Relation of the Fas and FasL gene polymorphisms with susceptibility to and severity of rheumatoid arthritis

To investigate associations of the Fas and FasL genes polymorphisms with rheumatoid arthritis (RA). One hundred patients with RA and age-, sex- and ethnically matched 101 controls were included. Four polymorphisms of Fas (-670 A>G rs1800682, -1377 G>A rs2234767) and FasL (IVS2nt-124 A>G rs5030772, -844 T>C rs763110) genes were typed from genomic DNA. Genotype distributions and allelic frequencies were compared between patients and control subjects. After the history and clinical examination of patients with RA, in terms of pain, fatigue and general health status were evaluated by visual analogue scale. Thereafter, erythrocyte sedimentation rate, C-reactive protein, blood count and rheumatoid factor levels were measured. The Disease Activity Score-28, Health Assessment Questionnaire and modified Sharp score were used to evaluate the disease activity, functional disability and radiological damage, and their relationships with the Fas and FasL gene polymorphisms were investigated. In patients with RA, CT and TT genotypes of FasL-844, polymorphism were twofold and 4.8-fold higher, and AA genotype of FasL IVS2nt-124 polymorphism was 3.4-fold higher than the control group (respectively, p = 0.05, p = 0.002, p = 0.039). T allele of FasL-844 polymorphism was more frequent in patients than controls (respectively, 52.5 vs. 41.4 %, p = 0.027). Any association was not detected between Fas (-670 A>G, -1377 G>A) and FasL (-844 T>C, IVS2nt-124 A>G) gene polymorphisms with the disease activity scores, functional disability and radiological damage. However, the Fas-670 A>G polymorphism was associated with drug therapy (p = 0.049). The distribution of GG genotype was higher compared to GA or AA genotypes in patients using triple disease-modifying antirheumatic drug therapy (71.4, 14.3 and 14.3 %, respectively). These findings suggest that the -844 T>C and IVS2nt-124 A>G polymorphisms in the FasL gene related with apoptosis may increase genetic susceptibility to RA in a Turkish population. In addition, the Fas-670 A>G gene polymorphism may be associated with disease progression. There is a need for further studies to clarify the genetic role of apoptosis in RA.     

Association of CTLA-4 but not CD28 gene polymorphisms with systemic lupus erythematosus in the Japanese population.

OBJECTIVE: Systemic lupus erythematosus (SLE) in a multisystem autoimmune disorder characterized by multiorgan pathology and autoantibodies against a variety of autoantigens. The CD28 and CTLA-4 genes might be candidate genes for SLE, because costimulation signals from CD80/CD86 to CD28/CTLA-4 have been suggested to play an important role in the activation or inactivation of T lymphocytes. METHODS: We investigated three polymorphic regions within the CTLA-4 gene, a C/T base exchange in the promoter region -318 (CTLA-4 -318C/T), an A/G substitution in the exon 1 position 49 (CTLA-4 49A/G), an (AT)(n) repeat polymorphism in the 3' untranslated region of exon 4 [CTLA-4 3' (AT)(n)], and a CD28 gene polymorphism, a T/C substitution in the intron 3 position +17 (CD28 IVS3+17T/C), in SLE patients and controls. RESULTS: SLE patients had significantly higher frequencies of the CTLA-4 49G allele (P=0.003) and of the CTLA-4 (AT)(n) 106 bp allele (P=0.0008) than controls. We also found a strong linkage disequilibrium between the A allele of CTLA-4 49A/G and the 86 bp allele of CTLA-4 3' (AT)(n). On the contrary, no association was found between SLE and CTLA-4 -318C/T or CD28 IVS3 +17T/C. CONCLUSION: We conclude that the CTLA-4 gene appears to play a significant role in the development of SLE in the Japanese population.     

