j ourna l homepage: www.e lsev ie r .com/ locate /gene
Association of PARP-1, NF-κB, NF-κBIA and IL-6, IL-1β and TNF-α withGraves Disease and Graves Ophthalmopathy
Mutlu Niyazoglu a, Onur Baykara b,⁎, Arzuhan Koc b, Pinar Aydoğdu b, Ilhan Onaran b, Fatma Dilek Dellal c,Ertuğrul Tasan d, Gönül Kanigur Sultuybek b
a Istanbul Training and Research Hospital, Endocrinology Department, Istanbul, Turkeyb Istanbul University, Cerrahpasa Medical Faculty, Department of Medical Biology and Genetics, Istanbul, Turkeyc Ankara Training and Research Hospital, Endocrinology Department, Ankara, Turkeyd Bezmialem Vakif University, Faculty of Medicine, Department of Internal Medicine, Istanbul, Turkey
Background:Graves Disease (GD) is an autoimmune disorder affected by an interaction of multiple genes such asNuclear Factor-κB (NF-κB), Nuclear Factor-κB Inhibitor (NF-κBIA), Poly (ADP-ribose) polymerase-1 (PARP-1)and cytokines like Interleukin-1β (IL-1β), Interleukin-6 (IL-6) and Tumor Necrosis Factor-α (TNF-α) andmostlyaccompanied by an ocular disorder, Graves Ophthalmopathy (GO). We hypothesize that there is a relationshipbetween GD, GO, polymorphisms of inflammatory related genes and their association with cytokines, whichmay play important roles in autoimmune and inflammatory processes.Subjects and methods: To confirm our hypothesis, we studied the polymorphisms and cytokine levels of120 patients with GD and GO using PCR-RFLP and ELISA methods, respectively.Results:We found that patientswith GG genotype and carriers of G allele of PARP-1G1672Apolymorphism are atrisk in the group having GD (p= 0.0007)while having GA genotypemay be protective against the disease. PARP-1C410T polymorphismwas found to be associated with GO by increasing the risk by 1.7 times (p= 0.004). Another
risk factor for development of GO was the polymorphism of del/ins of NFkB1 gene (p = 0.032) that increases therisk by 39%. Levels of cytokineswere also elevated in patients with GD, but no associationwas found between levelsof cytokines and the development of GO as there was no change in levels of cytokines.Conclusions: We suggest that, PARP-1 and NFkB1 gene polymorphisms may be risk factors for developing GravesDisease and Ophthalmopathy.
Graves' Disease (GD) is an organ specific autoimmune thyroid disor-der characterized by diffuse goiter, hyperthyroidism, dermopathy andan ocular disorder, Graves Ophthalmopathy (GO). Even though goiterand ophthalmopathy may not be present in every case, the presenceof ophthalmopathy is a clear symptom that helps diagnosis. Up to 70%of all GD patients have GO [1]. Stimulation of the thyroid gland withthe immunoglobulins present in the blood by binding to thyrotropin
pasa Tip Fakultesi, Tibbi BiyolojiTurkey.oglu), [email protected] (P. Aydoğdu),(F.D. Dellal),G.K. Sultuybek).
., Association of PARP-1, NF-κi.org/10.1016/j.gene.2014.06.0
receptors results in excessive secretion of thyroid hormones. GD is themost common cause of hyperthyroidism and causes significant weightloss, osteoporosis and sarcopenia and can also lead to cardiovascularcollapse and atrial fibrillation [2–4]. The incidence of GD is approxi-mately 5 per 1000/year and has a female to male ratio of 7:1 [5]. It'sbeen found as high as 79% for the contribution of inherited factors inGraves development [6,7] but it's not clear whether genetic factorshave a role in etiology or not. As GD is an autoimmune disorder, it isaffected by a co-operation of amixture of genes, cytokines and enzymessuch as Nuclear Factor-κB (NF-κB), Nuclear Factor-κB Inhibitor(NF-κBIA), Poly (ADP-ribose) polymerase-1 (PARP-1), Interleukin-1β(IL-1β), Interleukin-6 (IL-6) and Tumor Necrosis Factor-α (TNF-α)[8–29]. PARP-1 gene might be one of the candidates with two reasons.It's been shown that, inhibition of the gene or the enzyme provides aprotection against the systematic or tissue inflammation [8,9] and it'sbeen suggested that PARP-1 has a regulatory role in initiating the in-flammatory response by regulating the transcription-associated genes.There is supporting evidence that PARP-1 regulates the synthesis ofinflammatorymediators, which has a key role in pathophysiology in tis-sue destruction with inflammation, and also the transcription of NF-κB
B, NF-κBIA and IL-6, IL-1β and TNF-αwith Graves Disease and Graves38
in response to cytokines [10]. PARP-1 is a nuclear multifunctionalenzyme and a chromatin associated protein, which has a 113-kDaweight and coded by 1q41-q42 chromosome domains and PARP-1gene has 23 exons [11,12]. It has been recently implicated in the initialinflammatory response by modulating expression of inflammation re-lated genes like Interleukin gene family and it also plays an importantrole in response to oxidative stress, DNA repair, genomic stability andtranscription [13–15]. PARP-1 activity also promotes NF-κB driven tran-scription of proinflammatory molecules [15]. PARP-1 increases the se-cretion of cytokines that helps the production of autoantibodies fromB-lymphocytes, which is thought to play an important role in GD butthe role of the enzyme in autoimmunity and autoinflammatory processis not clear. It's been shown that serum IL-6 levels are higher in patientswith GD + hyperthyroiditis [16–19] and some studies have shownelevations in serum levels of TNF-α in patients with GD [20,21]. PARP-1concentration is strongly associated with the regulation of promoter ac-tivity of the gene. It's been shown that some polymorphisms in promoterregion have an effect on PARP-1 activity. Among these polymorphisms,PARP-1 C410T and G1672A single nucleotide polymorphisms (SNPs)have been investigated in some autoimmune and inflammatory diseasesand it's been suggested that these polymorphismsmay contribute to dis-ease susceptibility [15,22,23]. On the other hand, no study investigatingthe relationship between GD and the aforementioned polymorphismshas been published.
