IL28B and IL10R-1087 polymorphisms are protective for chronic genotype 1 HCV infection and predictors of response to interferon-based therapy in an East-Central European cohort

RESEARCH ARTICLE Open Access IL28B and IL10R −1087 polymo phisms a e p o ec i e o ch onic geno ype 1 HCV in ec ion and p edic o s o esponse o in e e on-based he apy in an Eas -Cen al Eu opean coho Alajos Pá 1*† , Gab iella Pá 1† , Is án To nai 2 , Fe enc Szalay 3 , Dalma Vá szegi 4 , Edi F á e 2 , Má ia Papp 2 , Gab iella Lengyel 5 , János Fehé 5 ˆ, Má a Va ga 6 , Judi Ge ain 7 , János Schulle 8 , Zsuzsanna Nemes 1 , Zol án Pé e i 1 , Anna Tusnádi 9 , Béla Hunyady 1 , A ila Ha agh 10 , Zsol Szinku 10 , Á on Vincze 1 , László Sze eday 11 , Pé e Kis ali 12 and Béla Melegh 12 Abs ac Backg ound: P e ious s udies ha e shown ha single nucleo ide polymo phisms (SNP) in IL28B and IL10R a e associa ed wi h sus ained i ological esponse (SVR) in ch onic hepa i is C pa ien s ea ed wi h pegila ed in e e on plus iba i in (P/R). The p esen s udy ex ends ou ea lie in es iga ions on a la ge Eas -Cen al Eu opean coho . The allele equencies o IL28B and IL10R in geno ype 1 HCV in ec ion we e compa ed wi h ha o heal hy con ols o he pu pose o examining he ela ionship be ween he polymo phisms and he SVR o P/R ea men . Me hods: A o al o 748 ch onic HCV1 in ec ed pa ien s (365 male, 383 emale; 18–82 yea s) and 105 olun a y blood dono s as con ols we e en olled. Fou hund ed and wen y HCV pa ien s we e ea ed wi h P/R o 24–72 weeks, ou o hem 195 (46.4%) achie ed SVR. The IL28 s12979860 SNP was de e mined using Cus om Taqman SNP Geno yping Assays. The IL10R −1087 (also known as IL10R −1082 ( s1800896) p omo e egion SNP was de e mined by RT-PCR and es ic ion agmen leng h polymo phism analysis. Resul s: The IL28B CC geno ype occu ed wi h lowe equency in HCV pa ien s han in con ols (26.1% s 51.4%, p<0.001). P/R ea ed pa ien s wi h he IL28B CC geno ype achie ed highe SVR a e, as compa ed o pa ien s wi h CT (58.6% s 40.8%, p=0.002). The p e alence o IL10R −1087 GG geno ype was lowe in pa ien s han in con ols (31.8 % s 52.2%, p<0.001). Among pa ien s achie ing SVR, he IL10R −1087 GG geno ype occu ed wi h highe equency han he AA (32.0% s 17.4%, p=0.013). The IL28B T allele plus IL10R A allele combina ion was ound wi h highe p e alence in pa ien s han in con ols (52% s 20.7%, p<0.001). The IL28B CC plus IL10R A allele combina ion occu ed wi h highe equency among pa ien s wi h SVR han in non- esponde s (21.3% s 12.8%, p=0.026). Bo h he IL28B CC plus IL10R GG and he IL28B CC plus IL10R A allele combina ions occu ed wi h lowe equency in pa ien s han in con ols. Conclusions: In ou HCV1 pa ien s, bo h he IL28B CC and IL10R GG geno ypes a e associa ed wi h clea ance o HCV. Mo eo e , dis inc IL28B and IL10R allele combina ions appea o be p o ec i e agains ch onic HCV1 in ec ion and p edic o s o esponse o P/R he apy. Keywo ds: Gene ic polymo phism, Hepa i is C i us, In e e on, In e leukin-28B, In e leukin-10 * Co espondence: [email p o ec ed] † Equal con ibu o s ˆDeceased 1 Fi s Depa men o Medicine, Uni e si y o Pécs, Rákóczi u. 2, 7623 Pécs, Hunga y Full lis o au ho in o ma ion is a ailable a he end o he a icle © 2014 Pá e al.; licensee BioMed Cen al L d. This is an open access a icle dis ibu ed unde he e