IL2RA Rs2104286 Research Articles

Effect of interleukin-2 (IL-2) polymorphisms on multiple myeloma: IL-2RA rs2104286, IL-2 rs2069762 and rs2069763 polymorphisms

Interleukin-2 (IL-2) is a cytokine secreted from T helper type 1 cells and released after induction of T helper cells with major histocompatibility complexes or antigens presented by antigen presenting cells. IL-2 activity and gene polymorphisms have been studied in both solid and hematological malignancies. In the present study, it was aimed to examine the effects of IL-2RA rs2104286, IL-2 rs2069762 and rs2069763 polymorphisms on multiple myeloma (MM) susceptibility, progression-free survival (PFS) and overall survival (OS). A total of 300 patients diagnosed with MM in our clinic between January 2010 and January 2021, and 170 healthy individuals were included. In addition to the demographic data of the patients, MM subtypes, initial stages, prognostic index scores, laboratory results, treatment preferences, and survival data were recorded. The genotypes of the IL-2RA rs2104286, IL-2 rs2069762 and rs2069763 polymorphisms were statistically compared between patients and healthy controls to reveal their effects on MM susceptibility and survival. In the statistical analysis performed to examine the effect of IL-2RA rs2104286, IL-2 rs2069762 and rs2069763 polymorphisms on disease susceptibility, no significant difference was found between the patient and healthy control groups. Patients with the TG genotype of IL-2 rs2069762 had a significantly shorter median PFS and OS compared to others. Patients with the GG genotype of IL-2 rs2069763 had a significantly shorter median PFS compared to others. Having the TG genotype of IL-2 rs2069762 has been shown to be protective for short PFS and OS. Our study results will be guiding in terms of IL-2 based therapies, the future for MM and MM epigenetics.

Interaction Of Immune Response Mediator Genes In A Predisposition To Juvenile Idiopathic Arthritis

Background/objective — The goal of our study was to investigate the role of interaction between the polymorphic loci of immune response mediator genes (TNFA rs1800629, LTA rs909253, IL1B rs16944, IL2-IL21 rs6822844, IL2RA rs2104286, IL6 rs1800795, IL10 rs1800872, MIF rs755622, CTLA4 rs3087243, NFKB1 rs28362491, PTPN22 rs2476601, and PADI4 rs2240336) in the formation of a genetic predisposition to juvenile idiopathic arthritis (JIA). Material and Methods — The study involved 330 JIA patients and 342 volunteers from the Republic of Bashkortostan. Genotyping was conducted via the real-time polymerase chain reaction. The gene-gene interactions were studied using the multifactor dimensionality reduction algorithm. Results — In general analysis, the best model of gene-gene interaction in JIA was a combination of IL1B rs16944 – IL10 rs1800872 – NFKB1 rs28362491 – PADI4 rs2240336 polymorphic loci. However, after gender-based stratification the best results were obtained when examining the combinations of IL6 rs1800795 – PADI4 rs2240336 loci in girls and of IL10 rs1800872 – IL6 rs1800795 – IL2RA rs2104286 loci in boys. Within all of these models, the genotype combinations associated with both augmented and reduced JIA risks were identified (taking into account gender-specific differences). Conclusion — The results of our study implied that an important role in the formation of a predisposition to JIA is played by gene-gene interactions of IL1B rs16944, IL2RA rs2104286, IL6 rs1800795, IL10 rs1800872, NFKB1 rs28362491, and PADI4 rs2240336 polymorphic loci (taking into account gender-specific differences).

PTPN22 gene and IL2RA rs11594656, rs2104286 gene variants: additional insights of polygenic single-nucleotide polymorphisms\u2019 pattern among Egyptian children with type 1 diabetes