NF-κB is a ubiquitous transcription factor first discovered by Sen andBaltimore in 1986 that has a key role in regulating the immune responseto infection, cell survival and proliferation, differentiation and immunity[24]. Active NF-κB takes role in controlling genes encoding pro andantiapoptotic proteins, growth factors, cytokines, etc. In mammaliancells, there is a family of NF-κB/Rel consisting of 5 protein members,which are RelA (p65), RelB, c-Rel, p50/p105 (NF-κB1) and p52/p100(NF-κB2). NF-κB is activatedwhen phosphorylated and it is translocatedto the nucleus to start the expression in target genes. Incorrect regula-tion of NF-κB has been linked to cancer, inflammatory and autoimmunediseases, septic shock, viral infection, and improper immune response.Therefore, NF-κB related genes are important candidates for susceptibil-ity to autoimmune disorders [25–27].
NF-κBIA (Iκ-Bα, nuclear factor of kappa light polypeptide gene en-hancer in B-cell inhibitor, alpha) is a gene located on 14q13, which in-hibits the NF-κB transcription by masking the nuclear localizationsignals (NLS) of NF-κB proteins and keeping them inactive in the cyto-plasm. It also prevents NF-κB to bind to DNA so NF-κB cannot functionproperly as a transcription factor [28,29].
Our aimwas to study the relationship between NF-κB1 [(−94 ins/delATTG) (rs28362491)], NF-κBIA (rs696) and PARP1 [C410T (rs2793378)and G1672A (rs7527192)] gene polymorphisms and cytokine levels ofTNF-α, IL-1β and IL-6 in patients with Graves Disease with or withoutophthalmopathy.
Fig. 1. Gel figure of PARP1 C410T polymorphism. Sample no. 1 shows TT genotype, nos. 2and 3 showCCgenotype and nos. 4 and 5 showCTgenotype. 45 bp is barely visible but and27 bp cannot be seen in the figure.
2. Materials and methods
A group of 120 patients with a confirmed diagnosis of BasedowGraves Disease, being followed in Istanbul University, CerrahpasaMedical Faculty, Department of Endocrinology, aged between 18 and65, were enrolled in the study and were divided into 2 groups ofpatientswith (n=45) andwithout ophthalmopathy (n=75). The con-trol group was consisted of randomly selected 150 healthy individualsshowing no symptoms of hyperthyroiditis. Control subjects were fre-quency matched to the cases by ethnicity and age. Demographic distri-bution of individuals is given in Table 1. An explanatory statementconcerning the study and the procedures was made to all patients.The statement was a regulated ethics statement prepared by The EthicsCommittee of Istanbul University CerrahpasaMedical Faculty. The com-mittee approved the study and written informed consent was obtainedfrom all patients.