ms o he C ea i e Commons A ibu ion License (h p://c ea i ecommons.o g/licenses/by/2.0), which pe mi s un es ic ed use, dis ibu ion, and ep oduc ion in any medium, p o ided he o iginal wo k is p ope ly ci ed. Pá e al. BMC Resea ch No es 2014, 7:12 h p://www.biomedcen al.com/1756-0500/7/12 Backg ound Hepa i is C i us (HCV) is a majo global heal h p oblem: cu en ly 170 million subjec s a e su e ing om HCV in ec ion wo ldwide [1,2]. The ou come o HCV in ec ion anges om spon aneous i al clea ance o hepa i is, ci hosis and hepa ocellula ca cinoma. Some indi iduals ha e apidly p og essi e li e disease, while o he s emain symp om- ee i us ca ie s. The exac causes o he di e - en disease cou ses a e no known. Immune mechanisms, as well as en i onmen al ac o s a e esponsible o he a ious HCV- ela ed e en s [3]. As gene ic ac o s con olling he hos immune esponse play a pi o al ole in HCV in ec ion, a gene ic p edisposi ion may also be c ucial [4-6]. Cy okines a e among he p edominan mechanisms o hos de ense agains in ec ion; hey induce in lamma o y esponse ha o en leads o issue inju y, bu also se e as an i i al e ec o s. Mo eo e , cy okine syn hesis capaci y has a signi ican gene ic componen . This explains why di e ences exis be ween indi iduals in hei abili y o p oduce cy okines, a ac which may also be due o single-nucleo ide polymo phisms (SNPs) wi hin he coding egions o cy okine genes. Cy okine genes a e polymo phic and ce ain SNPs modi y he cy okine p oduc ion and a ec he hos immune esponse. In HCV in ec ion, sec e ion o an inapp op ia e amoun o cy okines may be associa ed wi h ch onici y o esis ance o in e e on (IFN) ea men [7]. The in e leukin-28B (IL-28B)–also e e ed o as in e e onλ-3 (IFNλ-3) [8-12] –was shown o be in ol ed in he con ol o HCV in ec ion. The gene ic polymo phisms o he encoding IL28B gene egion de e - mine he spon aneous and ea men induced clea ance o geno ype 1 HCV (HCV1) [13-15]. IL-28B is exp essed by pe iphe al blood mononuclea cells, dend i ic cells, and hepa ocy es upon in ec ion wi h i uses o s imula ion wi h double-s anded RNA. IL28B in u n ac i a es signal ansduc ion h ough he JAK-STAT pa hway, exe s an i i al ac i i y and has an impac on na u al clea ance o HCV. IL-28B exhibi s ewe IFN-like ad e se e ec s because IL-28B ecep o s a e exp essed on a limi ed numbe o cell ypes. The ecep o o IL-28 is composed o a unique IL-28R-αchain ha pai s wi h he IL-10R-βchain [10,11]. IL28B gene on human ch omosome 19q was disco e ed using genomic sc eening p ocess in which he en i e human genome was scanned o pu a i e unc ional a ian s [8,9]. Ge e al. [12] iden i ied i s a SNP ( s12979860) loca ed only 3 kilobases ups eam om he IL28B gene, ha encodes IL-28B. They applied genome-wide associa ion s udy (GWAS), e ospec i ely analysed samples o 1,137 HCV in ec ed indi iduals pa icipa ing in a clinical ial wi h pegyla ed in e e on plus iba i in (P/R) he apy, and ound ha he high IL-28B p oduc ion CC geno ype was associa ed wi h app oxima ely a h ee old g ea e a e o SVR o P/R when compa ed wi h he TT geno ype. This inding was con i med by o he s [13,14]. A he same ime i was also shown ha he equency o he CC geno ype was signi ican ly lowe in HCV pa ien s when compa ed o ma ched con ols; hus, sugges ing ha his a ian may be linked o a highe a e