The genetic background of ankylosing spondylitis

UNCORRECTED PROOF Please ci e his a icle in p ess as: Vég á i A, e al. The gene ic backg ound o ankylosing spondyli is. Join Bone Spine (2009), doi:10.1016/j.jbspin.2009.02.006 ARTICLE IN PRESS +Model BONSOI30891–6 Join Bone Spine xxx (2009) xxx–xxx Re iew 1 The gene ic backg ound o ankylosing spondyli is2 Anikó Vég á ia, Zol án Szabóa, Sándo Szán óa, Tibo T. Glan b, Ka alin Mikeczb, Zol án Szekanecza,∗ 3 4 aDepa men o Rheuma ology, Ins i u e o Medicine, Uni e si y o Deb ecen Medical and Heal h Science Cen e , 22, Mó icz s ee , Deb ecen, H-4032, Hunga y 5 6 bSec ion o Molecula Medicine, Depa men o O hopedic Su ge y, Biochemis y and In e nal Medicine (Sec ion o Rheuma ology), Rush Uni e si y Medical Cen e , Chicago, Illinois, USA 7 8 Accep ed 24 Feb ua y 2009 9 Abs ac 10 I has long been known ha he majo his ocompa ibili y complex (MHC) is essen ially in ol ed in gene ic suscep ibili y o ankylosing spondyli is (AS). The HLA-B27 an igen has been accoun ed o 20 o 50% o he o al gene ic isk o his disease. Howe e , suscep ibili y o AS canno be ully explained by associa ions wi h he MHC. Recen s udies including linkage analyses as well as candida e gene and, mos ecen ly, genome-wide associa ion s udies indica e signi ican associa ions o he in e leukin-1 gene clus e , in e leukin-23 ecep o and ARTS1 genes as well as o he possible loci wi h AS. In he mu ine model o p o eoglycan-induced spondyli is, wo suscep ibili y loci e med Pgis1 and Pgis2 we e iden i ied. Thus, AS is no a single-gene disease and he in ol emen o mul iple non-MHC genes may accoun o he indi idual as well as geog aphical di e ences seen in AS. 11 12 13 14 15 16 17 © 2009 Published by Else ie Masson SAS on behal o he Socié é F ançaise de Rhuma ologie.18 Keywo ds: Ankylosing spondyli is; Gene ics; HLA-B27; Non-MHC genes; Linkage s udies; Genome-wide associa ion s udies 19 20 1. In oduc ion21 Ankylosing spondyli is (AS) is he p o o ype o spondy-22 loa h opa hies (SpA), a g oup o in lamma o y heuma ic23 diseases wi h sha ed gene ic backg ound as well as common24 clinical ea u es [1]. Family clus e ing is an impo an ea u e o 25 AS ha sugges s he ole o gene ic ac o s in suscep ibili y o AS26 [2,3]. Fo example, in amilies o SpA pa ien s, addi ional SpA27 cases occu mos ly among HLA-B27+ ela i es [4,5]. Rega d-28 ing win s udies in AS, in a Finnish s udy, he conco dance was29 50% be ween monozygo ic wins, 15% o e all among dizygo ic30 wins and 20% among HLA-B27+dizygo ic wins [6]. Di e -31 ences in conco dance a es be ween monozygo ic and dizygo ic 32 wins indica e he c ucial ole o gene ic ac o s in suscep ibili y33 o AS [6].34 Conside ing he ole o genes, he majo his ocompa ibili y35 complex (MHC) alone is no su icien o explain he he i abil-36 ∗Co esponding au ho . E-mail add esses: [email p o ec ed],[email p o ec ed] (Z. Szekanecz). i y o AS. While mo e han 90% o Caucasian AS pa ien s 37 a e HLA-B27+, only less han 5% o HLA-B27+membe s o 38 he gene al popula ion de elop AS [7–9]. Thus, HLA-B27 has 39 been accoun ed o only app oxima ely 20 o 50% o he o e all 40 gene ic suscep ibili y o AS [10,11].41 Al