Please cite this article as: Niyazoglu, M., et al., Association of PARP-1, NF-κOphthalmopathy, Gene (2014), http://dx.doi.org/10.1016/j.gene.2014.06.0
DNA was isolated with high salt DNA extraction method from pe-ripheral blood leukocytes and all the samples were isolated in −80 °Cuntil used. The polymorphisms of PARP-1, NF-κB1 and NF-κBIA geneswere investigated both in patient and healthy groups by PCR-RFLPmethod on blood samples obtained for routine clinical work-up. 297and 187 base pair PCR fragment of the PARP-1 C410T and G1672A pro-moter region was amplified in a 25 μl reaction volume containing100 ng genomic DNA, 200 pm of each dNTP, 10 mM Tris–HCl, pH 8.3,50 mM KCl, 1 U Taq Polymerase (Sigma, St. Louis, MO, USA) and2 mM MgCl2 (Fermentas, Lithuania). PCR conditions were included asfollows: a denaturing step of 95 °C (2 min), then 30 cycles of 95 °C(30 s), 60 °C (30 s), 72 °C (1 min), and final incubation at 72 °C(5 min). The products were digested with 5 U of HpyF3I (DdeI)(Fermentas, Lithuania) and Bsh1236I (Fermentas, Lithuania) at 37 °Cfor overnight andwere run on an ethidium bromide-stained 3% agarosegel for 45 min at 90 V and were directly detected under UV light. 285and 424 base pair PCR fragments of the NF-κB1 and NF-κBIA geneswere amplified with the same reaction mix. PCR conditions wereincluded as follows: a denaturing step of 95 °C (1 min), then 35 cyclesof 95 °C (30 s), 61 °C (30 s), 72 °C (1 min) and final incubation at72 °C (5 min). The products were digested with 5 U of PflMI (Van91I)and HaeIII (BsuRI) (Fermentas, Lithuania) at 37 °C for overnight andwere run on an ethidium bromide-stained 3% agarose gel for 45 minat 90 V and were directly detected under UV light (See Figs. 1- 4). Thelist of PCR primers are given in Table 2 and the products of enzyme di-gestion of the genes are given in Table 3.
Following the PCR-RFLP, cytokine levels of TNF-α, IL-1β and IL-6were measured by sandwich ELISA method using AssayPro HumanTNF-α, IL-1β, IL-6 ELISA kit (St. Charles, MO, USA) which is coatedwith antibodies specific to human leptine and adiponectine antibodiesaccording to manufacturer's protocols.
2.1. Statistical evaluation
All statistical analysis was performed using licensed SPSS 12.0 forWindows and GraphPad Prism 5. Parametric relations were evaluatedusing Spearman correlation analysis. Fisher's test and χ2 tests wereused for calculating distribution and frequencies of the groups. In com-parison of the quantitative data, Student t test was used for analyzingthe parameters between groups, which have a normal distribution,and Mann Whitney U test was used for analyzing the parameters be-tween groups, which don't have a normal distribution. Significancevalues are reported without Bonferroni correction.
B, NF-κBIA and IL-6, IL-1β and TNF-αwith Graves Disease and Graves38
Fig. 2.Gel figure of PARP1 G1672A polymorphism. Sample nos. 1 and 4 showGA genotype, nos. 2 and 3 showGGgenotype and no. 5 showAA genotype. 33 bp cannot be seen in thefigure.
3M. Niyazoglu et al. / Gene xxx (2014) xxx–xxx
A two-sided p value ≤0.05 was considered statistically significant.A post-hoc power analysis was also performed by using PS Power andSample Size Calculations Version 3.0.43.
3. Results
According to our results, patients with GG genotype of PARP-1G1672A polymorphism have a 2.4 times greater risk of having GravesDisease (p = 0.0007) whereas having GA or AA genotype has no effecton the disease. When allele frequencies are compared, having the G al-lele increases the risk factor for Graves Disease by 1.5 fold (p= 0.0247).On the contrary, no genotype of PARP-1 C410T polymorphism, norNF-κB1 and NF-κBIA has any effect on GD (p N 0.05) (Table 4). On theother hand, our power calculation for comparison of the allele frequen-cies indicated that at a significance level of 0.05 andwith a two-sided al-ternative hypothesis, our GD samples with n = 120 cases and n = 150controls had a range changing between 23% and 28% power to detect asignificant association with an assumed OR of 1.4 between tested poly-morphisms and the phenotype of GD.
When we studied the relationship between the polymorphismsand ophthalmopathy, we found a significant relationship between thePARP-1 C410T polymorphism and GD. We saw that having C allelemay be a risk factor for developing ophthalmopathy by increasing therisk by 1.8 times (p = 0.04).
Fig. 3. Gel figure of NF-κB1 polymorphism. Sample nos. 2 and 6 show del/del genotype,nos. 4, 5, 7, 8 and 10 show del/ins genotype and no. 9 show ins/ins genotype. 45 bp cannotbe seen in the figure.
Please cite this article as: Niyazoglu, M., et al., Association of PARP-1, NF-κOphthalmopathy, Gene (2014), http://dx.doi.org/10.1016/j.gene.2014.06.0
Also, having the polymorphism of del/ins of NF-κB1 genemay be re-lated to the development of ophthalmopathy (p = 0.032) as it may in-crease the risk of developing ophthalmopathy in patients with GD by39%.We didn't find any other significant relationship between the poly-morphisms of the other studied genes and ophthalmopathy (Table 5).