BackgroundType 1 diabetes mellitus (T1D) results from environmental and genetic factors.We aimed to investigate the distribution of PTPN22, IL2RA rs11594656, and rs2104286 variants and its association with T1D in children.A case-control study conducted on 100 diabetic patients and 100 control children. PTPN22 gene, IL2RA rs11594656, and rs2104286 polymorphisms study were done by PCR followed by restriction fragment length polymorphism (RFLP) assay.ResultsT allele of PTPN22 gene was presented more frequently 47% in patient group versus 30% in controls, while C allele was 53% in the diabetic group versus 70% in controls showing a statistically significant difference between patient and control groups. Similarly, TT 1858 genotype was found in higher frequency with a statistically significant difference in favor of T1D patients (p = 0.038), OR (CI 95% 3.16 (1.28–7.09).For IL2RA rs11594656 polymorphism, the frequency of TT, TA, and AA in patients at percentages of 20%, 60%, and 20% versus 4%, 60%, and 36% in controls respectively showed significant difference (p = 0.045). Also, T allele was detected more in patients group as evidenced by p = 0.059, OR (95% CI) of 2.38(1.49–6.12). Whereas, IL2RA rs2104286 polymorphism revealed a difference of otherwise non-statistical significance (p = 0.091). Those who harbored homozygous pattern of both IL2RA polymorphisms frequently had DKA and high mean HbA1C values.ConclusionPTPN22 (C1858T) and IL2RA rs11594656 polymorphisms increased the risk of T1DM development, while IL2RA rs2104286 polymorphism did not display any significant association among children with T1D. Having more than one risk allele could affect progression and control of T1D.

Polymorphisms within Genes Coding for IL-17A and F and Their Receptor as Clinical Hallmarks in Ankylosing Spondylitis.

IL-17A and IL-17F together with their coreceptor (IL-17RA/RC) were reported to play a significant role in the pathogenesis of spondyloarthritis. The group of axial spondyloarthritis comprises ankylosing spondylitis (AS), a rheumatic disease characterized by chronic inflammation of the joints in the spine. This study is aimed at investigating IL-17A, IL-17F, IL-17RA, and IL-17RC polymorphisms as potential biomarkers of disease susceptibility, clinical parameters, and anti-TNF treatment outcome in a cohort of Polish ankylosing spondylitis patients. In total, 328 subjects, including 138 AS patients and 190 healthy volunteers, participated in the study. Genotyping of IL-17A rs2275913 (G/A), IL-17F rs763780 (A/G), IL-17RA rs4819554 (A/G), and IL-17RC rs708567 (G/A) was performed on real-time PCR instrument using LightSNiP assays. No significant differences were revealed in genotype and allele distribution between patients and controls despite the association of the IL-17RC rs708567 AA homozygosity with the earlier onset of the disease. Moreover, some relationships between IL-17F rs763780 and IL-17RA rs4819554 polymorphisms with clinical parameters related to the disease activity and anti-TNF treatment outcome were observed. IL-17F rs763780 G allele was found to be associated with high disease activity and BASDAI after 6 months and poor response to the treatment while higher VAS values were more common among IL-17RA rs4819554 G variant carriers. In conclusion, the IL-17F rs763780 polymorphism should be considered as a promising biomarker of disease activity and anti-TNF treatment outcome. The IL-17RA rs48419554 G allele may serve as a potential marker of disease severity in Polish AS patients.

Genetic Factors of Predisposition and Clinical Characteristics of Rheumatoid Arthritis in Russian Patients.

Rheumatoid arthritis (RA) is a multifactorial disease caused by a genetic predisposition and environmental factors. Predisposing alleles of various genes have a relatively small influence on the disease risk when they appear separately, but in combination, they predispose an individual to RA development. We genotyped 125 patients with RA including 60 SNPs and sequenced coding part of six genes by next-generation sequencing (NGS) technology on a target panel (IAD177464_185). According to our data, the alleles HLA-DRB1*04, HLA-DRB1*01, HLA-B*27, PTPN22 (rs2476601), TNF (rs1800629), TPMT (rs2842934), and IL4 (rs2243250), and genotypes HLA-DRB1*04:04, HLA-DRB1*01:16, PTPN22 (rs2476601), TPMT (rs2842934), were significantly associated with the RA development. Associations with clinical criteria (DAS28-CRP, HAQ-DI, and CDAI) and biochemical factors were investigated. We have shown that the PADI4 genotypes (rs11203367, rs2240340, rs11203366, and rs874881) are significantly associated with the baseline levels of DAS28-CRP, HAQ-DI, and CDAI; genotypes IL23R (rs7530511) and TNFRSF1A (rs748004, rs2228144) with the level of anti citrullinated peptide antibodies (ACPA); the genotypes DHODH (rs3213422) and MTHFR (rs180113) with the concentration of C-reactive protein (CRP); and the genotypes IL2RA (rs2104286), IRAK3 (rs11541076), and IL4R (rs1801275) with the level of rheumatoid factor (RF). Application of targeted NGS panel contributes to expanded genotyping to identify risk groups among the RA patients.