hough he e iology o he disease is unknown, en i- 42 onmen al and gene ic componen s ha e been implica ed as 43 p edisposing ac o s. The dominan gene ic componen is he 44 class I MHC encoded human leukocy e an igen HLA-B27, bu 45 he p esence o HLA-B27 alone is insu icien o disease de el- 46 opmen [2–4,11,12]. The e a e wo majo hypo heses which 47 explain he associa ion o HLA-B27 wi h AS. The ecep o he- 48 o y assumes ha ce ain T cell ecep o s can ecognize a complex 49 o o eign and MHC sel pep ides when oge he , bu his pu a i e 50 pa hogenic pep ide is unknown [2–4]. The molecula mimic y 51 hypo hesizes ha mic oo ganisms which pa ially esemble o 52 c oss- eac wi h HLA molecules a e he sou ce o an igenic com- 53 ponen s. This hypo hesis o molecula mimic y a ge ed mos ly 54 Klebsiella and Ye sinia an igens, bu no app op ia e mic oo - 55 ganisms ha e ye been iden i ied in pa ien s wi h AS [11,13].56 The e o e, ex ensi e s udies ha e been unde aken o iden i y 57 o he non-MHC gene ic ac o s and, indeed, app oxima ely a 58 1297-319X/$ – see on ma e © 2009 Published by Else ie Masson SAS on behal o he Socié é F ançaise de Rhuma ologie. doi:10.1016/j.jbspin.2009.02.006 UNCORRECTED PROOF Please ci e his a icle in p ess as: Vég á i A, e al. The gene ic backg ound o ankylosing spondyli is. Join Bone Spine (2009), doi:10.1016/j.jbspin.2009.02.006 ARTICLE IN PRESS +Model BONSOI30891–6 2A. Vég á i e al. / Join Bone Spine xxx (2009) xxx–xxx dozen ch omosome egions o gene clus e s ha e been linked o59 AS [2–4].60 Linkage analysis, genome-wide sc eening and candida e61 gene associa ion s udies ha e led o he iden i ica ion o se - 62 e al non-MHC ch omosome egions possibly linked o AS [2,3].63 Some o hese loci, such as he in e leukin-1 (IL-1) gene clus e 64 has been consis en ly epo ed by independen esea ch g oups65 [2,14]. O he s, such as he genes o Aminopep idase Regula o 66 o TNF ecep o Shedding 1 (ARTS1) (also known as Endo-67 plasmic Re iculum-associa ed Aminopep idase 1 [ERAP1]) and68 IL-23 ecep o (IL-23R) ha e been desc ibed by he Wellcome69 T us Case-Con ol Conso ium (WTCCC) s udy g oup ha 70 had o me ly pe o med he genome-wide associa ion s udy o 71 14,000 cases o se en common diseases [15,16]. Ye , less in o -72 ma ion is a ailable ega ding he gene ics o AS in compa ison73 o, o example, heuma oid a h i is (RA). 74 Despi e o he inc easing amoun o da a abou gene ic con-75 ibu o s, AS is a mul i ac o ial disease, whe e he “conspi acy”76 o genes and en i onmen al ac o s lead o he de elopmen o 77 he well-known clinical symp oms. In his e iew, we summa-78 ize da a on he gene ic basis o AS based on bo h human and79 oden s s udies. We will e iew he mos ele an in o ma ion80 on HLA as well as non-MHC alleles. 