We also studied the relationship between the cytokine levels of TNF-α, IL-1β, IL-6 with the aforementioned genes and we found significantrelationships between the levels of cytokines and GD. The levels ofalmost all cytokines were elevated in patients with Graves Diseaseexcept levels of TNF-α had not changed between the patient and thecontrol groups who have the AA genotype of NF-κBIA gene (p =0.357). All other groups had significant elevations in levels of cytokines(p b 0.05) (Table 6).
In addition to these findings, we studied the relationship betweenthe levels of cytokines and polymorphisms in patients with or withoutophthalmopathy and we didn't find any significant relationship be-tween the groups (Table 7).
Finally, we studied the combined gene analysis of polymorphisms(analysis made with Graph Pad Prism 5) including insertions, deletionsand homozygous wild, homozygous mutant and heterozygous geno-types of NF-κB1-PARP-1 (G1672A polymorphism) and NF-κB1–NF-κBIA and we didn't find any significant relationship between thegenes (Tables 8 and 9).
Fig. 4. Gel figure of NF-κB1A polymorphism. Sample nos. 3 and 9 show AA genotype, nos.2, 4, 7 and 8 show GG genotype and nos. 5, 6 and 10 show GA genotype.
B, NF-κBIA and IL-6, IL-1β and TNF-αwith Graves Disease and Graves38
There are studies showing the relationship between various genepolymorphisms including single nucleotide polymorphisms (SNP) andsusceptibility to disease including GD. HLA, CTLA-4, CD40 and PTPN-22 are some genes, which may be associated with GD by influencing theimmune response [30,31]. Zhu et al. have suggested SNPs on 5q.31–33,which host the cytokine genes (IL-3, IL-4, IL-5, IL-9 and IL-13), may berisk factors for GD and GO [32].
We can assume that GO is a disease, which is developed and affectednot only by polymorphisms of a single gene but also complex interac-tions between different genes. Liu et al. and Anvari et al. have shownthe relationships between polymorphisms of IL-1β gene and IL-12,TNF-α, IFN-γ, IL-2 and IL-6 genes and Graves Ophthalmopathy butthese findings seem far away from explaining the pathogenesis andgenetics of the disease [33,34].
Studies in recent years conducted on PARP-1 deleted knockoutmiceand inflammatory related diseases have shown that PARP-1 inhibitorsprevent the progression or development of the disease [35]. It's beensuggested that the protective effects of PARP-1 inhibitors is dependenton the inhibition of inflammatory response [36]. Some studies haveshown that inhibition of PARP-1 represses production of some proin-flammatory cytotoxic cytokines such as TNF-α, IFN-γ, IL-6, IL-1β andIL-12 and elevates the level of IL-10, which is an anti-inflammatorycytokine [37]. Studies show that PARP-1 plays an important role ininflammatory response by regulating the expression of inflammationrelated genes by interacting with transcription factors [13]. It's alsobeen shown that, PARP-1 regulates the synthesis of inflammatorymedi-ators, which have a key role in tissue destruction [38].
Table 3Products of enzyme digestion.
PARP-1
C410T[HpyF3I (DdeI)]
G1672A[Bsh1236I]
CC 144 + 108 + 45 bp GG 154 + 33 bpCT 144 + 117 + 108 + 45 + 27 bp AG 187 + 154 + 33 bpTT 117 + 108 + 45 + 27 bp AA 187 bp
Please cite this article as: Niyazoglu, M., et al., Association of PARP-1, NF-κOphthalmopathy, Gene (2014), http://dx.doi.org/10.1016/j.gene.2014.06.0
Recent studies have showndifferent polymorphisms in PARP-1 genelocated on 1q41–43 [39]. There is an increasing number of publications,which show the relationship between the SNPs and pathology of thediseases including autoimmune and inflammatory diseases [40,41]. It'sbeen suggested that SNPs of the promoter region (C410T, C1362T,G1672A) polymorphisms, may affect the transcription of the gene [22].
Some researchers have studied the relationship between the PARP-1gene polymorphisms and different diseases. Infante et al. have shownthat in patients with Parkinson's Disease heterozygosity of C410T poly-morphismdecreases the risk of having the disease and allele T has a pro-tective effect on the disease, whereas no association has been found inpatient and control groups in G1672A polymorphism [15].
Pascual et al. have shown increased susceptibility to rheumatoidarthritis in cases of having C/T genotype in C410T polymorphism andC/C genotype in C1362T polymorphism [22].