The association of PTPN22 rs2476601 polymorphism and CTLA-4 rs231775 polymorphism with LADA risks: a systematic review and meta-analysis

Although the polymorphisms of PTPN22 and the variants of CTLA-4 have been reported to be the susceptibility genes, which increased risk of latent autoimmune diabetes in adults (LADA), the results remained inconclusive. The aim of this meta-analysis was to evaluate the association between the polymorphisms of two genes and LADA. We performed a systematic review by identifying relevant studies and applied meta-analysis to pool gene effects. Data from ten studies published between 2001 and 2013 were pooled for two polymorphisms: rs2476601 in the PTPN22 gene and rs231775 in the CTLA-4 gene. Data extraction and assessments for risk of bias were independently performed by two reviewers. Fixed-effect model and random-effect model were used to pool the odds ratios; meanwhile, heterogeneity test, publication bias and sensitive analysis were explored. The minor T allele at rs2476601 and the minor G at rs231775 carried estimated relative risks (odds ratio) of 1.52 (95 % CI 1.29–1.79) and 1.39 (95 % CI 1.11–1.74), respectively. These alleles contributed to an absolute lowering of the risk of all LADA by 4.88 and 14.93 % when individuals do not carry these alleles. The estimated lambdas were 0.49 and 0.63, suggesting a codominant model of effects was most likely for two genes. In summary, our systematic review has demonstrated that PTPN22 rs2476601 and CTLA-4 rs231775 are potential risk factors for LADA. An updated meta-analysis is required when more studies are published to increase the power of these polymorphisms and LADA.     

Do SNPs in folate pharmacokinetic pathway alter levels of intracellular methotrexate polyglutamates and affect response? A prospective study in Indian patients

This study investigated the impact of seven polymorphisms in genes of folate transport and (de)glutamation pathway on methotrexate polyglutamate levels and response in patients with rheumatoid arthritis. This prospective study included patients with rheumatoid arthritis. They were treated with methotrexate (up to 25 mg per week) for 24 weeks and categorized by EULAR response criteria into responders (good and moderate) and non-responders. Using real-time Taqman discrimination assay, SNPs were genotyped—rs1045642 (ABCB1 3435C>T), rs1128503 (ABCB1 1236C>T), rs10106 (FPGS 1994A>G), rs1544105 (FPGS G>A), rs11545078 (GGH 452C>T), rs3758149 (GGH -401C>T), and rs1051266 (RFC1 80G>A). RBC methotrexate polyglutamate_1–5(MTX-glu_1–5) levels were determined at 4, 8, 16, and 24 weeks using by reverse phase HPLC using C-18 column followed by post column photo-oxidation. This study included 117 patients with rheumatoid arthritis (M:F?=?14:103). The mean dose of methotrexate at 24 weeks was 22.0?±?4.0 mg, with data on DAS28(3) at 24 weeks available in 96 patients—61 responders and 35 non-responders. Minor allele of GGH 452C>T had an association with non-response (odds ratio 2.9, 95% CI 1.4–5.6) and assuming the dominance of C, the recessive genetic model found GGH 452C>T CC genotype (odds ratio 9.5, 95% CI 1.2 to 76.0) was significantly associated with response. However, there was no difference in MTX-glu_1–5 levels among the various genotypes of this SNP (p?=?0.9). Other SNPs were neither associated with response nor with alteration in methotrexate polyglutamate levels. On logistic regression, GGH 452C>T CC genotype and DAS28(3) at baseline were independent predictors of response. GGH 452C>T CC genotype was associated with response to methotrexate. None of the SNPs affected MTX-glu_1–5levels.     

Association of asthma severity and bronchial hyperresponsiveness with a polymorphism in the cytotoxic T-lymphocyte antigen-4 gene