The association of genetic variants IL2RA rs2104286, IFI30 rs11554159 and IKZF3 rs12946510 with multiple sclerosis onset and severity in patients from Serbia

An algorithm Probabilistic Identification of Causal SNPs, identified 434 causal variants for multiple sclerosis (MS) including IL2RA rs2104286, IFI30 rs11554159 and IKZF3 rs12946510. Analysis of individual and combined effects of these variants in the Serbian population identified that Il2RA rs2104286 G allele carriers had a lower risk for developing MS (gender adjusted OR = 0.63, p = .003). With regard to the IFI30 rs11554159 recessive genetic model, among HLA-DRB1*15:01 positive patients, the AA homozygote had a significantly higher MSSS compared to the G allele carriers (p = .003). This study confirms role of IL2RA rs2104286 in MS and suggest the role of IFI30 rs11554159 in disease severity, which needs validation.

Genetic polymorphism in IL17RA induces susceptibility to Toxoplasma gondii infection in Brazilian pregnant women

Congenital toxoplasmosis is a parasitic disease caused by Toxoplasma gondii, an obligate intracellular parasite which can cause fetal death/abortion and can induce damage in the brain and eyes of the infected babies. The environmental and genetic factors associated with T. gondii and the maternal immune response, drive part of the pathogenesis of congenital toxoplasmosis. Thus, in this study, we aimed to investigate the allelic and genotypic frequencies of specific single nucleotide polymorphisms (SNPs) in the IL17A and IL17RA genes, as well as the production of IL-17A, IL-33, and CCL2 in pregnant women, from the State of Rio Grande do Norte, Brazil, further relating these along with the clinical parameters, to the toxoplasmosis infection. Through PCR-RFLP techniques, two SNPs implicated in Th17 immune response, IL17A rs2275913 (G> A) and IL17RA rs4819554 (A> G) modulation were evaluated in pregnant women, either infected or not infected by T. gondii. These women were also evaluated in terms of plasma release of CCL2, IL-33, and IL-17A which relate to hypertension, number of abortions, and ethnic pattern. The results showed that the G-allele of the SNP rs2275913 (IL17A) appeared to be protective in this population, while the rs4819554 (IL17RA) SNP G allele was associated with greater susceptibility to T. gondii infection [ρ value = 0.025; OR = 2.815 (1.118–7.089); CI = 95%]. None of the cytokines had any influence on the analyzed parameters (abortion and hypertension). In conclusion, our data suggest an immunogenic evidence of susceptibility to T. gondii infection driven by the rs4819554 (IL17RA) SNP G allele in Brazilian pregnant women. Further studies are needed to reinforce this trial marker in populations from distinct geographical areas as well as to confirm the protective pattern related to the G-allele of the SNP rs2275913 (IL17A) in pregnant women.

The relationship of the immune response mediator genes’ polymorphic variants with the methotrexate efficacy in juvenile idiopathic arthritis

Background/aim The aim of the study was to analyze the relationship of the immune response mediator genes’ polymorphic loci (TNFA rs1800629, LTA rs909253, IL1B rs16944, IL2-IL21 rs6822844, IL2RA rs2104286, IL6 rs1800795, IL10 rs1800872, MIF rs755622, CTLA4 rs3087243, NFKB1 rs28362491, PTPN22 rs2476601, PADI4 rs2240336) variants with the methotrexate efficacy in juvenile idiopathic arthritis (JIA).Materials and methods The study included 274 JIA patients from the Republic of Bashkortostan, Russia. Achieving the American College of Rheumatology Pediatric 30 (ACR Pedi 30) response was regarded as the presence of the response to methotrexate (otherwise, as the absence), while achieving clinical remission on medication (Wallace et al., 2011) - as the sufficient response (otherwise, as the insufficient). Genotyping was conducted by the real-time polymerase chain reaction.Results Associations with an altered risk of the nonresponse to methotrexate in JIA were observed for the alleles/genotypes of the loci IL10 rs1800872 (in girls) and NFKB1 rs28362491 (in girls); with an altered risk of the insufficient response to methotrexate in JIA – for the alleles/genotypes of the loci IL1B rs16944 (in boys), CTLA4 rs3087243 (in boys), NFKB1 rs28362491 (in girls) and the haplotype TNFA rs1800629*A - LTA rs909253*G (in girls).Conclusion As a result of the study, the relationship of the alleles/genotypes of the IL1B rs16944, IL10 rs1800872, CTLA4 rs3087243, NFKB1 rs28362491 polymorphic loci and the TNFA rs1800629*A - LTA rs909253*G haplotype with the methotrexate efficacy in JIA was established (taking into account the differences by sex).

