DOUBLE DOSE¬OF¬THE¬3%¬ALLELE¬IS¬RELATIVELY¬RARE¬AMONG¬CONTROLS¬&INALLY

(134) ¬EVEN¬AMONG¬2!¬PATIENTS¬ WITH¬A¬DOUBLE¬DOSE¬OF¬THE¬3%¬ALLELE

(135) ¬APPROXIMATELY¬ONE THIRD¬WAS¬ANTI ##0¬NEGATIVE¬4HUS

(136) IT¬IS¬HIGHLY¬UNLIKELY¬THAT¬ANTI ##0¬ANTIBODIES¬ARE¬PRESENT¬IN¬HEALTHY¬CONTROLS !NOTHER¬INTRIGUING¬OBSERVATION¬IS¬THAT¬THE¬PROPORTION¬OF¬ANTI ##0 POSITIVE¬2!¬PATIENTS IS¬CLEARLY¬LESS¬IN¬INCEPTION¬COHORTS¬WITH¬INCIDENT¬CASES¬OF¬ARTHRITIS¬THAN¬IN¬GROUPS¬OF¬2! #HAPTER¬. PATIENTS¬WHO¬HAVE¬BEEN¬SELECTED¬FOR¬CHRONIC

(137) ¬WELL ESTABLISHED¬DISEASE¬

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(141) ¬THIS¬WAS¬DUE¬IN¬PART¬TO¬THE LOW¬RATE¬OF¬JOINT¬DESTRUCTION¬IN¬ANTI ##0 NEGATIVE¬PATIENTS¬4HUS

(142) ¬ADDITIONAL¬STUDIES¬WILL¬ BE¬REQUIRED¬TO¬MORE¬DEl¬NITIVELY¬ADDRESS¬THIS¬QUESTION 0RIOR¬TO¬THIS¬STUDY

(143) ¬WE¬DEl¬NED¬¬HYPOTHESES¬TO¬BE¬TESTED¬AND¬CONSERVATIVELY¬CONSIDERED¬ THEM¬AS¬INDEPENDENT¬TESTS

(144) ¬AND¬WE¬THEREFORE¬USED¬A¬THRESHOLD¬FOR¬STATISTICAL¬SIGNIl¬CANCE¬OF¬ 0 )¬¬!LTHOUGH¬ONE¬MAY¬ARGUE¬THAT¬THIS¬THRESHOLD¬IS¬TOO¬CONSERVATIVE

(145) ¬THIS¬DECISION¬DID NOT¬ALTER¬THE¬MAIN¬l¬NDINGS¬IN¬THIS¬STUDY

(146) ¬SINCE¬MOST¬OF¬THE¬RESULTS¬WERE¬ASSOCIATED¬WITH¬0 VALUES¬THAT¬WERE¬EITHER¬MUCH¬SMALLER¬THAN¬¬OR¬MUCH¬LARGER¬THAN¬ !¬STRENGTH¬OF¬THE¬CURRENT¬STUDY¬WAS¬THE¬DEMONSTRATION¬OF¬AN¬ASSOCIATION¬BETWEEN¬THE 3%¬ AND¬ ANTI ##0 POSITIVE¬ 2!¬ IN¬ ¬ INDEPENDENT¬ COHORTS¬ AND¬ USING¬ ¬ ANALYTIC¬ METHODS

(147) ¬ ASSOCIATION¬AND¬LINKAGE¬-OREOVER

(148) ¬A¬RECENT¬STUDY¬OF¬JUVENILE¬2!¬DEMONSTRATED¬THAT¬ANTI ##0 POSITIVE¬PATIENTS¬WERE¬¬TIMES¬MORE¬LIKELY¬TO¬BE¬$2¬POSITIVE¬COMPARED¬WITH¬ANTI ##0 NEGATIVE¬PATIENTS¬)NTRIGUINGLY

(149) ¬A¬STRONG¬ASSOCIATION¬WAS¬OBSERVED¬BETWEEN¬(,! $2¬.

(150) 2El¬NING¬THE¬2!¬PHENOTYPE. AND¬THE¬PRESENCE¬OF¬ANTI ##0¬ANTIBODIES¬IN¬HEALTHY¬CHILDREN¬AS¬WELL¬¬OF¬¬CHILDREN¬ TESTED¬ POSITIVE¬ FOR¬ ANTI ##0¬ ANTIBODIES

(151) ¬ AND¬ ALL¬ ¬ CHILDREN¬ CARRIED¬ THE¬ $2¬ ALLELE ¬ 5NFORTUNATELY

(152) ¬(,!¬TYPING¬IN¬THAT¬STUDY¬DID¬NOT¬ALLOW¬FOR¬DETERMINATION¬OF¬3%¬STATUS

(153) ¬BUT THOSE¬DATA¬ALSO¬SUPPORT¬THE¬THEORY¬THAT¬A¬BETTER¬l¬T¬IN¬THE¬3%¬OF¬CITRULLINATED¬ANTIGENS¬CAN¬ GIVE¬RISE¬TO¬THE¬ANTI ##0¬ANTIBODY¬RESPONSE )N¬SUMMARY

(154) ¬WE¬PROPOSE¬THAT¬REl¬NEMENT¬OF¬THE¬2!¬PHENOTYPE¬AS¬DEl¬NED¬BY¬THE¬!#2¬ CRITERIA ¬TO¬hDISEASE¬CHARACTERIZED¬BY¬THE¬PRESENCE¬OF¬ANTIBODIES¬TO¬CITRULLINATED¬PEPTIDESv¬ WILL¬FACILITATE¬THE¬SEARCH¬FOR¬THE¬MECHANISMS¬UNDERLYING¬THE¬PATHOPHYSIOLOGY¬OF¬THE¬DIS EASE¬)NDEED

(155) ¬DESPITE¬THE¬FACT¬THAT¬THE¬MOST¬PROMINENT¬GENETIC¬RISK¬FACTOR¬FOR¬2!¬HAS¬BEEN KNOWN¬FOR¬¬YEARS

(156) ¬OUR¬CURRENT¬DATA¬ILLUSTRATE¬THAT¬THE¬3%¬IS¬NOT¬ASSOCIATED¬WITH¬DISEASE IN¬A¬SUBSTANTIAL¬PROPORTION¬OF¬2!¬PATIENTS

(157) ¬BUT¬RATHER¬THAT¬IT¬IS¬ASSOCIATED¬WITH¬DISEASE¬IN¬ 2!¬PATIENTS¬WHO¬HAVE¬ANTI ##0¬ANTIBODIES¬4HUS

(158) ¬OUR¬DATA¬SUGGEST¬THE¬PRESENCE¬OF¬DISTINCT¬ PATHWAYS¬UNDERLYING¬DISEASE¬INDUCTIONPROGRESSION¬IN¬ANTI ##0 POSITIVE¬AND¬ANTI ##0 NEGATIVE¬2!

(159) ¬SINCE¬THESE¬¬PHENOTYPES¬EXHIBIT¬DIFFERENT¬GENETIC¬ASSOCIATIONS. .

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