OBJECTIVES: Cytotoxic T-lymphocyte antigen (CTLA)-4 is a homolog of CD28, which is expressed only on activated T cells. It binds to accessory molecule B7 and mediates T-cell-dependent immune response. Signaling through CTLA-4 may down-regulate type 1 T-helper cell proliferation; moreover, some studies suggest that CTLA-4 might also deliver a positive signal to type 2 T-helper cell activation. Disruption of this delicate balance of immune regulation may lead to autoimmune diseases or atopic diseases. To evaluate the possible role of CTLA-4 polymorphisms in bronchial asthma, we investigated the association between polymorphisms (exon 1 +49 A/G, promoter -318 C/T) and atopy, asthma severity, and bronchial hyperresponsiveness in bronchial asthma patients and a group of healthy control subjects. PATIENTS: Eighty-eight asthmatic patients and 88 healthy control subjects were studied. MEASUREMENTS AND RESULTS: Asthma severity assessment, methacholine challenge, allergy skinprick test, and serum total IgE measurements were performed. The genotypes of the CTLA-4 promoter (-318 C/T) and exon 1 (+49 A/G) in all subjects were determined using the polymerase chain reaction and restriction fragment length polymorphism. The CTLA-4 promoter (-318 C/T) polymorphism was shown to be associated with asthma severity, but not with asthma, atopy, or bronchial hyperresponsiveness. A significant association was found between severe asthma and the T allele (p = 0.037). The CTLA-4 exon 1 (+49 A/G) polymorphism was shown to be associated with bronchial hyperresponsiveness, but not with asthma, atopy, or asthma severity. Asthmatic patients of the GG genotype had more hyperresponsive airways than those with the AG or AA genotype (p = 0.019). CONCLUSIONS: The CTLA-4 promoter (-318 C/T) T allele may serve as a clinically useful marker of severe asthma. The CTLA-4 exon 1 (+49 A/G) polymorphism may have a disease-modifying effect in asthmatic airways.     

原发性胆汁性胆管炎患者血浆细胞毒性T淋巴细胞相关蛋白4基因多态性分析

目的 探讨原发性胆汁性胆管炎(PBC)患者血浆细胞毒性T淋巴细胞相关蛋白4(CTLA-4)基因多态性变化。方法 2015年9月～2020年12月我院诊治的PBC患者30例和同期健康体检者35例,采用聚合酶链反应-限制性片段长度多态性检测血浆CTLA－4基因rs231775、 rs4675369和rs7599230位点多态性。Logistic回归分析疾病风险关联。结果 PBC患者CTLA－4基因rs7599230位点基因型为CC型、CT型和TT型比率分别为16.7%、46.7%和36.6%,与健康人的20.0%、45.7%和34.3%比,无显著性差异(P＞0.05),等位基因C和T比率分别为40.0%和60.0%,与健康人群的42.9%和57.1%比,也无显著性差异(P＞0.05);PBC患者CTLA－4基因rs231775位点基因型为GG型和等位基因G比率分别为40.0%和61.7%,显著高于健康人的14.2%和35.7%(P＜0.05),AA基因型和等位基因A比率分别为16.7%和38.3%,显著低于健康人的42.9%和64.3%(P＜0.05);PBC患者CTLA－4基因rs4675369位点基因型为GG型和等位基因G比率分别为43.3%和65.0%,显著高于健康人的17.1%和41.4%(P＜0.05),AA基因型和等位基因A比率分别为13.4%和35.0%,显著低于健康人的34.3%和58.6%(P＜0.05);经非条件Logistic回归模型计算,校正性别和年龄,结果显示rs4675369位点GG基因型是影响PBC发生的危险基因型,其OR值为1.523((95%CI:1.113～2.085),rs231775位点GG基因型也是影响PBC发生的危险基因型,其OR值为1.636((95%CI:1.161～2.305) 。结论 CTLA-4基因rs231775和rs4675369位点GG基因型可能是PBC发生的易感基因型,值得进一步研究。     

CTLA-4 and MDR1 polymorphisms increase the risk for ulcerative colitis:A meta-analysis