o na u al clea ance o HCV. This hypo hesis was soon s eng hened by Thomas e al., who epo ed ha he IL28B CC geno ype enhanced he spon aneous eso- lu ion a e o HCV in ec ion [15]. Thus, i became e iden ha HCV pa ien s who ha bo he CC geno ype a s12979860 a e mo e p one o espond o P/R ea men and o clea he i us han pa ien s who do no possess his gene ic polymo phism. The s anda d o ca e (SOC) ea men o HCV in ec ion is pegin e e on plus iba i in (P/R) he apy o 24–72 mon h du a ion, depending on HCV geno ype, p e- ea men i al load and i al kine ic. This ype o ea men may esul in sus ained i ological esponse (unde ec able HCV RNA a e 24 weeks o he end o he apy) in app oxima ely 40–45% o pa ien s in ec ed by geno ype 1 HCV (HCV1) he mos common geno ype in Eu ope. In he pas 2 yea s, new compounds, “di ec ac ing an i i als”(DAAs)ha ealso been de eloped such as HCV p o ease- and polyme ase inhibi o s, ha signi ican ly enhance SVR compa ed wi h SOC e en o 68–74% in ea men -naï e HCV1 indi iduals [16]. Since he e a e con lic ing da a on he ole o he egula o y Th2 cy okine in e leukin-10 (IL-10) in HCV in ec ion [17-20], he polymo phism o he IL10R gene has also been examined. In ou p elimina y s udies, he i s om an Eas -Cen al Eu opean coun y, we epo ed ha no only IL28B bu also IL10R −1087 (also known as IL10R-1082) gene ic a ian s may play a ole in HCV in ec ion [21,22]. In e leukin-10 (IL-10), p oduced by monocy es, mac ophages and T cells, inhibi s bo h he ac i a ion o CD4+ T-helpe cells and he unc ion o cy o oxic CD8 + T, NK and an igen-p esen ing cells, and also modula es hepa ic s ella e cell collagen syn hesis. IL-10 plays a egula o y ole in immune eac ion and supp esses in lamma o y esponses by inhibi ing he p oduc ion o p o-in lamma o y cy okines. I s e ec is media ed h ough he IL-10 ecep o (IL-10R), which is a he e odime ha consis s o bo h IL-10R1 equi ed o binding, and IL-10R2 equi ed o signaling. Inc eased IL-10 p oduc ion was epo ed in associa ion wi h he -1082G, -819C, -592GCC IL-10 p omo e (ATA) haplo ype [23,24]. I mac ophages sec e e la ge amoun o IL-10, i may dec ease ci cula ing TFN-αand IL-6 le els, hus, educing hei ha m ul e ec s. A highe equency o IL10 -1082 GG geno ype was ound in olde heal hy con ols han in pa ien s wi h myoca diac in a c ion; high IL-10 p oduc ion was p o ec i e o longe i y [25]. Pá e al. BMC Resea ch No es 2014, 7:12 Page 2 o 7 h p://www.biomedcen al.com/1756-0500/7/12 The p esen s udy ex ends ou p e ious in es iga ions on a la ge Eas -Cen al Eu opean coho in Hunga y. The allele equencies o IL28B and IL10R −1087 in HCV1 in ec ion we e compa ed wi h ha o heal hy con ols o he pu pose o examining he ela ionship be ween he polymo phisms and he esponse o PEG-IFN and iba i in (P/R) ea men . We ind ha in HCV1-in ec ed Eas -Cen al Eu opean pa ien s, bo h he IL28B CC and IL10R GG geno ypes a e associa ed wi h clea ance o HCV. Mo eo e , dis inc IL28B and IL10R allele combina ions appea o be p o ec i e agains ch onic HCV1 in ec ion and p edic o s o esponse o P/R he apy. Me hods E hics This wo k has been ca ied ou in acco dance wi h he guidelines o he 1975 Decla a ion o Helsinki and has been app o ed by bo h he Na ional E hics Commi ee (ETT TUKEB Budapes , No 490/010) and he Regional E hics Commi ee a he Uni e si y o Pécs. All