We can assume that there is a relationship between GD, ophthal-mopathy, severity of the disease and the polymorphisms, which havebeen suggested to be associated with autoimmune and inflammatoryprocesses. Considering inhibition of PARP-1 protein suppressing inflam-matory response, it might be expected that the normal form of thePARP1 enzyme can be found more frequently in patients with respectto the variants causing alterations in enzyme activity and expressionlevels or the severity of the disease might be stronger in patients
NF-κB1 NF-κBIA
−94ATTG[PflMI (Van91I)]
[HaeIII (BsuRI)]
ins/ins 285 bp AA 424 bpdel/ins 285 + 240 + 45 bp GA 424 + 306 + 118 bpdel/del 240 + 45 bp GG 306 + 118 bp
B, NF-κBIA and IL-6, IL-1β and TNF-αwith Graves Disease and Graves38
carrying the variants. Assuming that PARP-1 enzyme is an effectednuclear protein that is playing an important role in expression of inflam-matory related genes and autoimmunity [10, 13], we can also expectdifferences in cytokine levels, which may cause autoimmunity andinflammatory process with respect to genotype groups. To our knowl-edge, this is the first study investigating the relationship between thementioned polymorphisms and Graves' Disease.
We found that, by means of G1672A polymorphism, patients withGG genotype and carriers of G allele are in a risk group of having GravesDisease. Patients with GG genotype and G allele have an increased riskof having the disease by 2.4 and 1.5 fold, respectively which can beinterpreted as having GA genotype may have a protective effect on the
Please cite this article as: Niyazoglu, M., et al., Association of PARP-1, NF-κOphthalmopathy, Gene (2014), http://dx.doi.org/10.1016/j.gene.2014.06.0
disease (Table 4). Molecular heterosis is a situation, which might befound in approximately 50% of all gene associations [42], and it maybe the reason why patients with GG genotype may have susceptibilityto the disease while heterozygosity may be protective. We did notfind a significant relationship or difference in patient and control groupsin C410T polymorphism. Due to technical problems, we didn't have thechance of studying PARP-1 C1362T polymorphism. Besides, it should bekept inmind that the small sample size, whichmay have influenced thestatistical power of our analysesmay be considered as our limitations inthe study. Although a study with low statistical power has a reducedchance of detecting a true effect, case–control studies with the smallsample size are still widely consulted today and they can be used to as-sess previously identified candidate regions under selection and moreprecisely determine targets of selection.
Nevertheless, taken the small sample size and limited ethnicity ofour study, we suggest that additional genetic and functional studiesare required to confirm our results.
We analyzed our patient groups by separating them into two groups,those with and without ophthalmopathy and investigated the effect ofpolymorphisms on these groups. We found that C410T polymorphismis associated with ophthalmopathy where having C allele may be arisk factor for developing ophthalmopathy by increasing the risk 1.8times. In addition to this finding, the polymorphism of del/ins ofNFkB1 gene may be related to the development of ophthalmopathy(0.032) as an increase in risk of developing ophthalmopathy in GD pa-tients by 39%was found and, we can conclude that having ins/ins geno-type may have a protective effect on the disease by 2.5 fold (Table 5).
Therefore, our data on PARP1 and NF-κB polymorphisms may haveadded new pieces into the puzzle of underlying mechanisms of GD,however our suggestion requires replication by other case control stud-ies before definitely establishing such a link.
PARP-1 plays an important role in inflammatory response as a co-activator in activation of NF-κB factor [43]. Activated NF-κB regulatesthe expression of TNF-α, IFN-γ, IL-6, IL-1β and some other cytokines[43,44]. What we expected from this study was measuring high TNF-α, IL-6, IL-1β serum cytokine levels in genotypes which are known toincrease gene activity due to polymorphisms. Several studies haveshown the elevated levels of cytokines in studies related with thyroiddisorders and PARP-1 [45–50]. As we expected, almost all cytokinelevels were elevated in patient groups except TNF-α in patients withAA genotype of NF-κBIA gene (Table 6). Patient groups with or withoutophthalmopathywere also comparedwith polymorphisms and levels ofcytokines but we did find not any significant relationship (Table 7)which may have been concluded as PARP-1–NF-κB1 association playsan important role in disease progression by activating cytokines but
ophthalmopathy has no effect on cytokine levels and there is no associ-ation between cytokine levels and developing ophthalmopathy, but asgenetic factors considered, having a C allele of PARP-1 C410T polymor-phism and polymorphism of del/ins of NF-κB1 gene may increase therisk of developing ophthalmopathy (Table 5). In literature, there areconflicting studies about the elevation of cytokine levels in patientswith GO in which Zsuszanna et al. have found no difference in interleu-kin levels between smokers and non-smokers, euthyroid vs. hyperthy-roid patients or in patients with active versus inactive GO patients[51] but three other studies have shown an association between theelevation in levels of cytokines and GO [52–54]. As it is a well-knownfact that some variants and/or genes working together increase therisk; we analyzed the relationship between the disease and genes byHaplotype analysis. Neither PARP-1 G1672A–NF-κB1 nor NF-κB1–NF-κBIA combined gene analysis showed statistically different results.However, we cannot exclude the possibility that these results mayhave been influenced by the size of our study population.