81 2. Role o HLA-B27 and o he majo his ocompa ibili y82 complex genes 83 The associa ion be ween HLA-B27 and AS was i s epo ed84 in he ea ly 1970s [17,18]. The p e alence o HLA-B27 is abou 85 6 o 8% in he gene al popula ion and mo e han 90% among AS86 pa ien s [3,7]. As es ima ed by linkage analysis as well as HLA-87 B27-dependen mul iplica i e model, he gene ic con ibu ion o 88 HLA-B27 is abou 20 o 35% [10,11,19–21]. The conco dance89 a es o HLA-B27+mono- and dizygo ic wins a e 63 and 23%,90 espec i ely [6].91 Al hough he e is no doub ha HLA-B27 is he majo sus-92 cep ibili y gene o AS, i s mechanism o ac ion is s ill no 93 known. All mani es a ions o SpA spon aneously de elop in94 HLA-B27 ansgenic a s indica ing a di ec ole o his gene95 in disease suscep ibili y [22]. Among he 25 known HLA-B2796 alleles, HLA-B*2705, he p edominan allele in he Caucasian97 popula ion, may be he o iginal allele and all o he alleles may be98 de i ed om HLA-B*2705 by mu a ion. Mos allelic mu a ions99 a ec he a iable egion and hus esul in al e ed in e ac ions100 be ween T cell ecep o s and an igenic pep ides [23]. While mos 101 o he HLA-B27 alleles ha e been associa ed wi h SpA, HLA-102 B*2706 and HLA-B*2709 occu ing in Sou h-Eas Asia and103 Sa dinia, espec i ely, show no associa ion wi h SpA [23].104 In HLA-B alleles ha con e suscep ibili y o SpA, a p esence105 o glu amic acid a posi ion 45 and ha o cys eine a posi ion106 67 o he HLA-B molecule is he speci ic pa e n p esen in107 all alleles associa ed wi h SpA bu absen in SpA-independen 108 alleles. Based on hese s uc u al al e a ions, unc ional heo ies109 ha e eme ged. The a h i ogenic pep ide heo y sugges s ha his 110 molecula s uc u e enables he p esen a ion o speci ic pep ides 111 ha induce an au oimmune esponse. Rega ding he impai ed112 olding heo y, disul ide b idges a e o med be ween wo cys- 113 eines a posi ion 67 esul ing in al e ed in acellula a icking 114 o he molecules [24,25].115 MHC genes o he han HLA-B may also be in ol ed in he 116 de elopmen o SpA. These genes may include class II MHC 117 alleles (HLA-DR genes), umo nec osis ac o -␣(TNF-␣) and 118 complemen genes as well as some genes in ol ed in an igen 119 p esen a ion by class I MHC molecules including TAP, LMP2 120 and LMP7 [2–4]. Un o una ely, he p edominan ole o HLA- 121 B27 highly in luences he in e p e a ion o hese esul s as he 122 epo ed associa ions may a he be a ibu able o linkage dis- 123 equilib ium be ween he men ioned loci and HLA-B27. Only 124 he di ec addi ional e ec o HLA-DR4 has been con i med in 125 HLA-B27+ ela i es o SpA pa ien s [24].126 3. Non-majo his ocompa ibili y complex alleles in 127 ankylosing spondyli is 128 As discussed abo e, MHC accoun s o less han 50% o 129 he gene ic isk o AS. Va ious echniques ha e been used o 130 s udy he con ibu ion o non-MHC genes o suscep ibili y o 131 and se e i y o human AS [2–4] (Table 1). 132 Animal models a e in aluable aids o he esea ch o human 133 (au oimmune) diso de s. The ank/ank mouse has a loss-o - 134 unc ion mu a ion in he ank gene and de elops a p og essi e 135 SpA, simila o human AS [19,26], bu he ank gene, ei he 136 in humans o mice, is no in ol ed in au oimmune p ocesses 137 [26,27]. O he models o SpA ha e been de eloped in HLA- 138 B27 ansgenic oden s [21], o in ansgenic mice exp essing a 139 mu an ype IX collagen o a unca ed o m o TNF-␣[28].In 140 addi ion o human da a, p o eoglycan (PG)-induced spondyli- 141 is (PGIS), an au oimmune mu ine model o SpA will also be 142 b ie ly discussed [29,30].143 4. Linkage s udies 144 Linkage exis s