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Autoimmune diseases (AIDs) are complex diseases characterized by persistent or recurrent inflammation, alteration of immune response, and production of specific autoantibodies. It is known that different AIDs share several susceptibility genetic loci. Tumor necrosis factor alpha inducible protein 3 (TNFAIP3) encodes the ubiquitin-modifying enzyme A20, which downregulates inflammation by restricting NF-κB, a transcription factor that regulates expression of various proinflammatory genes. Variants in TNFAIP3 gene have been described as associated with susceptibility to several AIDs. Here, we analyzed two TNFAIP3 polymorphisms in Italian patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and primary Sjogren’s syndrome (pSS), to verify if the genetic variability of TNFAIP3 gene is involved in genetic predisposition to AIDs also in the Italian population. We recruited 313 SLE patients, 256 RA patients, 195 pSS patients, and 236 healthy controls. Genotyping of rs2230926 and rs6920220 in TNFAIP3 gene was performed by an allelic discrimination assay. We carried out a case/control association study and a genotype/phenotype correlation analysis. A higher risk to develop SLE was observed for rs2230926 (P=0.02, OR=1.92). No association was observed between this SNP and the susceptibility to pSS or RA. However, the rs2230926 variant allele seems to confer a higher risk to develop lymphoma in pSS patients, while in RA patients, the presence of RF resulted significantly associated with the variant allele. Regarding the rs6920220 SNP, we observed a significant association of the variant allele with SLE (P=0.03, OR=1.53), pSS (P=0.016, OR=1.69), and RA (P=0.0001, OR=2.35) susceptibility. Furthermore, SLE patients carrying the variant allele showed a higher risk to develop pericarditis, pleurisy, and kidney complications. Our results support the importance of the TNFAIP3 gene variant role in the development of different autoimmune diseases in the Italian population and furtherly confirm a sharing of genetic predisposing factors among these three pathologies.

Despite the high prevalence of diabetic neuropathy, its early start, and its impact on quality of life and mortality, unresolved clinical issues persist in the field regarding its screening implementation, the understanding of its mechanisms, and the search for valid biomarkers, as well as disease-modifying treatment. Genetics may address these needs by providing genetic biomarkers of susceptibility, giving insights into pathogenesis, and shedding light on how to select possible responders to treatment. After a brief summary of recent studies on the genetics of diabetic neuropathy, the current review focused mainly on microRNAs (miRNAs), including the authors’ results in this field. It summarized the findings of animal and human studies that associate miRNAs with diabetic neuropathy and explored the possible pathogenetic meanings of these associations, in particular regarding miR-128a, miR-155a, and miR-499a, as well as their application for diabetic neuropathy screening. Moreover, from a genetic perspective, it examined new findings of polymorphisms of miRNA genes in diabetic neuropathy. It considered in more depth the pathogenetic implications for diabetic neuropathy of the polymorphism of MIR499A and the related changes in the downstream action of miR-499a, showing how epigenetic and genetic studies may provide insight into pathogenetic mechanisms like mitochondrial dysfunction. Finally, the concept and the data of genotype-phenotype association for polymorphism of miRNA genes were described. In conclusion, although at a very preliminary stage, the findings linking the genetics and epigenetics of miRNAs might contribute to the identification of exploratory risk biomarkers, a comprehensive definition of susceptibility to specific pathogenetic mechanisms, and the development of mechanism-based treatment of diabetic neuropathy, thus addressing the goals of genetic studies.