he pa ien s ag eed o pa icipa e in he s udy, and p o ided w i en in o med consen . Pa ien s A o al o 748 HCV1 in ec ed pa ien s (365 men, 383 emale, anging in age om 18 o 82 yea s, mean 54 ± 10 yea s) we e en olled. All subjec s we e inpa ien s in 10 Hunga ian ci y hospi als o uni e si y clinics be ween Janua y 2007 and Decembe 2009. The diagnosis o ch onic hepa i is C was based on pe sis en ele a ion o se um alanine amino ans e ase (ALT) le els >6 mon hs in he p esence o an i-HCV by ELISA and HCV RNA by eal- ime e e se ansc ip ase- polyme ase chain eac ion (RT-PCR). Quan i a ion o plasma HCV RNA was ca ied ou using Cobas Amplico 2.0 (Ho mann-La Roche Inc.). HCV geno ype was de e - mined by a geno ype speci ic p obe based assay in he 5′ un ansla ed egion (LiPA; Innogen ics, Ghen , Belgium). (In Hunga y, >95% o HCV pa ien s ha e been in ec ed wi h HCV geno ype 1. In Eas e n Eu opean coun ies he p e alence o geno ype 1 anges be ween 57% and 99% [26]). In 70% o ou pa ien s pe cu aneous li e biopsy was pe o med. O he 748 HCV1 pa ien s, 420 we e ea ed wi h pegy- la ed in e e on al a 2a/2b (Pegasys, Ho mann-La Roche Inc./Pegin on, SP Labo N.V. Belgium) 135–180 μg/1.0- 1.5 μg/kg subcu aneously pe week, and iba i in (Copegus, Ho mann-La Roche Inc./Rebe ol, SP Labo N.V. Belgium) 1000–1200 mg o ally pe day o 24–72 weeks, hen ollowed up o 24 weeks. Subjec s who had unde ec able HCV RNA le els ollowing 24 weeks o he apy we e designa ed as sus ained i ological esponse (SVR), unde ec able se um HCV RNA a week 4 a e s a ing ea men as apid i ological esponse (RVR), unde ec able HCV RNA a week 12 a e s a ing he apy as ea ly i ological esponse (EVR). In ou pape , pa ien s who did no achie e SVR we e ega ded as “non- esponde s”(non-SVR). One hund ed and i e heal hy indi iduals (64 men, 41 emale, mean age 45 ± 3 yea s), who we e consecu i e olun a y blood dono s wi h no mal li e unc ion es s and nega i e o HBV, HCV and HIV se ology, se ed as con ols. Geno yping DNA was isola ed om pe iphe al blood by a s anda d desal ing me hod. The IL28B s12979860 SNP was de e mined using Cus om Taqman SNP Geno yping Assays (Applied Biosys ems, Li e Technologies, Fos e , CA, USA). The IL10R −1087 (also known as IL10R −1082) ( s1800896) p omo e egion was equi ed o he o ma ion o he EcoNI ecogni ion sequence 5′-AAGACAACAC TACTAAGGCT-3′; helowe p ime was5′-TAAA TATCCTCAAAGTTCC-3′. A e cu ing he ampli ied p oduc (584 bp) by EcoNI, homozygo e GG was iden i ied by wo agmen s 315 and 279 bp, while he e ozygo e AG had 310, 280, 252 and 28 bp agmen s and homozygo e AA had 310, 252 and 28 bp agmen s [27]. S a is ical analysis S a is ical analysis was ca ied ou using he SPSS 16.0 o Windows (SPSS Inc., Chicago, IL, USA). The allele and geno ype equencies we e compa ed wi h Pea son’s χ2 es . Bina y logis ic eg ession analysis was pe o med o obse e he indi idual con ibu ions o he polymo phisms. A p alue o <0.05 was conside ed signi ican . Resul s O 420 pegin e e on and iba i in (P/R) ea ed pa ien s 195 (46.4%) achie ed SVR. Pa ien s wi h RVR (20% o ea ed) achie ed a 86% SVR a e, while hose wi h EVR (55% o ea ed) showed a 65% SVR a e. As shown in Table 1, when compa ing he IL28B geno ype equencies be ween g oups o heal hy con ols and pa ien s, he CC geno ype occu ed wi h lowe equency in