Haplotype Analysis of Candidate Genes Involved in Inflammation and Oxidative Stress and the Susceptibility to Preeclampsia.

Unbalanced inflammatory reactions and oxidative stress are inseparably interconnected, and both may play crucial roles in the pathophysiological mechanisms of preeclampsia (PE). In the published previous studies, we have genotyped for SNPs that related to inflammation (rs2227485, rs153109, rs17855750, rs2027432, rs2275913, rs763780, rs4819554, and rs13015714) and oxidative stress (rs1695, rs4680, rs1800566, rs4807542, rs713041, rs7579, rs230813, rs1004467, rs3824755, and rs9932581) to investigate whether these polymorphisms were associated with susceptibility to PE in a Chinese Han population. In this present study, we collected these data of experimental and clinical from above studies for haplotype analysis of inflammation-related SNPs in 631 PE patients and 720 normal pregnancy and oxidative stress-related SNPs in 342 PE patients and 457 normal pregnancies for susceptibility to PE. The data of genotype distribution and allele frequency comparisons after correction for multiple comparisons (P/8 or P/10) showed 2 among the 8 candidate inflammation-related SNPs have significant differences (rs2027432 genotype χ2 = 407.377, p < 0.001, p < 0.00625). Moreover, the minor alleles of rs2027432 T (minor allele χ2 = 450.923, p < 0.001, p < 0.00625; OR = 21.439, 95%CI = 15.181‐30.278) and rs4819554 G (minor allele χ2 = 163.465, p < 0.001, p < 0.00625; OR = 5.814, 95%CI = 4.380‐7.719) were confirmed as risk allele of PE, respectively. Our analysis revealed rs2027432 (TT) of NLRP3 and rs4819554 (GG) of IL-17RA are risk factors for PE. However, no significant difference was found at the oxidative stress-related SNPs. In the candidate loci for oxidative stress, we also identified 3 SNP matches (rs4807542 and rs713041, rs230813 and rs75799, rs1004467 and rs3824755) that had high linkage disequilibrium (LD) with each other and were selected as a block (r2 = 0.98, r2 = 0.97, r2 = 0.97, r2 > 0.9), and the GT and GC haplotypes of rs4807542 and rs713041 in GPX4 showed significant differences between the PE and control groups (χ2 = 5.143, p = 0.0233, p < 0.05; χ2 = 6.373, p = 0.0116, p < 0.05). So, we inferred that polymorphisms of NLRP3 rs2027432 and IL-17RA rs4819554, which are related to inflammation, and the rs713041 variant of GPX4, which is related to oxidative stress, were associated with susceptibility to PE. The GT and GC haplotypes of rs4807542 and rs713041 in GPX4 may increase the risk of PE in the Chinese Han population.

Type 1 diabetes linked PTPN22 gene polymorphism is associated with the frequency of circulating regulatory T cells.

Dysfunction of FOXP3-positive regulatory Tcells (Tregs) likely plays a major role in the pathogenesis of multiple autoimmune diseases including type 1 diabetes (T1D). Whether genetic polymorphisms associated with the risk of autoimmune diseases affect Treg frequency or function is currently unclear. Here, we analysed the effect of T1D-associated major HLA class II haplotypes and seven single nucleotide polymorphisms in six non-HLA genes [INS (rs689), PTPN22 (rs2476601), IL2RA (rs12722495 and rs2104286), PTPN2 (rs45450798), CTLA4 (rs3087243), and ERBB3 (rs2292239)] on peripheral blood Treg frequencies. These were determined by flow cytometry in 65 subjects who had progressed to T1D, 86 islet autoantibody-positive at-risk subjects, and 215 islet autoantibody-negative healthy controls. The PTPN22 rs2476601 risk allele A was associated with an increase in total (p = 6 × 10-6 ) and naïve (p = 4 × 10-5 ) CD4+CD25+CD127lowFOXP3+ Treg frequencies. These findings were validated in a separate cohort comprising ten trios of healthy islet autoantibody-negative children carrying each of the three PTPN22 rs2476601 genotypes AA, AG, and GG (p = 0.005 for total and p = 0.03 for naïve Tregs, respectively). In conclusion, our analysis implicates the autoimmune PTPN22 rs2476601 risk allele A in controlling the frequency of Tregs in human peripheral blood.