when a candida e gene and ano he known 145 locus a e e y close o each o he , he e o e, he wo loci a e 146 ansmi ed oge he . Such linkage s udies can be ca ied ou in 147 la ge amilies wi h many amily membe s a ec ed by a gi en dis- 148 ease. In hese s udies, esul s a e p esen ed as a non-pa ame ic 149 linkage sco e (NPL), which is hen con e ed o a log odds a io 150 (LOD) sco e. High LOD alues (LOD ≥3.6) indica e signi i- 151 can associa ions, while LOD g ea e o equal o 2.2 alues a e 152 sugges i e [31].153 The e ha e been ou la ge linkage s udies wi h espec o 154 suscep ibili y o AS. In he No h-Ame ican Spondyli is Conso - 155 ium (NASC) s udy, 185 amilies wi h 255 a ec ed sibling pai s 156 we e analyzed. The mos signi ican associa ions we e a ibu ed 157 o he MHC locus loca ed on ch omosome 6 (LOD = 15.6) and a 158 single non-MHC locus on ch omosome 16 (LOD = 4.7). O he 159 loci wi h sugges i e LOD alues we e loca ed on ch omosomes 160 1, 3, 4, 5, 10, 11, 17 and 19 [19]. In he F ench AS gene ics 161 coho (GFEGS), 180 amilies wi h 244 a ec ed sibling pai s 162 we e assessed. Again, he MHC locus had he s onges linkage 163 [21]. Also in his coho , a egion on he sho a m o ch omo- 164 some 9 was signi ican ly associa ed wi h acu e an e io u ei is 165 bu no wi h AS [21]. Two s udies om Ox o d s udies con i med 166 UNCORRECTED PROOF Please ci e his a icle in p ess as: Vég á i A, e al. The gene ic backg ound o ankylosing spondyli is. Join Bone Spine (2009), doi:10.1016/j.jbspin.2009.02.006 ARTICLE IN PRESS +Model BONSOI30891–6 A. Vég á i e al. / Join Bone Spine xxx (2009) xxx–xxx 3 Table 1 Associa ions o non-majo his ocompa ibili y genes wi h ankylosing spondyli is. Type o s udy Gene ic linkage Re e ence(s) Genome-wide associa ion s udies (WTCCC) In e leukin-23 ecep o (IL-23R; ch omosome 1)a[15,16] ARTS1 (ch omosome 5)a[15,16] Candida e gene associa ion s udies In e leukin-1 gene clus e (IL-1A, IL-1B, IL-1RN) (ch omosome 2)a[14,35,36,38–41] Linkage s udies Ch omosome 1 [26] Ch omosome 3 [20] Ch omosome 4 [19] Ch omosome 9 [20,26] Ch omosome 10a[19,20,26] Ch omosome 11 [19] Ch omosome 13 [21] Ch omosome 16a[19–21,26] Ch omosome 17 [19,21] Ch omosome 19 [19,20,26] WTCCC: Wellcome T us Case-Con ol Conso ium aCon i med s ong associa ion. he s onges linkage wi h he MHC egion and sugges ed link-167 age wi h loci on ch omosomes 2, 3, 9, 10, 11, 16 and 19 [26]168 (Table 1).169 A pooled me a-analysis indica ed he mos clea e idence o 170 linkage o MHC on ch omosome 6. Addi ional s ong linkage171 was obse ed wi h egions on ch omosomes 16 and 10, while172 mode a e linkage was seen wi h loci on ch omosomes 2, 3, 4, 5,173 6, 11 and 17 [14].174 Some loci we e also associa ed wi h disease ac i i y and 175 unc ional se e i y. While MHC showed no linkage, egions on176 ch omosome 18 we e signi ican ly associa ed wi h he BASDAI177 sco e. In addi ion, egions on he long a m o ch omosome 2178 exe ed sugges i e linkage wi h he BASFI unc ional impai - 179 men sco e [27].180 5. Candida e gene associa ions 181 The e ha e been con lic ing esul s ega ding he IL-1 gene182 clus e . This gene complex is loca ed on ch omosome 2 and183 includes