Background:Psoriatic arthritis (PsA) is a chronic inflammatory disease, characterized by heterogeneous articular and periarticular manifestations. The achievement of remission or low disease activity is the goal of therapy. However, some patients experience primary failure and lack or loss of response to cs-, b- and ts-DMARDs. The treatment response could be affected by multiple factors, including epigenetic factors. Recently, some studies have suggested the possible involvement of lncRNAs in modulating treatment response [1]. In this context, the identification of genetic and epigenetic factors associated to treatment response could help to define new biomarkers for a more effective and personalized therapy.Objectives:The main aim of this study was to prospectively investigate lncRNAs potentially related to treatment response in a cohort of PsA patients treated with TNFi and IL17i, to identify potential predictors of drug treatment effectiveness. In addition, we analysed retrospectively a cohort of PsA patients treated with TNFi to look for possible association between lncRNAs genetic variants and the response after 6 and 12 months of TNFi.Methods:For the expression study, a cohort of 48 PsA patients starting a TNFi (n=28) or IL17i (n=20) drugs was recruited, monitoring their treatment response for 12 months in order to identify subgroup of patients Reponder e Non-Responder. For the genotyping study, we retrospectively analysed 163 PsA patients treated with TNFi. For each patient was estimated the Disease Activity in Psoriatic Arthritis (DAPsA) score at 6 and 12 months after the beginning of therapy. The expression level of lncRNA was analysed in a panel of 84 lncRNAs, after the extraction of total RNA from PBMCs. Then we validated the differentially expressed lncRNAs, resulted from the array experiments, by qRT-PCR using specific primer assay. Web-based data analysis tool (NPInter v4.0 and DIANALncBase v3) were used to confirm miRNA target genes of the validated lncRNAs. For the genotyping study, we extracted genomic DNA from PBMCs and we performed allelic discrimination assay by TaqMan assays. We evaluated a possible association between the selected SNPs and the response to therapy at 6 and 12 months from the beginning of the TNFi treatment, using the clinical parameter of DAPsA value.Results:We observed a significant difference in the expression level between Responder and non-Responder patients, of 4 lncRNAs in the group of PsA patients treated with TNFi and of 3 lncRNAs in the group of patients treated with IL17i. Then, we confirmed a significant decrease of MEG3 expression in non-Responder patients compared to Responder patients, both considering the whole cohort (P= 0.01) and stratifying patients by drugs (P= 0.05 and P= 0.03, respectively for TNFi and IL17i) (Figure 1). In addition, we observed an association between the variant allele of rs7158663 and a lower expression of MEG3 compared to the wild-type allele, although without statistical significance. We also observed that the variant allele of rs941576 (MEG3) was associated with a better response at T6 and T12, with a linear decrease of mean DAPsA value among wildtype, heterozygous and homozygous variant patients. Interestingly, we noticed that the variant allele of rs941576 SNV resulted associated with a better response regarding joints involvement. Indeed, the number of TJ and SJ decreases more in patients carrying the variant allele, both at T6 and T12 (P= 0.0006 and P= 0.032, respectively) (Table 1).Conclusion:Our study suggests a possible role, both in terms of genetic variability and expression, of the lncRNA MEG3 in the treatment response to TNFi and IL17i in PsA patients.REFERENCES:[1] De Benedittis G, Latini A, Ciccacci C, et al. Impact of TRAF3IP2, IL10 and HCP5 Genetic Polymorphisms in the Response to TNF-i Treatment in Patients with Psoriatic Arthritis. J Pers Med. 2022;12(7):1094.Acknowledgements:NIL.Disclosure of Interests:None declared.