AIM:To evaluate the correlations between cytotoxic T lymphocyte-associated antigen-4(CTLA-4) and multidrug resistance 1(MDR1) genes polymorphisms with ulcerative colitis(UC) risk.METHODS:Pub Med,EMBASE,Web of Science,Cochrane Library,CBM databases,Springerlink,Wiley,EBSCO,Ovid,Wanfang database,VIP database,China National Knowledge Infrastructure,and Weipu Journal databases were exhaustively searched using combinations of keywords relating to CTLA-4,MDR1 and UC. The published studies were filtered using our stringent inclusion and exclusion criteria,the quality assessment for each eligible study was conducted using Critical Appraisal Skill Program and the resultant high-quality data from final selected studies were analyzed using Comprehensive Meta-analysis 2.0(CMA 2.0) software. The correlations between SNPs of CTLA-4 gene,MDR1 gene and the risk of UC were evaluated by OR at 95%CI. Z test was carried out to evaluate the significance of overall effect values. Cochran's Q-statistic and I2 tests were applied to quantify heterogeneity among studies. Funnel plots,classic fail-safe N and Egger's linear regression test were inspected for indication of publication bias.RESULTS:A total of 107 studies were initially retrieved and 12 studies were eventually selected for metaanalysis. These 12 case-control studies involved 1860 UC patients and 2663 healthy controls. Our major result revealed that single nucleotide polymorphisms(SNPs) of CTLA-4 gene rs3087243 G A and rs231775 G A may increase the risk of UC(rs3087243 G A:allele model:OR = 1.365,95%CI:1.023-1.822,P = 0.035; dominant model:OR = 1.569,95%CI:1.269-1.940,P 0.001; rs231775 G A:allele model:OR = 1.583,95%CI:= 1.306-1.918,P 0.001; dominant model:OR = 1.805,95%CI:1.393-2.340,P 0.001). In addition,based on our result,SNPs of MDR1 gene rs1045642 C T might also confer a significant increases for the risk of UC(allele model:OR = 1.389,95%CI:1.214-1.590,P 0.001; dominant model:OR = 1.518,95%CI:1.222-1.886,P 0.001).CONCLUSION:CTLA-4 gene rs3087243 G A and rs231775 G A,and MDR1 gene rs1045642 C T might confer an increase for UC risk.     

Long-term disease and patient-reported outcomes of a continuous treat-to-target approach in patients with early rheumatoid arthritis in daily clinical practice

Patients in real life may differ from those in clinical trials. The aim of this study is to report 5-year outcomes of a continuous treat-to-target (T2T) approach in patients with rheumatoid arthritis (RA) in daily clinical practice. In the Dutch RhEumatoid Arthritis Monitoring cohort, all patients with a clinical diagnosis of RA were treated according to a protocolled T2T strategy, aimed at 28-joint Disease Activity Score (DAS28) <?2.6. Outcomes were percentages of patients in distinct levels of disease activity, mean course of DAS28 and prevalence of sustained (drug-free) remission. Also, data on functional disability (Health Assessment Questionnaire) and health-related quality of life (Short-Form 36) were examined. Mean DAS28 improved from 4.93 (95% CI 4.81–5.05) at baseline to 2.49 (95% CI 2.35–2.63) after 12 months and remained stable thereafter. Percentages of patients at 12 months with DAS28 <?2.6 (remission), DAS28 ≥?2.6 and ≤?3.2 (low disease activity), DAS28 >?3.2 and ≤?5.1 (moderate disease activity) and DAS28?>?5.1 (high disease activity) were 63, 16, 18 and 3%, respectively. Sustained remission (DAS28?<?2.6 during ≥?6 months) was observed at least once in 84% of the patients and drug-free remission (DAS28?<?2.6 during ≥?6 months after withdrawal of all disease-modifying anti-rheumatic drugs) in 36% of the patients. Functional disability and health-related quality of life significantly improved during the first 24 weeks. Continuous application of T2T in real-life RA patients leads to favourable disease- and patient-related outcomes.     