genes encoding IL-1␣(IL-1A), IL-1␤(IL-1B), IL-1184 ecep o an agonis (IL-1RN) and o he genes (IL1F5.IL1F10)185 [32]. This gene clus e co esponds o he egion on ch omosome186 2 iden i ied in linkage s udies desc ibed abo e [14,26]. IL-1␣187 and IL-1␤a e p o-in lamma o y cy okines p ima ily p oduced 188 by monocy e/mac ophages, which s imula e he elease o o he 189 in lamma o y media o s including p os aglandins, ma ix me -190 allop o einases and o he cy okines as well as he exp ession o 191 a ious adhesion ecep o s [33,34]. IL-1Ra compe i i ely block 192 he binding o IL-1␣and IL-1␤ o hei ecep o and hus an ago-193 nize he e ec s o hese cy okines [34]. While ea ly small s udies194 sugges ed associa ion be ween AS and he IL-1RN gene encod-195 ing IL-1Ra [35,36], u he la ge s udies could no con i m his196 associa ion [37–39]. Howe e , some small s udies and a ecen 197 me a-analysis showed highe ca iage o a a iable nucleo ide198 andem epea (VNTR) in in on 2 o he IL-1RN gene in AS 199 pa ien s compa ed o con ols [35,36,40]. Mo eo e , wo SNP 200 in exon 6 o he IL-1RN gene we e also associa ed wi h AS [40]. 201 Rega ding o he genes in he IL-1 clus e , al oge he 14 SNP in202 he IL-1A and IL-1B genes exe ed signi ican associa ions wi h 203 AS [39,41]. Among hese SNP, SNP s3783526 in he IL-1A and 204 s1143627 in he IL-1B gene showed he mos signi ican associ- 205 a ions [39]. In addi ion, SNP s2856836, s17561 and s1894399 206 in he IL-1A gene also showed e y s ong associa ions [41] 207 (Table 1). 208 6. Genome-wide associa ion s udies 209 As desc ibed abo e, he WTCCC ini ia i e iden i ied wo new 210 loci s ongly associa ed wi h AS, IL-23R and ARTS1 [15,16] 211 (Table 1). IL-23R has been implica ed in he pa hogenesis o 212 RA, pso iasis and in lamma o y bowel diseases (IBD) [42–44].213 IL-23 is a po en p o-in lamma o y cy okine ha s imula es he 214 gene a ion o Th17 cells as well as he p oduc ion o o he 215 cy okines including TNF-␣, IL-6, IL-17 and IL-22. The gene 216 o he IL-23R p o ein is loca ed on ch omosome 1. Suscep ibil- 217 i y o C ohn’s disease and pso iasis has been associa ed wi h he 218 SNP s11209026 [42,43]. In addi ion, SNP s7530511 is also 219 associa ed wi h pso iasis [43]. Apa om he SNP men ioned 220 abo e, se e al o he SNP including s10889677 and s2201841 221 also had signi ican ly inc eased p e alence in C ohn’s disease 222 in compa ison o con ols [42]. We ha e ecen ly con i med 223 ha SNP s10889677 and s2201841 a e no only associa ed 224 wi h IBD, bu also wi h RA [44]. In he WTCCC coho , eigh 225 IL-23R SNP we e geno yped in 1000 AS pa ien s and 1500 226 con ols. Se en ou o hese eigh SNP showed associa ion 227 wi h AS. Highly signi ican associa ions we e ound wi h SNP 228 s11209032, s11209026 and s10489629 [16,45]. Associa ions 229 be ween IL-23R gene polymo phisms and AS ha e ecen ly 230 been con i med in a Spanish coho [46]. The IL-23R gene is 231 esponsible o 9% o he popula ion-a ibu able isk o AS 232 [15,16].233 As a as ARTS1 is conce ned, his p o ein is an aminopep- 234 idase in he endoplasmic e iculum. ARTS1, also known as 235 ERAP1, clea es ecep o s o cy okines including TNF-␣(TNF- 236 