Background:Telomeres are specific regions of repetitive nucleotide sequences that protect chromosome ends and preserve genetic information. In each cell division, telomeres shorten, leading finally to apoptosis and cell cycle arrest when reaching a critical point. The telomere-associated protein (telomeric repeat-binding factor 1 [TERF1]) is essential for the maintenance of telomeres, acting as an inhibitor of telomerase, and its levels correlate with telomere length (TL).Shortened telomeres have been demonstrated in Rheumatoid Arthritis (RA). Furthermore, they are a recognized risk factor for idiopathic pulmonary fibrosis. Few data are present in the literature regarding TL in RA-associated interstitial lung disease (RA-ILD), while no data are present regarding TERF1 in RA and RA-ILD.Objectives:We aimed to evaluate the TL and TERF1 expression levels in RA-ILD.Methods:TL and TERF1 expression levels were evaluated in patients with RA-ILD compared to age-matched RA patients without lung involvement (RA-non-ILD) and healthy controls. Genomic DNA and total RNA were isolated from peripheral blood mononuclear cells. Relative TL was measured using real-time quantitative polymerase chain reaction (qPCR) assay, which quantifies a ratio of telomeric repeat copy signal and a reference single-copy gene (human beta globin) signal. Expression analysis of TERF1 was performed by qPCR assay. T-test was used to compare mean TL and TERF1 expression data among the different phenotypic groups. RA patients were divided according to whether their TL fell within or above the first quartile of the cohort. A multivariate logistic regression analysis was used to correct the p-value for sex, age and disease duration.Results:Eighty-nine RA patients were included (mean age 63.6 ± 13.8 years, median disease duration 9 [IQR 8.4-11.6] years): 42 RA-ILD and 47 RA-non-ILD. 21 age- and sex-matched controls were collected. RA-ILD patients were older and with minor disease duration than RA-non-ILD patients. They exhibited higher disease activity, CRP levels, positivity for RF and ACPA, and were more treated with bDMARDs than RA-non-ILD patients (Table 1). TL in all patients was significantly shorter compared to controls (p = 0.0016). RA-ILD patients presented significantly shorter TL compared to controls (p = 0.00001) and compared to RA-non-ILD (p = 0.0006) (Figure 1A). In the multivariate regression analysis, TL was reduced in RA-ILD compared with RA-non-ILD when adjusted for sex, age and disease duration (p<0.001). After patients stratification according to their TL, it is observed that the prevalence of ILD was significantly higher in patients with short vs normal-length telomeres (82.6% vs 34.8% p=0.00008). In RA-ILD, TL correlated negatively with disease duration (p= 0.007 r= -0.408). TERF1 expression levels were reduced in RA compared with controls (p= 2.17E-17). Both RA-ILD patients and RA-non-ILD patients exhibited reduced TERF1 expression levels than controls (p= 3.37E-10 and p= 2.78E-10, respectively. Figure 1B). TERF1 levels correlated positively with TL (p= 0.004 r= 0.328).Conclusion:Telomere shortening is a feature of immunosenescence and it has been linked to more severe articular disease. Shorter TL and reduced TERF1 expression levels characterize RA. In particular, RA-ILD patients displayed higher disease activity, negative prognostic factors, received more biologic treatments, and exhibited shorten TL than RA-non-ILD patients suggesting that TL might represent a hallmark of a more aggressive disease with lung involvement.Table 1.Figure 1.Acknowledgements:NIL.Disclosure of Interests:None declared.

Psoriatic arthritis (PsA) is a chronic inflammatory joint disease typically associated with psoriasis and classified in the group of spondyloarthritis (1). The pathogenesis is based on an interplay of different genes interacting with several environmental factors including stress, trauma, infections, triggering an inflammatory response related to the activation of innate and acquired immunity in different tissues and organs (2). However, the risk for the development of PsA is not clearly understood. The aim of this study was to evaluate, in a cohort of Italian PsA out-patients of the Rheumatology Unit of the University of Rome Tor Vergata, the association of genetic variants in candidate genes for PSA susceptibility and their possible contribute in the modulation of clinical and laboratory features. The genes were selected according to previous studies describing these genes as involved in susceptibility to rheumatoid arthritis (RA) (3), since a common genetic background can be shared between these diseases. Nine SNPs (single nucleotide polymorphism) in eight candidate genes were analysed: STAT4 (rs7574865), TRAF3IP2 (rs33980500), TNFAIP3 (rs6920220 