Serum progranulin irrelated with Breg cell levels,but elevated in RA patients,reflecting high disease activity

Soluble progranulin (PGRN) is known to directly regulate regulatory T cells; however, whether PGRN levels are elevated in patients with rheumatoid arthritis and affect the regulatory subsets of B cells remain unknown. In this study, a total of 80 RA patients and 60 healthy controls were studied. Serum progranulin levels were determined using enzyme-linked immune-sorbent assay. A receiver operating characteristic (ROC) curve was used to evaluate the feasibility of serum PGRN as a biomarker for distinguishing patients with RA. CD19⁺CD5⁺GrB⁺ B cells were analyzed by flow cytometry in peripheral blood mononuclear cells (PBMCs). Serum progranulin levels in RA patients (median, 59.4 ng/mL) and in RA patients DAS28 > 5.1 (median, 71.98 ng/mL) were much higher than those in normal controls (median, 46.3 ng/mL; P < 0.001). The area under the ROC curve for progranulin levels was 0.705 for RA versus normal controls and the area under the ROC curve for progranulin levels in RA patients DAS28 > 5.1 was 0.977 versus normal controls (P < 0.001). Interestingly, serum progranulin and DAS28, CRP, ESR were all positively correlated in RA patients (P < 0.001). The number of CD19⁺CD5⁺GrB⁺ B cells was significantly higher in RA patients (P < 0.05); however, the level of Breg cells was not related to PGRN (P > 0.05). Our findings indicated that induction of PGRN expression may play a role in RA immune reaction and PGRN levels could be a useful biomarker in RA inflammatory response, but irrelated with Breg cell levels.     

CTLA-4 +49A>G polymorphism of recipients of HLA-matched sibling allogeneic stem cell transplantation is associated with survival and relapse incidence

Conflicting observations have been reported about the role of CTLA-4 gene polymorphisms in the clinical outcome of allogeneic hematopoietic stem cell transplantation (HSCT). We have investigated three polymorphisms of the CTLA-4 gene (?318C>T, +49A>G, CT60G>A) in 133 donor/recipient pairs who underwent HLA-matched sibling donor HSCT for hematological malignancies. We found no association of the clinical outcome of the HSCT with either recipient or donor ?318C>T and CT60G>A polymorphisms. At variance, we found a significant association of donor +49A>G G/G genotype with longer overall survival (OS; log-rank test, P?=?0.04), and the number of +49A>G G-alleles in the recipient with longer OS (P?=?0.027), longer disease-free survival (P?=?0.036) and reduced relapse rate (P?=?0.042). However, only recipient +49A>G polymorphism was retained as independent prognostic factor in a multivariate analysis, suggesting that the expression of CTLA-4 on the cells of recipient may be relevant for the clinical outcome of HSCT.     

No association of polymorphisms of the CTLA-4 exon 1(+49) and promoter(-318) genes with rheumatoid arthritis in the Korean population

The aim of this study is to investigate the significance of the polymorphisms of the cytotoxic T lymphocyte associated antigen-4 (CTLA-4) exon 1(+49) and promoter(-318) genes in rheumatoid arthritis (RA). Polymerase chain reaction of genomic DNA-restriction fragment length polymorphism was used to determine genotypes of the CTLA-4 exon 1(+49) and promoter(-318) in 86 RA patients and 86 healthy control subjects. There was no significant difference in genotype, allele and phenotype frequencies of the CTLA-4 exon 1(+49) and promoter(-318) genes between RA patients and control subjects. There was no significant difference in age at onset, severity, functional class (> or = 3), physician global assessment, ESR, CRP or RF titer in patients with RA according to the CTLA-4 polymorphisms. Our data show that the polymorphisms within the CTLA-4 exon 1(+49) and promoter(-318) genes are not associated with susceptibility to RA and its clinical/serological manifestations in the Korean population.     

Cytotoxic T lymphocyte associated antigen-4 gene polymorphisms confer susceptibility to primary biliary cirrhosis and autoimmune hepatitis in Chinese population