HCV pa ien s han in con ols, hus, sugges ing i s p o ec i e e ec agains ch onic hepa i i s C. On he o he hand, CT he e ozygosi y and T alleles we e mo e p e alen in pa ien s, and may, he e o e, con ey suscep ibili y o he disease. As shown in Table 2, subjec s ha ecei ed P/R he apy and who had he IL28B CC geno ype achie ed highe a es o SVR han subjec s who had CT geno ype (58.6% s 40.8%) (OR 2.057, 95% CI: 1.305-3.058, p = 0.002), o hose ca ying he T allele (41.8%, OR 1.976, 95% CI: 1.263-3.058, p = 0.002). As shown in Table 3, IL10R GG geno ype occu ed wi h lowe equency in pa ien s (31.8%) han in con ols Pá e al. BMC Resea ch No es 2014, 7:12 Page 3 o 7 h p://www.biomedcen al.com/1756-0500/7/12 (52.2%) (OR: 0.428, p < 0.001). The p e alence o IL10R AA allele was 68.15% in pa ien s and 47.8% in heal hy indi iduals (OR: 2.335, p < 0.001). Among P/R ea ed pa ien s wi h SVR, he IL10R GG geno ype occu ed wi h highe equency han he AA geno ype, (57/178, 32.0% s 31/178, 17.4%, (OR: 1.84, 95% CI 1.13-2.98, p = 0.013). The SVR a e in pa ien s wi h IL10R GG geno ype was 42.2% (59/125); in hose wi h GA 47.4% (88/178) and in AA pa ien s 39.7% (31/78). HCV pa ien s wi h Aallele (non-GG geno ype) achie ed SVR in 46.4% (119/256). Geno ype combina ions Heal hy con ols and HCV1 pa ien s The p e alence o he double wild ype combina ion o he IL28B CC plus IL10R GG was lowe (9.2%) in HCV pa ien s han in heal hy con ols (23.9%) (OR 0.322, p < 0.001). The IL28B CC plus IL10R A allele combina ion likewise occu ed wi h lowe equency in pa ien s (16.1%) when compa ed wi h con ols (27.2,%, OR 0.515, p = 0.009). Bo h combina ions sugges a p o ec i e e ec agains ch onic HCV in ec ion. The p e alence o IL28B T allele plus IL10R A allele combina ion was highe in pa ien s (52.4%) han in heal hy con ols (20.7%), hus, leading o a mo e han ou old isk inc ease o he disease (OR 4.231, p < 0.001) (Table 4). Compa ison o subjec s wi h sus ained i ologic esponse (SVR) e sus non- esponde (non-SVR) pa ien s The IL28B CC plus IL10R −1087 AA allele combina ion was ound wi h highe equency among pa ien s achie ing SVR (21.3%), han in non- esponde s (12.8%, OR 1.848, 95% CI 1.070-3.190, p = 0.026). In pa ien s wi h SVR, he p e alence o he IL28B CC plus IL10R GG combina ion was 12.4%, whe eas in non- esponde s i was 7.9% (OR 1.648, NS) (Table 4). Cumula i ely, he da a sugges ha SNPs in bo h IL28B and he IL-10 p omo e egion, and speci ic combina ions he eo , a e associa ed wi h p o ec ion agains HCV in ec ion and di e en ial esponsi eness o IFN he apy. Discussion P e ious s udies ha e shown ha IL28B SNP a he poly- mo phic si e s129798060 wi h he CC geno ype, and IL10 ecep o SNP a −1082 wi h he G allele a e associa ed wi h suscep ibili y o ch onic hepa i is C i us in ec ion and esponse o combined an i i al he apy [12-14,17,28,29]. In ou coho o Hunga ian pa ien s, we e alua ed hese SNPs in a o al o 748 pa ien s in ec ed wi h geno ype 1 HCV om 10 cen e s h oughou Hunga y. To ou knowledge, his is la ges s udy o i s ype on HCV-in ec ed subjec s om Eas -Cen al Eu ope. Ou esul s show ha polymo - phisms o bo h IL28B and IL10R genes play a ole in he ou come o ch onic hepa i is C in a new coho . We we e able o demons a e ha IL28B CC geno ype is a s ong p edic o o SVR in pa ien s ea ed wi h P/R, and p o ec s agains he disease. The cu en s udy on a la ge coho con i ms he esul s o ou ea lie s udies [21,22]. This gen- e ic a ian o IL28B may be associa ed wi h an ele a ed p oduc ion o IL-28B (IFNλ-3) bu his has no been ound in all s udies [12]. Table 2 Sus ained i ological esponse (SVR) a e s a i ied by IL28B geno ypes in Hunga ian HCV pa ien s T ea ed SVR IL28B geno ype n Numbe o pa ien s Pe cen age CC 116 68 58.6% CT 228 93 40.8% TT 76 34 44. 