and rs2230926), MIR146A (rs2910164), PSORS1C1 (rs2233945), IL-10 (rs1800872), HCP5 (rs3099844) and ERAP1 (rs27524). Polymorphisms were analysed in 163 consecutive PsA out-patients and 198 healthy controls (HC). Genotyping was performed by allelic discrimination by TaqMan assay. Alleles frequencies differences between cases and controls or between phenotypic groups were compared using Pearson's χ 2 test. We have observed an association between PSA susceptibility and the variant alleles of STAT4 [OR= 1.60 (1.15-2.21), P= 0.005], TRAF3IP2 [OR= 1.65 (1.01-2.65), P= 0.04], ERAP1 [OR= 1.40 (1.05-1.85), P= 0.02] and TNFAIP3 (rs6920220) [OR= 1.75 (1.19-2.57), P= 0.004]. On the contrary, the variant allele of IL-10 polymorphism seems to play a protective role [OR= 0.74 (1.05-1.85), P= 0.05]. Moreover, in order to define a genetic risk profile, we have counted the total number of risk alleles in each subject, considering as risk alleles the allelic variant of rs7574865 (STAT4), rs33980500 (TRAF3IP2), rs6920220 (TNFAIP3) and rs27524 (ERAP1) SNPs. Then, we have compared the risk allele number distribution between patients and HC (Fig.1). Classes with 3 or more risk alleles are significantly more represented in patients than in HC (OR= 2.03, P=0.004). The risk to develop the disease increases significantly in subjects with at least four risk alleles (OR= 2.96, P=0.002). We confirm the associations between five SNPs, already studied in RA, and PSA susceptibility, suggesting a common inflammatory pathway in chronic inflammatory rheumatological diseases. Moreover, we show how the genotyping of only few associated SNPs could help to define a genetic risk profile for PSA development. [1]Calabresi E, et al. One year in review 2019: psoriatic arthritis. Clin Exp Rheumatol. 2020;38:1046-55. [2]Chimenti MS, Triggianese P, De Martino E, Conigliaro P, Fonti GL, Sunzini F, Caso F, Perricone C, Costa L, Perricone R. An update on pathogenesis of psoriatic arthritis and potential therapeutic targets. Expert Rev Clin Immunol. 2019 Aug;15(8):823-836. [3]Ciccacci C, et al. Polymorphisms in STAT-4, IL-10, PSORS1C1, PTPN2 and MIR146A genes are associated differently with prognostic factors in Italian patients affected by rheumatoid arthritis. Clin Exp Immunol. 2016;186:157-63. None declared [Display omitted]

PurposeThe goal was to develop a simple model for predicting the individual risk profile for age-related macular degeneration (AMD) on the basis of genetic information, disease family history, and smoking habits.Patients and methodsThe study enrolled 151 AMD patients following specific clinical and environmental inclusion criteria: age >55 years, positive family history for AMD, presence of at least one first-degree relative affected by AMD, and smoking habits. All of the samples were genotyped for rs1061170 (CFH) and rs10490924 (ARMS2) with a TaqMan assay, using a 7500 Fast Real Time PCR device. Statistical analysis was subsequently employed to calculate the real individual risk (OR) based on the genetic data (ORgn), family history (ORf), and smoking habits (ORsm).Results and conclusionThe combination of ORgn, ORf, and ORsm allowed the calculation of the Ort that represented the realistic individual risk for developing AMD. In this report, we present a computational model for the estimation of the individual risk for AMD. Moreover, we show that the average distribution of risk alleles in the general population and the knowledge of parents' genotype can be decisive to assess the real disease risk. In this contest, genetic counseling is crucial to provide the patients with an understanding of their individual risk and the availability for preventive actions.

One of the most successful applications of pharmacogenetics research is the genetic screening for HLA-B*57:01 , strongly associated with an increased risk to develop hypersensitivity reaction in HIV-positive patients following abacavir administration. Taking into consideration the limits of current genotyping methodologies, we have developed and validated (150 buccal swabs) an inexpensive pharmacogenetic approach for HLA-B*57:01 typing. In our assay DNA extraction and amplification are combined in one single step (direct PCR protocol), which is performed directly on the biological sample without the need of extraction and sequencing passages. The amplicons obtained by direct PCR can be easily separated on the agarose gel under ultraviolet. As per our results, the direct PCR represents a good alternative to the traditional methods of HLA-B*57:01 pharmacogenetic test, especially for those laboratories or countries where currently available approaches are often not available or not affordable. Furthermore it is an innovative approach, promoting a personalized, safer and cost-effective therapy.