The role of the immune response mediator genes polymorphism in the predisposition to juvenile idiopathic arthritis

Objective ― The aim of the work was to study the contribution of the immune response mediator genes polymorphism (TNFA rs1800629, LTA rs909253, IL1B rs16944, IL2-IL21 rs6822844, IL2RA rs2104286, IL6 rs1800795, IL10 rs1800872, MIF rs755622, CTLA4 rs3087243, NFKB1 rs28362491, PTPN22 rs2476601, PADI4 rs2240336) to the formation of the predisposition to juvenile idiopathic arthritis (JIA) and its clinical variants. Material and Methods ― The JIA group included 330 patients and the control group – 342 volunteers without autoimmune diseases from the Republic of Bashkortostan, Russia. Genotyping was conducted by the real-time polymerase chain reaction. Results ― Taking into account the differences by sex, it was established, that the alleles/genotypes of the TNFA rs1800629, LTA rs909253, IL2-IL21 rs6822844, PTPN22 rs2476601 polymorphic loci and the TNFA rs1800629*G – LTA rs909253*G haplotype are associated with the development of JIA as a whole (p&lt;0.05); alleles/genotypes of the LTA rs909253, IL1B rs16944, IL2-IL21 rs6822844, IL2RA rs2104286, IL6 rs1800795, IL10 rs1800872, MIF rs755622, CTLA4 rs3087243, NFKB1 rs28362491, PTPN22 rs2476601 polymorphic loci and the TNFA rs1800629*G – LTA rs909253*G haplotype – with some of JIA clinical variants (p&lt;0.05). Conclusion ― In this work, the relationship of the alleles, genotypes and haplotypes of a number of the immune response mediator genes polymorphic loci with the risk of the development of JIA and its clinical variants was established. Specific associations were observed for girls and boys, which indicates the existence of sexual dimorphism in the JIA pathogenesis.

Genetic differences between primary progressive and relapsing-remitting multiple sclerosis: The impact of immune-related genes variability

BackgroundMultiple sclerosis (MS) is a chronic autoimmune disease of CNS with a highly heterogeneous clinical course. The role of the genetic variability in determination of MS course is not yet well established. We aimed to estimate the impact of immune-related genes variability in the genetic architecture of two clinically different MS courses – primary progressive (PPMS) and relapsing-remitting (RRMS). MethodsWe performed the association analysis of 31 immune-related genes’ variants in pairwise comparisons of 110 PPMS patients, 564 RRMS patients and 424 healthy individuals (HI). ResultsHLA-DRB1*11 and *15, IL7RA rs6897932*C/C, CXCR5 rs523604*A/A, and CLEC16A rs6498169*G/G were found as MS-associated variants common for PPMS and RRMS. HLA-DRB1*07, IL4 rs2243250*C/C, IRF5 rs4728142*A/A, and IFNAR2 rs2248202*C were PPMS- associated when compared to HI and RRMS, while HLA-DRB1*09 and IL6 rs1800795*C were RRMS-associated when compared to HI and PPMS. In multiple logistic regression and ROC curve analyses composite regression models were characterized by area under the curve values of 0.769, 0.726, and 0.679 in comparisons “PPMS vs HI”, “RRMS vs HI”, and “PPMS vs RRMS”, respectively. ConclusionWe revealed genetic variants associated with PPMS, among which both variants common for two MS courses and distinguishing PPMS and RRMS were found. Observed genetic features of two MS courses may underlie different impact of autoimmune inflammatory processes in development of PPMS and RRMS, however additional studies on larger PPMS samples are strictly needed.

A genetic link between CXCR5 and IL2RA gene polymorphisms and susceptibility to multiple sclerosis

ABSTRACTObjectives: Multiple sclerosis (MS) is a T-cell-mediated disease of the central nervous system that develops in individuals possessing a complex susceptibility trait. We explored relationship between gene polymorphisms in MS.Methods: To identify the associations of CXCR5 and IL2RA gene polymorphisms with susceptibility to MS, we recruited 263 MS patients from the Han nationality and 138 from the Hui nationality as MS group and 284 healthy volunteers from the Han nationality and 156 from the Hui nationality as controls. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was employed to test gene polymorphisms of IL2RA (rs2104286 and rs12722489). Sequenom MassARRAY system was applied to analyze genotyping of CXCR5 (rs3922).Results: The genotypes and allele frequency distributions at the loci of IL2RA rs2104286 and rs12722489 showed significant differences between the MS and control groups. The gene polymorphisms at the loci of IL2RA rs2104286 and rs12722489 may increase the onset risk of MS. IL2RA-rs2104286 showed a positive relationship with CXCR5-rs3922. The same relationship was also observed between IL2RA-rs12722489 and CXCR5-rs3922. The genotypes and allele frequencies of loci of rs2104286 and rs12722489 were significantly different in MS clinical subtypes and severity (EDSS score). Additionally, CAC and TGC haplotype at rs3922-rs12722489-rs2104286 may reduce the risk of MS, while CGT and TGT haplotypes increase the risk.Conclusion: The gene polymorphisms at the loci of IL2RA rs2104286 and rs12722489 are closely associated with susceptibility to MS in the Han and Hui nationalities.