AIM: To investigate the association between Chinese patients with autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and the polymorphisms of cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) gene promoter (-318) and exon 1 (+49). METHODS: CTLA-4 promoter (-318 T/C) and exon1 (+49A/G) polymorphisms were genotyped via restriction fragment length polymorphism methods in 62 Chinese AIH patients, 77 Chinese PBC patients and 160 healthy controls. RESULTS: We found a significant association in CTLA-4 gene exon1 49 A/G polymorphism between PBC patients and controls (P = 0.006) and the frequency of G alleles was significantly increased in comparison with controls (P = 0.0046, OR = 1.8). We also found the frequency of C alleles in promoter -318 was significantly increased in AIH patients compared with controls (P = 0.02, OR = 0.41). Although the genotype distribution of the CTLA-4 exon 1-promoter gene was not significantly different between AIH and PBC patients and controls, the occurrence of GG-CC was increased in two groups of patients (AIH: 32.3%, PBC: 37.7%, control: 22.5%). CONCLUSION: Polymorphisms of CTLA-4 gene probably confer susceptibility to AIH and PBC in Chinese population.     

CTLA-4 gene polymorphisms in Chinese patients with ulcerative colitis

BACKGROUND: Ulcerative colitis (UC) is characterized by chronic inflammation of the colon and rectum as a result of an exaggerated T-cell response. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is a T cell-restricted surface molecule induced with TCR or CD28 activation. There is evidence for genetic involvement of CTLA-4 in several autoimmune diseases, with the focus on the possible role of genetic variation of the CTLA-4 locus. The aim of this study was to investigate CTLA-4 gene polymorphisms in patients with UC in a Chinese population with Han nationality. METHODS: The C-318T polymorphism in the promoter region and A+49G polymorphism in exon 1 of the CTLA-4 gene were studied by a polymerase chain reaction-sequence-specific primer method. We studied 82 unrelated patients with UC and 204 healthy controls in a Chinese population with Han nationality. RESULTS: The frequency of the haplotype 2,3 (-318C+49G/-318T+49A) was 26% in patients with UC and 41% in healthy controls (Fisher exact test P = 0.0147, odds ratio = 0.4918, 95% confidence interval: 0.2784 - 0.8688), but this significance disappeared when Bonferoni correction was applied. No other significant differences in the distribution of allele and genotype frequencies were observed between C-318T and A+49G gene polymorphisms and UC in the Chinese Han population. CONCLUSION: The C-318T and A+49G polymorphisms of the CTLA-4 gene were not associated with UC in Chinese Han patients.     

CTLA-4基因多态性与中国南方汉族人Graves病的相关性

用PCR-RFLP和PCR．SSLP分别确定CTLA-4基因第1外显子49位点基因型和第4外显子3，末端AT重复序列的基因型，分析广东汉族120例Graves病患者及123名正常对照组CTLA-4基因多态性。结果显示CTLA-4基因外显子1A49G及外显子4（AT）n多态性与广东汉族人GD不相关。     

Effect of total knee arthroplasty on disease activity in patients with established rheumatoid arthritis: 3-year follow-up results of combined medical therapy and surgical intervention

Though excellent clinical results have been reported for total knee arthroplasty (TKA) in rheumatoid arthritis (RA) patients, the medium-term effect of TKA on RA disease activity remains unknown. This analysis aimed to assess changes in disease activity after TKA in patients with established RA. We analyzed the systemic effects of TKA on RA disease activity 3 years after intervention. Routine clinical and laboratory assessments were recorded at baseline, less than less than 0.5 years after TKA, and 3 years after TKA. Of the registered RA patients, 130 TKA patients were followed for 3 years after surgery. RA disease activity was measured using the Disease Activity Score 28 (DAS28). Patients were divided into three groups by preoperative baseline DAS28: low (DAS28 ≤ 3.2, n = 8), moderate (DAS28 > 3.2 but ≤5.1, n = 68), and high (DAS28 > 5.1, n = 54) disease activity. The postoperative DAS28 (<0.5 years [DAS1] and 3 years [DAS3] after surgery) scores of each patient were compared to their baseline (DAS0) scores using the paired t-test. The mean DAS28 decreased from 4.85 (DAS0) to 4.14 (DAS1; P = 1.07E-12), and this decrease was sustained at 3 years (DAS3 = 3.97; P = 4.73E-15). Subanalysis results revealed a systemic effect of TKA on disease activity in patients with moderate or high disease activity (DAS0 = 4.33; DAS1 = 3.72 [P = 5.94E-06]; DAS3 = 3.81 [P = 7.89E-06]; and DAS0 = 5.79; DAS1 = 4.86 [P = 1.14E-08]; DAS3 = 4.37 [P = 1.03E-11], respectively). While no significant changes in medication were noted, the average dose of prednisolone tended to decrease over time. We conclude that TKA, which is known to result in good clinical outcomes for damaged knees, has a secondary systemic effect on RA disease activity. Combination therapy consisting of medical treatment and surgical intervention is thought to effectively improve the condition of RA patients who have destructive arthritis in the knee joint, with the effect lasting for at least 3 years.     