BackgroundSystemic lupus erythematosus (SLE) is a chronic autoimmune disease with a complex pathogenesis in which genes and environmental factors interact leading to a protean clinical picture. Treat-to-target recommendations have identified ‘remission’ as a target in SLE, since achievement of remission improves the outcome and is associated with decreased damage progression. Nonetheless, predicting factors for the achievement of remission are lacking. It is likely that genes associated with SLE pathogenesis may influence the disease course.ObjectivesThus, our aim was to analyse previously identified loci associated with SLE in a cohort of SLE patients to evaluate their influence on remission achievement.MethodsWe recruited 117 Italian SLE patients. A panel of 34 SNPs in 19 genes involved in immune response, autophagy and inflammation, was selected. SNPs genotyping was performed by allelic discrimination assay by TaqMan assays (Applied Biosystems, Foster City, CA, USA) and ABI PRISM 7000. The main clinical/laboratory features (including injury index and disease activity) were collected on an electronic platform. Remission was defined according to Zen et al.1 and evaluated over 5 years. A genotype/phenotype correlation analysis was performed.ResultsThe variant alleles of rs7574965 (STAT4) (p<0.001) and rs2910164 (MIR146a) (p=0.031) were significantly associated with lack of achievement of 5 years remission in SLE. Specifically, patients carrying the C allele of MIR146a were less likely to achieve 5 years remission (p=0.01, OR 0.235, 95% CI 0.074–0.752) as well as to achieve remission after 1, 2 and 3 years of evaluation (p=0.002, p=0.001, p=0.002, respectively). Among the clinical and laboratory features, 5 years remission was less likely to be achieved by patients who had arthritis in their clinical history (p=0.007), and who tested positive for anti-dsDNA (p=0.005). In a multinomial logistic regression analysis, arthritis (p=0.022, Exp(B)=0.255, 95% CI 0.079–0.820), anti-dsDNA (p=0.003, Exp(B)=0.166, 95% CI 0.051–0.537) and MIR146a rs2910164 gene variant (p=0.046, Exp(B)=0.250, 95% CI 0.064–0.974) were confirmed to be independent risk factors for unreached 5 years remission (table 1).Abstract FRI0260 – Table 1REMISSIONExp(B)Exp (B) 95% CI LowerUpperArthritis025500790,82anti-dsDNA016600510537STAT403540,111139mir146A0,2500640974ConclusionsWe describe for the first time the contribution of STAT4 and MIR146a SNPs as predicting factors for the achievement of 5 years remission in SLE. No genetic study has been performed so far in SLE, while a genetic profile of patients may be useful to predict the disease outcome.Reference[1] Zen, et al. Ann Rheum Dis. 2017Mar;76(3):562–565.Disclosure of InterestNone declared

BackgroundRheumatoid Arthritis (RA) is a systemic autoimmune disease resulting in chronic inflammation of the synovium and consequent cartilage and bone erosion. RA is strongly associated with the presence of rheumatoid factor (RF) and consists of clinical subsets of anti-citrullinated protein antibody (ACPA)-positive and negative patients. Several genes have been proven to contribute to the disease susceptibility and they may be associated with a particular pattern of disease and with the response or toxicity to therapy. It is important to identify novel genomic biomarkers associated not only with disease susceptibility but also able to detect early those patients with negative prognostic factors who may benefit from a more aggressive therapeutic approach.ObjectivesThis study was designed to evaluate whether the most relevant single nucleotide polymorphisms (SNPs) associated with RA and other autoimmune disorders are related to RF, ACPA, and clinical phenotype in a cohort of biologic-naïve Italian RA patients.MethodsA total of 192 RA patients [female n=147 (76.5%), age 54.1 ± 13.2 years, disease duration 7.8 ± 9 years, positive RF n=130 (67.7%), positive ACPA n=137 (71.7%), 28 joint count disease activity score (DAS28) 5.2 ± 1.3, bone erosions at diagnosis n=69 (60%), disease modifying anti-rheumatic drugs (DMARDs) n=148 (77.1%)] were enrolled. 