7% T allele (non-CC) 304 127 41.8% Table 1 P e alence o IL28B geno ypes in Hunga ian HCV pa ien s and heal hy con ols IL28B geno ype HCV1 (n = 748) Con ols (n = 105) OR CC 195 (26.1%) 54 (51.4%) 0.333 (0.22 - 0.505) P < 0.001 CT 411 (54.9%) 39 (37.1%) 2.064 (1.354 - 3.145) p = 0.001 C allele 606 (81.02%) 93 (88.6%) 0.551 (0.294-1.032) p = 0.059 TT 142 (19.0%) 12 (11.4%) 1.816 (0.969 –3.404) p = 0.059 T allele (non-CC) 553 (73.9%) 51 (48.6%) 3.003 (1.981 –4.552) P < 0.001 Table 3 P e alence o IL10R −1087 geno ypes in HCV pa ien s and heal hy con ols IL10R −1087 Geno ype HCV1 (n = 672) Con ols (n = 92) OR GG 214 (31.8) 48 (52.2%) 0.428 (0.276 - 0.665) p < 0.001 GA 333 (49.6%) 32 (34.8%) 1.842 (1.169 –2.903) p = 0.008 G allele 547 (81.4%) 80 (87.0%) 0.656 (0.347-1.241) p = 0.192 AA 125 (18.6%) 12 (13.0%) 1.523 (0.806 –2.881) p = 0.192 A allele (non-GG) 458 (68.15%) 44 (47.8%) 2.335 (1.504 –3.625) p < 0.001 Pá e al. BMC Resea ch No es 2014, 7:12 Page 4 o 7 h p://www.biomedcen al.com/1756-0500/7/12 Ou esul s a e in acco dance wi h he p e ious indings [12-14]. The equency o IL28B CC in HCV1 pa ien s was lowe han in heal hy con ols, his ac may mean ha indi iduals wi h IL28B CC geno ype a e p o ec ed agains ch onic hepa i is C. Pa ien s wi h IL28 CC geno- ype may ha e a high likelihood o SVR and possibly need only he s anda d o ca e P/R ea men , pa icula ly i hey ha e o he posi i e p edic o s: low i al load, young age, emale, sho du a ion o in ec ion, absence o ci ho- sis and low BMI. Unde such ci cums ances, an IL28B CC will no only p edic SVR bu also mo i a e bo h he pa- ien and he doc o , se ing o enhance adhe ence as well Howe e , i mus be also emphasised ha he s onges posi i e p edic o o SVR is no he IL28B CC, bu he RVR [30,31] as i was ound in ou cases oo, when 86% o pa ien s wi h RVR elimina ed hei HCV1 in ec ions. The ques ion a ises whe he HCV1 pa ien s ca ying he IL28B TT geno ype always equi e a mo e complex (e.g. iple) he apy wi h di ec ac ing an i i als (DAAs)? I is concei able ha pa ien s wi h he TT homozygosi y, who also ha e o he nega i e p edic o s (such as p e i- ous non- esponse, high i al load, ci hosis, obesi y, insulin esis ance), will be candida es o ea men wi h DAAs. Recen ly, i was ound ha bo h he iple he apy wi h DAAs, (e.g. p o ease inhibi o s plus P/R) and he IFN- ee an i-HCV ea men may o e come he e ec o he un a ou able TT IL28B polymo phism. Thus, in he u u e, he ele ance o IL28B geno yping may become limi ed in he indi idualized ea men o HCV1 in ec ion [32-35]. Howe e , B onowicki e al. epo ed ha 100% o ea men -nai e HCV1 pa ien s wi h IL28B CC achie ed SVR, e en wi h 12 weeks o a p o ease inhibi o elap e i and P/R combina ion he apy [36]. The e o e, IL28B geno ypingmaycon inue obeo impo ancein he sho ening o ea men du a ion. Thus, he indings o IL28B polymo phisms will allow