R1), IL-1 (IL-1R2) and IL-6 (IL-6R␣) om he cell su ace 237 [47]. ARTS1 is also in ol ed in he p ocessing o an igenic 238 UNCORRECTED PROOF Please ci e his a icle in p ess as: Vég á i A, e al. The gene ic backg ound o ankylosing spondyli is. Join Bone Spine (2009), doi:10.1016/j.jbspin.2009.02.006 ARTICLE IN PRESS +Model BONSOI30891–6 4A. Vég á i e al. / Join Bone Spine xxx (2009) xxx–xxx pep ides o op imal leng h o an igen p esen a ion [48]. The239 h ee genes encoding ARTS1 a e loca ed on ch omosome 5 [49].240 In he WTCCC coho and ollow-up s udies, i e SNP includ-241 ing s27044, s30187, s17482078, s10050860 and s2287987 242 we e associa ed wi h AS [16]. In addi ion, he e is no associ-243 a ion be ween any ARTS1 SNP and ei he C ohn’s disease o 244 ulce a i e coli is [16]. Thus, ARTS1 may no be in ol ed in he245 pa hogenesis o a ious SpA bu i s e ec s may be speci ic o 246 AS wi hin he SpA amily. The ARTS1 gene is esponsible o 247 26% o he o e all isk o AS [15,16].248 7. O he genes wi h unconfi med associa ions249 As discussed abo e, he associa ions o IL-1 clus e genes,250 IL-23R and ARTS1 genes ha e been con i med in la ge coho s.251 The e ha e been small s udies sugges ing he associa ions o 252 o he genes wi h AS.253 Some alleles o he cy och ome P450 CYP2D6 gene loca ed 254 on ch omosome 22 ha e been weakly associa ed wi h AS [50].255 The e ha e been con o e sies ega ding possible associa ions o 256 AS wi h he ans o ming g ow h ac o -␤(TGF-␤), ANKH and257 Toll-like ecep o 4 (TLR4) genes. While some s udies sugges ed258 ma ginal associa ions o hese genes wi h AS [51–53], o he 259 s udies could no con i m his [54–56]. Finally, NOD2/CARD15260 mu a ions ha e been associa ed wi h C ohn’s disease, howe e ,261 se e al s udies con i med ha he e we e no such associa ions 262 wi h AS [57].263 8. Lessons om he p o eoglycan-induced spondyli is 264 model265 Polya h i is and spondyli is can be induced in suscep i-266 ble mouse s ains by immuniza ion wi h human ca ilage PG 267 [58,59]. PGIS shows simila i ies o AS in e ms o clinical and268 adiological ea u es. PGIS was induced in suscep ible BALB/c269 and C3H/HeJC (C3H) s ains o mice, and in hei F1 and270 F2 gene a ions de i ed om in e c osses wi h a h i is- and/o 271 spondyli is- esis an DBA/2 and DBA/1 pa en s ains, by sys-272 emic immuniza ion wi h ca ilage PG. Almos all (97–100%)273 PG-immunized BALB/c and C3H mice de eloped pe iphe al274 a h i is by 2 weeks a e he hi d an igen injec ion. Massi e275 in lamma o y cell in il a ion, pannus o ma ion, and ca ilage276 and bone e osion cha ac e ized he his opa hologic pic u e o 277 he a ec ed join s. None o he DBA/1 o DBA/2 pa en s no 278 he (BALB/c ×DBA/2) F1 hyb ids de eloped a h i is un il he279 end o he 14–18-week expe imen al pe iod. The incidence and280 se e i y o spondyli is we e highly compa able in bo h PGIS-281 suscep ible inb ed s ains (BALB/c and C3H) [29].282 Al hough F1 hyb ids o he BALB/c ×DBA/2 in e c oss283 we e ully esis an o pe iphe al PGIA, unexpec edly, mo e han284 30% o hem de eloped PGIS, whe eas none o he F1 hyb ids285 o BALB/c ×DBA/1 de eloped PGIS [23]. These obse a ions286 sugges ha he DBA/1 