278 age-matched healthy controls were included. We analyzed a total of 12 SNPs in STAT4, IL10, PSORS1C1, PTPN2, ERAP1, TRAF3IP2 and MIR146A genes by allelic discrimination assays. Case-control association studies and genotype/phenotype correlation analyses were performed (Figure 1A-B).ResultsA higher risk to develop RA was observed for rs7574865 in STAT4 gene (P=0.035, OR=1.41). We observed a significant association between the variant alleles of rs1800872 in IL-10 gene and RA susceptibility. Subjects carrying the variant alleles (in heterozygous and homozygous status) showed a lower risk to develop RA in comparison with wildtype individuals (P=0.014, OR=0.63). The presence of RF resulted significantly associated with rs1800872 variant in IL10 (P=0.032, OR=2) while rs2910164 in MIR146A was protective (P=0.05, OR=0.55). ACPA were significantly associated with rs7574865 in STAT4 (P=0.004, OR=2.64). The SNP rs2233945 in PSORS1C1 gene was protective regarding the presence of bone erosions (P=0.042, OR=0.44) while rs2542151 in PTPN2 gene was associated with joint damage (P=0.044, OR=3.26).ConclusionsOur results confirm that polymorphisms in STAT4 and IL10 genes confer susceptibility to RA. For the first time we described that SNPs in PSORS1C1, PTPN2 and MIR146A genes were differently associated with a severe disease phenotype in terms of autoantibody status and radiographic damage in an Italian RA population.Disclosure of InterestNone declared

BackgroundPrimary Sjögren syndrome (pSS) is a systemic inflammatory condition characterized by lymphocytic infiltrates in exocrine glands. STAT4 is one of the genes involved in “interferon (IFN) signature” and a single nuclear polymorphism (SNP), rs7574865 has been found associated with pSS. Other SNPs in TRAF3IP2 (rs33980500 and rs13193677) and HCP5 (rs3099844) genes, have been previously associated with the susceptibility to systemic lupus erythematosus (SLE), and seem to influence the disease phenotype.ObjectivesTo evaluate the association of different SNPs [STAT4 (rs7574865), TRAF3IP2 (rs33980500), HCP5 (rs3099844)] with the susceptibility to pSS and their role in modulation of clinical and laboratory features.MethodsOne hundred thirty-five consecutive patients with pSS (AECC) were enrolled and clinical and laboratory data collected. Three hundred age and sex-matched healthy subjects were used as controls. Genomic DNA was isolated from peripheral blood mononuclear cells (Qiagen blood DNA mini kit). Genotyping was performed by allelic discrimination assays (Applied Biosystems, Foster City, CA, USA).ResultsClinical and laboratory features are reported in table.Clinical featuresNumber (%)Laboratory featuresNumber (%)Sex (M/F)5/130ANA116/135 (85.9)Age (mean ± SD), yrs59±12.1Anti-Ro/SSA81/135 (60)Age at diagnosis (mean ± SD), yrs53,2±12,2Anti-La/SSB56/135 (41.4)Xerophthalmia124/135 (91.8)Hypergammaglobulinemia44/135 (32.5)Xerostomia124/135 (91.8)Rheumatoid factor46/135 (34)Glandular swelling27/135 (20)Leucopenia28/135 (20.7)Arhritis16/135 (11.8)Hypocomplementemia11/135 (8.1)Lymphoma4/135 (2.9)Monoclonal component13/135 (9.6)Cryoglobulinemia6/135 (4.4)Deviations from Hardy–Weinberg equilibrium were not observed. The SNPs rs7574865 of STAT4 and rs3099844 of HCP5 were found associated with pSS at both the genotypic and allelic level (p<0.001, OR=1.84, 95%CI=1.28–2.65 and p<0.05, OR=2.28, 95%CI=1–3.7, respectively) and the data was confirmed after adjustment for other variables. STAT4 was found associated with the presence of monoclonal component (p=0.021). HCP5 was associated with the presence of leukopenia (p=0.021, OR=2.91, 95%CI=1.15–7.38) and lymphoma (p<0.001).ConclusionsThis study confirms the association between the rs7574865 polymorphism of STAT4 and the susceptibility for pSS, and shows for the first time the association with a variant of HCP5. STAT4 was associated with monoclonal component supporting the role of IFN signature in autoantibodies production. Furthermore, HCP5 seem to be able to influence the disease phenotype predisposing to the development of leukopenia and lymphoma. These data need to be validated on larger cohorts of patients.Disclosure of InterestNone declared