one o p edic wi h be e accu acy which pa ien s a e likely o espond o he s anda d o ca e P/R he apy. Howe e , i mus be s essed ha he e ec o he a ou able a ian is no absolu e: no all ca ie s o he “good esponse geno ype”clea he i us; no do all pa ien s lacking i ail o bene i om he P/R ea men [30,31]. I was no ed p e iously ha IL10 -1082 GG geno ype was equen in HCV, when mononuclea cells p oduced wo- old g ea e quan i ies o IL-10 compa ed wi h pa ien s wi h IL10 AA geno ype [25,26]. Vigidal e al. epo ed, ha IL10 gene p omo e −1082 GG geno ype occu ed mo e equen ly in HCV pa ien s han in con ols and ha he GG homozygosi y was associa ed wi h poo esponse o IFN. This geno ype was iden i ied in 34.6% o 80 HCV pa ien s compa ed wi h 6/33 (16.7%) o con ols (p = 0.048). Howe e , his s udy ocused on limi ed numbe s o bo h pa ien s and con ol subjec s [28]. Me a-analysis o Zhang e al., also showed ha he IL10 -1082 GG geno ype was associa ed wi h suscep ibili y o ch onic HCV in ec ion [29]. Ye , A zal e al. epo ed ha he equency o −1082 GA geno ype was highe in heal hy indi iduals han in HCV pa ien s, sugges ing he p o ec i e e ec o his a ian [19]. Lio e al. no ed ha he IL10 -1082 GG was associa ed wi h spon aneous eco e y om HCV in ec ion [18], while acco ding o Gao e al. -1082 AA con e ed an inc eased isk o pe sis en HCV in ec ion [37]. Knapp e al. ound ha HCV pa ien s wi h SVR showed highe equency o IL10 -1082 GG geno ype han non- esponde s (26.9% s 14.0% OR 2.28, 95% CI 1.21-4.32, p = 0.05) [17]. In his s udy we in es iga ed he IL10R p omo e gene polymo phisms a posi ion −1087 ela i e o ansc ip ion s a si e and p o ed ha he −1087 GG occu s a a lowe equency in HCV pa ien s as compa ed wi h con ols; hus, his a ian may be p o ec i e agains he disease. A Table 4 IL28B and IL10R −1087 geno ype combina ions in he di e en s udy g oups IL28B geno ype CC CC T allele T allele IL10R geno ype HCV n = 664 GG 61 (9.2%) OR:0.322 (0.186-0.556) 148 (22.3%) 0.728 (0.446-1.188) A allele 107 (16.1%) p < 0.001 348 (52.4%) p = 0.202 Con ols n = 92 GG 22 (23.9%) OR:0.515 (0.311-0.852) 26 (28.3%) OR:4.231 (2.497-7.169) A allele 25 (27.2%) p = 0.009 19 (20.7%) p < 0.001 SVR n = 178 GG 22 (12.4%) OR:1.648 (0.837-3.247) 37 (20.8%) OR:0.803 (0.496-1.301) A allele 38 (21.3%) p = 0.146 81 (45.6%) p = 0.372 Non- esponde s n = 203 GG 16 (7.9%) OR: 1.848 (1.070-3.190) 50 (24.6%) OR:0.692 (0.462-1.037) A allele 26 (12.8%) p = 0.026 (54.7%)111 p = 0.074 P e alence o IL28B CC plus IL10R GG in HCV pa ien s s. con ols OR: 0.322. IL28B CC plus IL10R A allele OR: 0.515. IL28B T allele plus IL10R A allele OR: 4.231. P e alence o IL28B CC plus IL10R A allele in p s wi h SVR s. non- esponde s OR:1.848. Pá e al. BMC Resea ch No es 2014, 7:12 Page 5 o 7 h p://www.biomedcen al.com/1756-0500/7/12 he same ime, he equency o GA geno ype and A allele was highe in he pa ien s’g oup - as a po en ial gene ic ma ke o suscep ibili y o he HCV1 in ec ion. In pa ien s who achie ed SVR, he IL10R GG geno ype occu ed wi h highe (32.