Please cite this article as: Niyazoglu, M., et al., Association of PARP-1, NF-κOphthalmopathy, Gene (2014), http://dx.doi.org/10.1016/j.gene.2014.06.0
5. Conclusion
As a result, polymorphism of PARP-1 G1672A may contribute todevelopment of GD whereas polymorphisms of PARP-1 G1672A andNF-κB1 (del/ins) may contribute to development of GO. Elevatedserum levels of cytokines may be the supportive evidence of GD but itmay be difficult to determine the development of GO by measuringcytokines. Further studies have to be made to understand the completeinteraction between the genes and cytokines for enlightening the path-ogenesis of GD.
Conflict of interest
The authors declare no conflict of interest.
Acknowledgment
The present work has been supported by the Research Fund ofIstanbul University (project number: 15351).
References
Burch, H.B., Bahn, R., 2006]. Graves ophthalmopathy. In: DeGroot, L.J., Jameson, L.J. (Eds.),Endocrinology, 2, pp. 2029–2042.
Scerrino, G., Morfino, G., Paladino, N.C., Di Paola, V., Amodio, E., Gulotta, G., Bonventre, S.,2012]. Does thyroid surgery for Graves' disease improve health-related quality oflife? Surg. Today. http://dx.doi.org/10.1007/s00595-012-0442-z (e-pub ahead ofprint 11 December 2012).
Bahn, S., 2012]. Emerging pharmacotherapy for treatment of Graves' disease. Expert. Rev.Clin. Pharmacol. 5 (6), 605–660.
Heemstra, K.A., Smit, J.W.A., 2008]. Advances in the treatment of Graves' disease—a focuson Rituximab. Eur. Endocrinol. 4 (2), 107–109.
Gough, S.C.L., 2000]. The genetic of Graves disease. Endocrinol. Metab. Clin. N. Am. 29-2,255.
Kabalak, T., 2009]. Tiroid ve Otoimmünite. Tiroid El KitabıGuven yayıncılık, pp. 353–360.Virag, L., Szabo, C., 2002]. The therapeutic potential of poly(ADP-ribose) polymerase
inhibitors. Pharmacol. Rev. 54, 375–429.Jagtap, P., Szabo, C., 2005]. Poly(ADP-ribose) polymerase and the therapeutic effects of its
inhibitors. Nat. Rev. Drug Discov. 4, 421–440.Yelamos, J., Olive, F.J., 2002]. Role of poly (ADP-ribose) polymerase-1 (PARP-1) in the
inflammatory response. Immunologia 21 (4), 219–227.Burkle, A., 2005]. Poly (ADP-ribose). The most elaborate metabolite of NAD+. Febs J. 272
(18), 4576–4589.Ame', J.C., Spenlehauer, C., de Murcia, G., 2004]. The PARP superfamily. BioEssays 26,
882–893.Infante, J., Llorca, J., Mateo, I., Rodrigues-Rodrigues, E., Quintana, C.S., Juan, P.S., Fernández-
Viadero, C., Peña, N., Berciano, J., Combarros, O., 2007]. Interaction between poly(ADP-Ribose) polymerase 1 and interleukin 1A genes is associated with Alzheimer's diseaserisk. Dement. Geriatr. Cogn. Disord. 23, 215–218.
B, NF-κBIA and IL-6, IL-1β and TNF-αwith Graves Disease and Graves38
Onaran, I., Tezcan, G., Ozgononel, L., Cetin, E., Ozdemir, A.E., Kanigur-Sultuybek, G., 2009].The Val762Ala polymorphism in the poly(ADP-ribose) polymerase-1 gene is notassociated with susceptibility in Turkish rheumatoid arthritis patients. Rheumatol.Int. 29, 797–800.
Infante, J., Juan, P.S., Mateo, I., Rodriguez-Rodriguez, E., Sanchez-Quintana, C., Llorca, J.,Fontalba, A., Terrazas, J., Oterino, A., Berciano, J., Combarros, O., 2007]. Poly (ADP-ribose) polymerase-1 (PARP-1) genetic variants are protective against Parkinson'sdisease. J. Neurol. Sci. 256, 68–70.
Bartalena, L., Brogioni, S., Grasso, L., 1993]. Increased serum interleukin-6 concentrationsin patients with subacute thyroiditis: relationship with concomitant changes inserum T4-binding globulin concentrations. J. Endocrinol. Inv. 16, 213–218.
Bartalena, L., Grasso, L., Brogioni, S., 1994]. Serum interleukin-6 in amiodarone-inducedthyrotoxicosis. J. Clin. Endocrinol. Metab. 78, 423–427.
Salvi, M., Girasole, G., Pedrazzoni, M., Passeri, M., Giuliani, N., Minelli, R., Braverman, L.E.,Roti, E., 1996]. Increased serum concentrations of interleukin (IL)-6 and soluble IL-6receptor in patients with Graves' disease. J. Clin. Endocrinol. Metab. 81, 2976–2979.