Association of common gene variants in vitamin D modulating genes and colon cancer recurrence

Purpose

Low concentrations of 25-hydroxyvitamin D3 (25(OH)D) have been associated with increased risk and poor prognosis of various cancer types, including colon cancer. Common genetic variants in genes that influence circulating 25(OH)D levels may affect vitamin D concentrations and risk of vitamin D insufficiency. In the present study, we investigated the association of three functional gene variants in GC (rs2282679 T>G), DHCR7 (rs12785878 G>T) and CYP2R1 (rs10741657 A>G) with time to recurrence (TTR) in patients with stages II and III colon cancer.

Methods

Two hundred and sixty-four patients were included in this retrospective study. Genomic DNA was genotyped for GC rs2282679 T>G, DHCR7 rs12785878 G>T and CYP2R1 rs10741657 A>G by 5′-exonuclease (TaqMan?) technology.

Results

In the univariate analysis, GC rs2282679 GG was significantly associated with decreased TTR (HR = 3.30, 95 % CI 1.09–9.97, p = 0.034) in patients with surgery alone and remained significantly associated in multivariate analysis including lymph node involvement and clinical stage (HR = 3.64, 95 % CI 1.16–11.46, p = 0.027). In patients with adjuvant chemotherapy, GC rs2282679 T>G was not significantly associated with TTR (HR = 1.02, 95 % CI 0.44–2.37, p = 0.964). Furthermore, we observed a trend toward decreased TTR in patients harboring the CYP2R1 rs10741657 A>G gene variant including all patients (HR = 1.50, 95 % CI 0.98–2.28, p = 0.060). No association was found between DHCR7 rs12785878 G>T and TTR in our study cohort.

Conclusion

In conclusion, our results may indicate a prognostic effect of GC rs2282679 in stages II and III colon cancer patients with surgery alone. Larger studies have to be performed to validate our findings.     

-174G/C interleukin-6 gene promoter polymorphism predicts therapeutic response to etanercept in rheumatoid arthritis

To examine whether -174G/C interleukin-6 (IL-6) gene polymorphism, previously reported to correlate with IL-6 level, influences response to etanercept therapy in patients with rheumatoid arthritis. Seventy-seven patients with active RA were studied, at baseline and 6- and 12-month follow-up after etanercept therapy. Treatment response was estimated according to the European League Against Rheumatism response criteria. RA patients were genotyped for -174G/C IL-6 gene polymorphism by the PCR–RFLP method, and influence of genotype at this polymorphism to clinical response to etanercept was assessed. After 12 months of treatment, the percentage of responders (patients who had DAS28 improvement >1.2) was significantly increased in patients carrying the IL-6 -174G/G genotype (95.7 %) compared with those with the G/C (75.6 %) or CC (44.4 %) genotype (p = 0.006 by Chi-square test). No significant difference in the mean values of DAS28 improvement was observed between groups with different genotype. RA patients with an IL-6 -174GG genotype respond to etanercept better than patients with GC or CC genotype. This finding, if confirmed in future studies, suggests that the -174G/C IL-6 polymorphism may be a genetic marker of responsiveness to tumor necrosis factor-alpha (TNF-α) blockers in RA.     