The immune response mediator genes polymorphic variants as predictors of the etanercept efficacy in juvenile idiopathic arthritis

Objective ― The aim of the study was to investigate the relationship of the alleles and genotypes of the immune response mediator genes polymorphic loci (rs1800629, rs909253, rs16944, rs6822844, rs2104286, rs1800795, rs1800872, rs3087243, rs755622 rs28362491, rs2240336, rs2476601) with the etanercept efficacy in juvenile idiopathic arthritis (JIA) patients. Material and Methods ― The study included 39 JIA patients from Bashkortostan, Russia. Achieving the American College of Rheumatology Pediatric 70 (ACR Pedi 70) response was regarded as the presence of the response to etanercept (otherwise – as the absence), while achieving clinical remission on medication – as the sufficient response (otherwise – as the insufficient). Genotyping was performed using real-time polymerase chain reaction method. Results ― The predictors of an increased risk of the non-response to etanercept were the IL1B rs16944*TT (pcor=0.023), NFKB1 rs28362491*II (pcor=0.042) genotypes, and of the increased risk of the insufficient response to etanercept – the IL2RA rs2104286*AA (pcor=0.010), NFKB1 rs28362491*II (pcor=0.026) genotypes. The markers of the decreased risk of the non-response to etanercept were the IL1B rs16944*C (pcor=0.046), NFKB1 rs28362491*D (pcor=0.029) alleles, and of the decreased risk of the insufficient response to etanercept – the IL2RA rs2104286*AG genotype (pcor=0.049), IL2RA rs2104286*G allele (pcor=0.005). Conclusion ― In this study the association of the alleles and genotypes of the IL1B rs16944, IL2RA rs2104286, NFKB1 rs28362491 polymorphic loci with the etanercept efficacy in JIA patients was established.

The IL7RA rs6897932 polymorphism is associated with progression of liver fibrosis in patients with chronic hepatitis C: Repeated measurements design.

The polymorphisms at the α-chain of the IL-7 receptor (IL7RA) have been related to T-cell homeostasis and development and may contribute to immune system deregulation. In the present study, we analyzed the association between IL7RA polymorphisms and the progression of liver fibrosis in patients infected with HCV. We carried out a retrospective study with a design consisting of repeated measurements in 187 HCV-infected patients, to study the risk prediction of liver fibrosis progression using genetic factors. We genotyped the rs6897932, rs987106 and rs3194051 IL7RA polymorphisms using the Agena Bioscience’s MassARRAY. Transient elastography was used to measure liver stiffness. The used cut-offs were: <7.1 kPa (F0-F1), 7.1–9.4 kPa (F2; significant fibrosis), 9.5-12.4 kPa (F3; advanced fibrosis), and ≥12.5 kPa (F4; cirrhosis). All HCV genotypes were analyzed. The median of follow-up time was 47.9 months. Baseline liver stiffness measurement (LSM) values did not show significant statistical differences for IL7RA genotypes (p>0.05). In univariate analysis, the rs6897932 T allele had a positive relationship with an increase in LSM (arithmetic mean ratio (AMR) = 1.21 (95%CI = 1.08; 1.36); p = 0.001), progression to advanced fibrosis (F≥3) (odds ratio (OR) = 2.51 (95%CI = 1.29; 4.88); p = 0.006) and progression to cirrhosis (F4) (OR = 2.71 (95%CI = 0.94; 5.03); p = 0.069). In multivariable analysis, the rs6897932 T allele was related to a higher increase of LSM values during follow-up (adjusted AMR = 1.27 (95%CI = 1.13; 1.42); p<0.001) and higher odds of progression to advanced fibrosis [adjusted OR = 4.46 (95%CI = 1.87; 10.62); p = 0.001], and progression to cirrhosis [adjusted OR = 3.92 (95%CI = 1.30; 11.77); p = 0.015]. Regarding IL7RA rs987106 and rs3194051 polymorphisms, we did not find significant results except for the relationship between IL7RA rs987106 and the increase in LSM values [adjusted OR = 1.12 (95%CI = 1.02; 1.23); p = 0.015]. The IL7RA rs6897932 polymorphism seems to be related to increased risk of liver fibrosis progression in HCV-infected patients. Thus, the rs6897932 polymorphism could be related to the physiopathology of CHC and might be used to successfully stratify the risk of CHC progression.