Siddiqi, A., Monson, J.P., Wood, D.F., 1999]. Serum cytokines in thyrotoxicosis. J. Clin.Endocrinol. Metab. 84, 435–439.
Chopra, I.J., Sakane, S., Teco, C., 1991]. A study of the serum concentration of tumor necro-sis factor-α in thyroidal and nonthyroidal illnesses. J. Clin. Endocrinol. Metab. 72,1113–1116.
Celik, I., Akalin, S., Erbas, T., 1995]. Serum levels of interleukin (IL)-6 and tumor necrosisfactor-α in hyperthyroid patients before and after propylthiouracil treatment. Eur. J.Endocrinol. 132, 668–672.
Pascual, M., L'opez-Nevot, M.A., C'aliz, R., Ferrer, M.A., Balsa, A., Pascual-Salcedo, M.,Martin, J., 2003]. A poly(ADP-ribose) polymerase haplotype spanning the promoterregion confers susceptibility to rheumatoid arthritis. Arthritis Rheum. 48 (3),638–641.
Liu, H.P., Lin, W.Y., Wu, B.T., Liu, S.H., Wang, W.F., Tsai, C.H., 2010]. Evaluation of thepoly(ADP-ribose) polymerase-1 gene variants in Alzheimer's disease. J. Clin. Lab.Ann. 24 (3), 182–186.
Sen, R., Baltimore, D., 1986]. Inducibility of kappa immunoglobulin enhancer-bindingprotein Nf-kappaB by a posttranslational mechanism. Cell 47 (6), 921–928.
Tuncay, S.S., Okyay, P., Bardakci, F., 2010]. Identification of NF-kB1 and NF-kBIA polymor-phisms using PCR-RFLP Assay in a Turkish population. Biochem. Genet. 48, 104–112.
Kurylowicz, A., Hiromatsu, Y., Jurecka-lubieniecka, B., Kula, D., Kowalska, M., Ichimura, M.,Koga, H., Kaku, H., Bar-Andziak, E., Nauman, J., Jarzab, B., Ploski, R., Bednarczuk, T.,2007]. Association of NFKB1—94ins/del ATTg promoter polymorphism with suscepti-bility to and phenotype of Graves's Disease. Genes Immun. 8 (7), 532–538.
Kurylowicz, A., Mis'kiewicz, P., Bar-Andziak, E., Nauman, J., Bednarczuk, T., 2009]. Associ-ation of polymorphism in genes encoding κB inhibitors (IκB) with susceptibility toand phenotype of Graves' disease: a case–control study. Thyroid. Res. 2, 10.
Verma, I.M., Stevenson, J.K., Schwarz, E.M., Van Antwerp, D., Miyamoto, S., 1995]. Rel/NF-kappa B/I kappa B family: intimate tales of association and dissociation. GenesDev. 9 (22), 2723–2735.
Daroszewski, J., Pawlak, E., Karabon, L., Frydecka, I., Jonkisz, A., Slowik, M., Bolanowski, M.,2009]. Soluble CTLA-4 receptor an immunological marker of Graves' disease andseverity of ophthalmopathy is associated with CTLA-4 Jo31 and CT60 gene polymor-phisms. Eur. J. Endocrinol. 161, 787–793.
Zhu, W., Liu, N., Zhao, Y., Jia, H., Cui, B., Ning, G., 2010]. Association analysis of polymor-phisms in IL-3, IL-4, IL-5, IL-9, and IL-13 with Graves' disease. J. Endocrinol. Invest.33 (10), 751–755.
Liu, N., Li, X., Liu, C., Zhao, Y., Cui, B., Ning, G., 2010]. The association of interleukin-1alphaand interleukin-1beta polymorphisms with the risk of Graves' disease in a case–control study and meta-analysis. Hum. Immunol. 71 (4), 397–401.
Please cite this article as: Niyazoglu, M., et al., Association of PARP-1, NF-κOphthalmopathy, Gene (2014), http://dx.doi.org/10.1016/j.gene.2014.06.0
Anvar, M., Khalilzadeh, O., Esteghamati, A., Esfahani, S.A., Rashidi, A., Etemadi, A., Mahmoudi,M., Amirzargar, A.A., 2010]. Genetic susceptibility to Graves' ophthalmopathy: the roleof polymorphisms in proinflammatory cytokine genes. Eye (Lond) 24 (6), 1058–1063.
Liaudet, L., Soriano, F.G., Szabo, E., Virag, L., Mabley, J.G., Salzman, A.L., Szabo, C., 2000].Protection against hemorrhagic shock in mice genetically deficient in poly(ADP-ribose) polymerase. Proc. Natl. Acad. Sci. U.S.A. 97, 10203–10208.