%) equency han AA (17.4%), and he IL28B CC plus IL10R −1087 A allele combina ion was also ound wi h highe a e among pa ien s achie ing SVR (21.3%), han in non- esponde s (12.8%). Ou indings on he ole o IL10R gene polymo phism in HCV1 in ec ion a e a he con lic ing, and may con adic bo h some o he p e iously published da a [28,29] as well as he known biological e ec o IL-10. The easons o hese disc epancies a e no clea . The s udy popula ions may di e wi h ega d o ac o s ha in luence SVR: i al load, obesi y, ib osis, e hnici y and sex. Addi ional s udies a e equi ed o de ine he oles o hese ac o s in connec ion wi h IL10 polymo phisms in ch onic hepa i is C. Conclusions We demons a ed ha no only IL28B CC bu also IL10R GG geno ype and ce ain IL28B plus IL10R allele combina ions may be p o ec i e gene ic a ian s in Hunga ian pa ien s wi h ch onic HCV1 in ec ion. By p edic ing which pe sons a e mos likely o espond o IFN-based he apy, he examina ion o hese polymo phisms may help o manage an indi idualized app oach o ea HCV pa ien s. Geno yping bo h IL28B and IL10R may o e a baseline sc eening es , ha , howe e , should be combined wi h o he well-known p e- and on- ea men p edic o s o he ou come o he disease and choosing he mos app op ia e ype o an i-HCV he apy. In he e a o DAAs o he ea men o HCV in ec ion, he p ognos- ic ole o hese gene ic es s may be o less impo ance. Ye , in ce ain ci cums ances, he IL28B geno yping can be use ul; e.g. in he sho ening o ea men du a ion in P/R plus DAA- ea ed HCV pa ien s. I is e iden , howe e , ha as an on- ea men p edic o , apid i o- logical esponse emains he s onges p ognos ic ac o , e en ac oss IL28B geno ypes [38]. Abb e ia ions ALT: Alanine amino ans e ase; DDA: Di ec ac ing an i i al; GWAS: Genome- wide associa ion s udy; HCV: Hepa i is C i us; IFN: In e e on; IL: In e leukin; NK: Na u al kille ; PEG-IFN: Pegyla ed in e e on; P/R: Pegyla ed in e e on plus iba i in; RBV: Riba i in; RVR: Rapid i ological esponse; SNP: Single nucleo id polymo phism; SVR: Sus ained i ological esponse; Th: T helpe ; TNF: Tumo nec osis ac o . Compe ing in e es s The au ho s decla e ha hey ha e no compe ing in e es s. Au ho s’con ibu ions AP, GP, IT, FS, BH ini ia ed and pa icipa ed in he design o he s udy, PK ca ied ou he geno yping s udies; DV, EF, MP, GL, JF, MV, JG, JS, ZN ZP, AT, AH, ZS, ÁV con ibu ed o acquisi ion o pa ien s and hei da a; AP, GP, LS d a ed he manusc ip ; BM e ised he pape c i ically o in ellec ual con en . All au ho s ead and app o ed he inal manusc ip . Acknowledgemen s Alajos Pá has ecei ed esea ch unding om he Hunga ian Na ional Resea ch Fund (OTKA K81454) and om he Uni ed Eu opean Gas oen e ology Fede a ion (UEGF) (2011 Top Abs ac P ize). The au ho s hank Noemi Polga and Laszlo Po a o pe o ming s a is ical analysis. 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J Hepa ol 2011, 55:69–75. doi:10.1186/1756-0500-7-12 Ci e his a icle as: Pá e al.:IL28B and IL10R −1087 polymo phisms a e p o ec i e o ch onic geno ype 1 HCV in ec ion and p edic o s o esponse o in e e on-based he apy in an Eas -Cen al Eu opean coho . BMC Resea ch No es 2014 7:12. Submi you nex manusc ip o BioMed Cen al and ake ull ad an age o : • Con enien online submission • Tho ough pee e iew • No space cons ain s o colo figu e cha ges • Immedia e publica ion on accep ance • Inclusion in PubMed, CAS, Scopus and Google Schola • Resea ch which is eely a ailable o edis ibu ion Submi you manusc ip a www.biomedcen al.com/submi Pá e al. BMC Resea ch No es 2014, 7:12 Page 7 o 7 h p://www.biomedcen al.com/1756-0500/7/12