Analysis of Associations of Polymorphisms of Genes Encoding Cytokine Receptors with the Clinical Features of Multiple Sclerosis

Objectives. To analyze the associations of gene polymorphisms in the IL7RA (rs689932), IL2RA (rs2104286), and TNFRSF1A (rs1800693) genes with the severity and early clinical characteristics of remitting multiple sclerosis (MS). Materials and methods. Genotyping studies were performed on the polymorphic loci of the IL7RA (rs689932), IL2RA (rs2104286), and TNFRSF1A (rs1800693) genes from 508 ethnically Russian patients with debut of remitting MS followed by analysis of associations of variants of these genes with the severity and variants of MS and the duration of the first remission. Results and conclusions. Assessments on the MSSS identified significant increases in the frequency of the TNFRSF1A*T/T genotype in the group of patients with mild MS (MSSS ≤ 3) and of the TNFRSF1A*C allele in the group of patients with moderate and severe MS (MSSS > 3). Depending on the variant of the manifestations of MS, there was a significant increase in the frequency of the TNFRSF1A*T allele in patients with favorable variants of the manifestations of MS (optical neuritis or sensory impairments), while there was a significant increase in the frequency of the TNFRSF1A*C/C allele in patients with unfavorable variants of manifestations. No associations were found between polymorphisms of the genes of interest with the duration of first remission. Associations between variants of the study genes and the clinical characteristics of MS being compared were also sought in relation to the polymorphic locus of the CTLA4 gene (rs231775), for which an association has previously been established between carriership of the CTLA4*G allele and short-duration first remissions (up to one year). Carriership of the (CTLA4*G + TNFRSF1A*C) combination was more significant than carriership of CTLA4*G alone and was associated with this same characteristic. An additional combination was found, the (CTLA4*G/G + IL7RA*T) combination, which was associated with short first remission. No other differences in carriership frequencies of allele combinations were seen in relation to the clinical characteristics of MS.

Assessment of IL-7RA T244I Polymorphism as a Risk Factor of Multiple Sclerosis in Turkish Population.

The T244I variant of the IL-7RA gene, rs6897932, is one of the first polymorphisms found to be associated with the development of multiple sclerosis (MS). Although several studies provided evidence for the association of MS and this variant, other studies could not confirm this result. These inconsistent results suggest that the role of this polymorphism in the development of disease is associated with ethnicity. We investigated rs6897932 polymorphisms in a large cohort of patients with MS and healthy controls in a turkish population. In our study, there were no significant differences in genotype frequencies in the IL-7RA rs6897932 polymorphism and no significant difference between C and T alleles in patients with MS and controls. This study is the first to evaluate the risk of the rs6897932 polymorphism in turkish patients with MS.

Impact of Immune response-associated gene polymorphisms on tumor response in rectal cancer patients treated with capecitabine +/- oxaliplatine and radiation in the ACCORD-12/PRODIGE-2 phase III trial.