Szabó, C., Dawson, V.L., 1998]. Role of poly(ADP-ribose) synthetase in inflammation andischaemia–reperfusion. Trends Pharmacol. Sci. 19, 287–298.
Hassa, P.O., Covic, M., Hasan, S., Imhof, R., Hottiger, M.O., 2001]. The enzymatic and DNAbinding activity of PARP-1 are not required for NF-kB coactivator function. J. Biol.Chem. 276, 45588–45597.
Cottet, F., Blanche, H., Verasdonck, P., Le Galli, P., Schächter, F., Bürkle, A., Muiras, M.L., 2000].New polymorphisms in the human poly (ADP-ribose) polymerase-1 coding sequence:lack of association with longevity or with increased cellular poly (ADP-ribosyl)ationcapacity. J. Mol. Med. 78, 471–480.
Nikitin, A.G., Chudakova, D.A., Strokov, I.A., Bursa, T.R., Chistiakov, D.A., Nosikov, V.V., 2008].Leu54Phe and Val762Ala polymorphisms in the poly(ADP-ribose)polymerase-1 geneare associated with diabetic polyneuropathy in Russian type 1 diabetic patients.Diabetes Res. Clin. Pract. 79 (3), 446–452.
Hur, J.W., Sung, Y.K., Shin, H.D., Park, B.L., Cheong, H.S., Bae, S.C., 2006]. Poly(ADP-ribose)polymerase (PARP) polymorphisms associated with 58 nephritis and arthritis in sys-temic lupus erythematosus. Rheumatology (Oxford) 45 (6), 711–717.
Hassa, P.O., Hottiger, M.O., 2002]. The functional role of poly(ADP-ribose)polymerase 1 asnovel coactivator of NFк-B in inflammatory disorders. Cell. Mol. Life Sci. 59, 1534–1553.
Shen, H., Oesterling, E., Stromberg, A., Toborek, M., MacDonald, R., Hennig, B., 2008]. Zincdeficiency induces vascular pro-inflammatory parameters associated with NF-kappaB and PPAR signaling. J. Am. Coll. Nutr. 27 (5), 577–587.
Huang, D., Yang, C.Z., Yao, L., Wang, Y., Liao, Y.H., Huang, K., 2008]. Activation and overex-pression of PARP-1 in circulatingmononuclear cells promote TNF-α and IL-6 expressionin patients with unstable angina. Arch. Med. Res. 39 (8), 775–784.
Kiziltunc, A., Basoglu,M., Avci, B., Capoglu, I., 1999]. Serum IL-6 and TNF-a in patients withthyroid disorders. Tr. J. Med. Sci. 29, 25–29.
Salvi, M., Pedrazzoni, M., Girasole, G., Giuliani, N., Minelli, R., Wall, J.R., Roti, E., 2000].Serum concentrations of proinflammatory cytokines in Graves' disease: effect oftreatment, thyroid function, ophthalmopathy and cigarette smoking. Eur. J.Endocrinol. 143, 197–202.
Al-Humaidi, M.A., 2000]. Serum cytokines levels in Graves' Disease. Saudi Med. J. 21 (7),639–644.
Laddha, N.C., Dwivedi, M., Begum, R., 2012]. Increased tumor necrosis factor (TNF)-a andits promoter polymorphisms correlate with disease progression and higher suscepti-bility towards vitiligo. PLoS ONE 7 (12), e52298. http://dx.doi.org/10.1371/journal.pone.0052298.
Wakelkamp, J., Gerding, M.N., van der Meer, J.W.C., Bakker, O., Prummel, M.F., Wiersinga,W.M., 2000]. Both Th1 and Th2 derived cytokines in serum are elevated in Graves'ophthalmopathy. Clin. Exp. Immunol. 121, 453–457.
Antonelli, A., Rotondi, M., Ferrari, S.M., Fallahi, P., Romagnani, P., Franceschini, S.S., Serio,M., Ferrannini, E., 2006]. Interferon-γ-inducible α-chemokine CXCL10 involvementin Graves' ophthalmopathy: modulation by peroxisome proliferator-activatedreceptor-γ agonists. J. Clin. Endocrinol. Metab. 91 (2), 614–620.
Wakelkamp, I.M.M.J., Bakker, O., Baldeschi, L., Wiersinga, W.M., Prummel, M.F., 2003].TSH-R expression and cytokine profile in orbital tissue of active vs. inactive Graves'ophthalmopathy patients. Clin. Endocrinol. 58 (3), 280–287.
B, NF-κBIA and IL-6, IL-1β and TNF-αwith Graves Disease and Graves38
![[Autocrine IL-1beta secretion leads to NF-kappabeta-mediated chemoresistance in pancreatic carcinoma cells in vivo]](https://static.documents.pub/doc/80x56/635d108b88f33c6f8200802a/autocrine-il-1beta-secretion-leads-to-nf-kappabeta-mediated-chemoresistance-in.jpg)