s ain ca ies e y s ong p o ec i e 287 genes agains SpA, while he DBA/2 genome may con ain bo h 288 spondyli is suscep ibili y and p o ec i e genes ha migh be289 silen in he o iginal backg ound. 290 Quan i a i e ai analysis was used in o de o iden i y and 291 cha ac e ize non-MHC ch omosome loci ha may be highly 292 associa ed wi h he de elopmen o PGIS [30]. Two majo 293 loci exe ed highly signi ican linkage, accoun ing o 40% 294 o he ai a iance in he BALB/c ×DBA/2 F2 gene a ion. 295 The dominan spondyli is-suscep ibili y allele o he Pgis2 296 locus (mouse ch omosome 2) was de i ed om he BALB/c 297 s ain, whe eas he Pgis1 (ch omosome 18) ecessi e allele 298 was p esen in he a h i is- esis an DBA/2 s ain. The Pgis1 299 locus signi ican ly a ec ed he disease-con olling Pgis2 locus, 300 inducing as high incidence o spondyli is in F2 hyb ids as 301 was ound in he spondyli is-suscep ible pa en BALB/c s ain. 302 Addi ional disease-con olling loci wi h sugges i e linkage we e 303 mapped o he ch omosomes 12, 15, and 19. A majo locus 304 con olling IL-6 p oduc ion was ound on ch omosome 14 305 close o he gene o os eoclas di e en ia ion ac o Tn s 11.306 Locus on ch omosome 11 nea he S a 3 and S a 5 genes 307 con olled se um le els o he immunoglobulin IgG2a iso- 308 ype. The wo majo gene ic loci Pgis1 and Pgis2 o mu ine 309 spondyli is we e homologous o ch omosome egions in human 310 genome, which con ol AS in human pa ien s [30]. The i s 311 mu ine locus (Pgis1) is homologous o human ch omosomes 312 5q and 18q, bo h o which ha e signi ican linkage wi h AS 313 ound in B i ish and Eu opean kind eds [19,27,60]. The Pgia2 314 locus o e laps wi h he clus e o IL-1 and A s genes impli- 315 ca ed in suscep ibili y o AS in humans as desc ibed abo e 316 [2,15,16,38].317 9. Conclusions 318 I is e iden ha he MHC, especially HLA-B27, plays a cen- 319 al ole in suscep ibili y o AS. Fo example, HLA-B27 con e s 320 app oxima ely 20 o 50% o he o al gene ic isk o his dis- 321 ease. Howe e , AS is de ini ely no a single gene disease and he 322 gene ic backg ound o AS canno be ully explained by associa- 323 ions wi h he MHC. Candida e gene and, ecen ly, genome-wide 324 associa ion s udies ha e con i med he s ong associa ion o IL- 325 1 clus e on ch omosome 2, IL-23R gene on ch omosome 1 and 326 ARTS1 genes on ch omosome 5 wi h AS. Linkage analysis con- 327 i med possible associa ions wi h o he egions. The s onges 328 linkage was obse ed o loci on ch omosome 16, while mod- 329 e a e linkage was sugges ed a si es on ch omosomes 3, 10, 11, 330 17 and 19. In he PGIS animal model, wo suscep ibili y loci 331 e med Pgis1 and Pgis2 we e iden i ied. 332 Re e ences 333 [1] an de Linden SM, an de Heijde D, Maksymowych WP. Ankylosing 334 spondyli is. In: Fi es ein GS, Budd RC, Ha is J ED, McInnes IB, Ruddy 335 S, Se gen JS, edi o s. Kelley’s ex book o heuma ology, II, 8 h edi ion 336 Philadelphia: Saunde s-Else ie ; 2008. p. 1169–90 [Chap e 70]. 337 [2] B ionez TF, Re eille JD. The con ibu ion o genes ou side he majo his- 338 ocompa ibili y complex o suscep ibili y o ankylosing spondyli is. 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