CTLA-4 exon 1 polymorphism in patients with autoimmune blood disorders

CTLA-4 is a CD28 homologue that plays an important role in negative regulation of T-cell responses. Its transient expression on the surface of activated T cells antagonizes the activating signals and terminates the T-cell response. An A to G polymorphism at position 49 of the CTLA-4 first exon has recently been associated with several autoimmune disorders. In the present study we have examined the prevalence of the A and G alleles of the CTLA-4 gene in 50 patients with autoimmune hemolytic anemia (AIHA), of which 20 had idiopathic AIHA and 30 had AIHA and chronic lymphocytic leukemia (CLL), and in 60 patients with immune thrombocytopenic purpura (ITP). Control subjects were 100 healthy individuals and 100 CLL patients without clinical evidence for an autoimmune disease. The G allele was present at a significantly higher frequency among the patients with AIHA (P = 0.003), whereas no difference was observed between patients with ITP and controls. The G allele frequency was highest among CLL patients who had developed AIHA. The obtained data indicate that the G allele of CTLA-4 predisposes to the development of AIHA, particularly among patients with CLL.     

Apoptosis-related Fas and FasL gene polymorphisms’ associations with knee osteoarthritis

To investigate the associations between Fas and FasL gene polymorphisms and susceptibility to knee osteoarthritis. Genomic DNA was obtained from 146 patients with knee osteoarthritis and 102 healthy controls. Genotype distributions and allelic frequencies of four polymorphisms of Fas (-670 G>A rs1800682, -1377 G>A rs2234767) and FasL (IVS2nt-124 A>G rs5030772, -844 T>C rs763110) genes were compared between the groups. Thereafter, this association was investigated between patients and controls of the same sex. There were significant differences between patients with knee osteoarthritis and controls regarding the genotype distributions and allelic frequencies of Fas-1377 G>A polymorphism (P = 0.0001 and P = 0.005, respectively). The Fas-1377 GG genotype and G allele were significantly more frequent in patients with knee osteoarthritis than in controls. Genotype distributions and allelic frequencies of Fas-670 G>A, FasL-844 T>C, and FasL IVS2nt-124 A>G polymorphisms did not differ between the groups (P > 0.05). However, there were no significant differences between patients and controls of the same sex (P > 0.05). These findings suggest that the Fas-1377 G>A polymorphism in the Fas gene related with apoptosis may contribute to susceptibility to knee osteoarthritis in the Turkish population. There is a need for further studies to evaluate the role of apoptosis in large cohorts.     

Cytotoxic T-lymphocyte antigen-4 gene polymorphisms and human T-cell lymphotrophic virus-1 infection: their associations with Hashimoto's thyroiditis in Japanese patients.

Cytotoxic T-lymphocyte antigen-4 (CTLA-4) decreases the immune response of T cells by inactivating the signal that occurs with interaction between CD28 on T cells and B7 on antigen-presenting cells. Gene polymorphisms involving CTLA-4 promoter (-318 C/T), exon 1 (49 A/G), and exon 4 (microsatellite (AT)n) have been linked to Hashimoto's thyroiditis (HT) and other autoimmune diseases. HT also has a reported association with human T-cell lymphotrophic virus-1 (HTLV-1) infection. We investigated the occurrence of CTLA-4 polymorphisms in Japanese patients with HT with and without anti-HTLV-1 antibodies (HTLV-1 Ab). DNA samples from 143 patients with HT and 199 controls were subjected to polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis using the restriction enzymes, Bbv 1, Tse 1, and Mse 1. In the HTLV-1 Ab-positive group the exon 1 G allele was more frequent in patients with HT than in controls (67% vs. 53%, p = 0.0377), and in HTLV-1 Ab-negative group it was also frequent in patients with HT than in controls (68% vs. 53%, p = 0.0041). Frequency of the G allele in HT with HTLV-1 Ab was comparable to those without HTLV-1 Ab. Frequency of polymorphism in the promoter did not differ between patients with HT and controls, nor between controls with and without HTLV-1 Ab. HTLV-1 infection is not associated with CTLA-4 polymorphisms in either HT or controls. HTLV-1 infection is not regulated by genetic factor such as CTLA-4, and may affect occurrence of HT as an independent purely environmental factor.