e15151 Background: We examined whether 133 germline polymorphisms (SNPs) in 15 candidate genes (CSF1R, IL8RA, TLR4, IL10, IL10RA, CTLA4, IL2, IL2RA, TGF b1, ICOS, IL13, IL13RA2, IFNgR, IL15 and IL15RA) would predict clinical outcome in the ACCORD-12 phase III trial which randomly compared neoadjuvant radiotherapy (RT) plus capecitabine (CAP45) with dose-intensified RT plus capecitabine and oxaliplatin (CAPOX50) in T3-4 Nx M0 resectable rectal cancer. Methods: A candidate-gene association study was conducted in 316 patients (n = 161 in the CAPOX50 and n = 155 in the CAP45 arm). The primary end-point was tumor response according to the Dworak score in each arm. Logistic regressions were used to assess univariate/multivariate associations. The Storey and Tibshirani method based on the control of false discovery rate was used ( q-value &lt; 0.10 (adjusted p-value) considered as true discovery). Multivariate models adjusted on treatment arm and T stage were performed to determine prognostic and predictive values of SNPs for tumor response. Results: In univariate analysis, two SNPs in IL2RA (rs11256456: OR = 5.1 [2.38; 11] and rs706781: OR = 4.2 [1.98 ; 8.74]) were significantly associated with the Dworak score in the CAP45 arm, and one in IL2RA the CAPOX50 arm (rs2104286: OR = 0.11 [0.01 ; 0.90]. All were confirmed in the multivariate analysis. A significant haplotypic effect was observed in the CAP-45 arm (p = 0.0001). Interaction was significant for IL2RA rs11256456 ( p= 0.03) and rs706781 ( p= 0.002) and no significant for IL2RA rs2104286 ( p= 0.722), suggesting a predictive deleterious effect the first two ones for response to oxaliplatin-based chemoRT, and a prognostic effect of the third one for response to chemoRT (+/- oxaliplatin). None of the three IL2RA SNPs were correlated with survival in the multivariate analysis. Conclusions: This pharmacogenetic analysis shows that SNPs in IL2RA have a significant association with response to chemoRT with capecitabine in patients with locally advanced rectal cancer. Their predictive effect may identify patients in whom oxaliplatin addition to chemoRT is deleterious.

CD6 gene polymorphism rs17824933 is associated with multiple sclerosis in Indian population.

Background:Multiple sclerosis (MS) prevalence has increased worldwide. The known genetic association for MS in the west has not been studied in detail in nonwhite populations and particularly Indians.Objective:The objective of this study was to evaluate some known genetic variations outside the major histocompatibility complex (MHC) region associated with MS in patients of Indian origin.Materials and Methods:We investigated 10 gene-associated single nucleotide polymorphisms (SNP's) outside the MHC region in 300 patients and 720 unrelated controls. Genotyping was performed on an ABI7500 real-time polymerase chain reaction genotyping platform using predesigned TaqMan SNP genotyping assays.Results:CD6 gene associated SNP (rs17824933) showed significant association with MS (P = 4.2 × 10−5, odds ratio [OR] = 2.24, confidence interval (CI) = 1.51–3.33). A modest association was also noted for TMEM39A rs1132200 (P = 0.023, OR = 1.41, CI = 1.05–1.91) and IL2RA rs2104286 (P = 0.04, OR = 1.3, CI = 1.006–1.67). In the remaining SNPs, the allele frequencies were overexpressed in patients when compared to healthy controls.Conclusion:Our data illustrate the similarity in risk association between Indian and European populations for MS.

Association analysis of cytokine receptors' genes polymorphisms with clinical features of multiple sclerosis

To study the association of polymorphisms in the IL2RA and TNFRSF1A genes with severity and early clinical manifestations of remitted multiple sclerosis (MS). Five hundred and eight patients of Russian ethnicity with bout-onset MS were genotyped for IL7RA (rs6897932), IL2RA (rs2104286) and TNFRSF1A (rs1800693) polymorphisms. Association analysis of the gene variants with disease severity, variants of MS manifestation, and first remission duration was performed. Dividing the MS patients by disease severity, estimated with the MSSS, we found a significant increase in the TNFRSF1A*T/T genotype carriage in patients with milder MS course (MSSS≤3), and, respectively, in the TNFRSF1A*C allele carriage in patients with moderate to severe MS (MSSS> 3). Dividing the MS patients into two groups according to their MS manifestation variants, we revealed a significant increase in the TNFRSF1A*T allele carriage in patients with favorable variants of MS manifestation (optic neuritis or sensory disturbances), and of the TNFRSF1A*C/C genotype in patients with unfavorable variants (motor disorders, brain stem disorders, impaired coordination, pelvic disorders, mental disorders or polysymptomatic onset). No associations with first remission duration were observed. Multi-locus analysis to search for allelic combinations associated with the studied clinical features of MS was applied. In this analysis, a polymorphic variant of CTLA4 gene (rs231775), for which we have previously reported the association of the CTLA4*G allele with short first remission (less than 1 year), was also included. The carriage of biallelic combination (CTLA4*G + TNFRSF1A*C) was associated with short first remission more significantly than the carriage of CTLA4*G by itself. One more biallelic combination associated with short first remission (CTLA4*G/G + IL7RA*T), was identified. No other biallelic combinations significantly associated with the clinical features studied were observed.