Associations Between microRNA-related Genetic Polymorphisms and Clinical Response to Methotrexate in Chinese Rheumatoid Arthritis Patients.

BACKGROUND: Emerging evidence indicates that microRNA (miRNA)-related genetic polymorphisms are strongly involved in the post-transcriptional regulation of the expression of pharmacokinetics and pharmacodynamics- related genes, therefore contributing to the genetic variability of drug response. OBJECTIVE: To investigate the associations of miRNA-related genetic polymorphisms, including miRNA-5189 rs562929801, miRNA-595 rs4909237, SLCO1A2 rs4149009 and MTHFR rs3737966, and clinical response to methotrexate in Chinese rheumatoid arthritis patients. METHODS: One hundred patients treated with MTX for approximately 3 months were prospectively followed up to evaluate the clinical response according to European League Against Rheumatism (EULAR) good and moderate response, disease activity score in 28 joint counts - erythrocyte sedimentation rate (DAS28-ESR) low disease activity (LDA) and remission (REM), change in DAS28-ESR (ΔDAS28-ESR) and ΔDAS28-ESR > 0.6. Genetic polymorphisms were genotyped utilizing the HI-SNP technology. RESULTS: Of the 100 patients with a mean age of 52.23 ± 12.71 years, 81 patients were female (81.00%). After adjusting potential confounders, the major allele of miRNA-5189 rs562929801 was found to be significantly associated with EULAR response (A/A + A/G versus G/G, RR = 0.81, 95% CI = 0.67-0.99, P = 0.04) and ΔDAS28-ESR > 0.6 under dominant model (A/A + A/G versus G/G, RR = 0.83, 95% CI = 0.71-0.98, P = 0.03). However, nonsignificant evidence was detected for the remaining three miRNA-related genetic polymorphisms in neither univariable analysis nor multivariable analysis. CONCLUSION: Our results indicated that miRNA-5189 rs562929801 was significantly associated with clinical response to MTX, and this association warrants further replication studies with larger sample sizes.

Associations Between Genetic Polymorphisms Within Transporter Genes and Clinical Response to Methotrexate in Chinese Rheumatoid Arthritis Patients: A Pilot Study.

Purpose: To investigate the associations between genetic polymorphisms within transporter genes and clinical response to methotrexate (MTX) in Chinese rheumatoid arthritis (RA) patients. Patients and Methods: A total of 100 RA patients receiving MTX were prospectively followed up for approximately 3 months to determine the clinical response based on several criteria, including European League Against Rheumatism (EULAR) good and moderate response, disease activity score in 28 joint counts - erythrocyte sedimentation rate (DAS28-ESR) low disease activity (LDA), change in DAS28-ESR (ΔDAS28-ESR) and ΔDAS28-ESR >0.6. Fifty-four single nucleotide polymorphisms (SNPs) within seven transporter genes, including SLC19A1, ABCB1, ABCC1~4 and ABCG2, were genotyped. Results: Multivariable analysis revealed that SLC19A1 rs12659 and rs3788200, ABCC2 rs3740066, rs4148396 and rs717620 were significantly associated with EULAR good and moderate response, and ABCC2 rs3740066 and rs717620 were significantly associated with DAS28-ESR LDA, and ABCB1 rs1128503, rs4148737 and ABCC3 rs2277624, rs4148416 were significantly associated with ΔDAS28-ESR. Moreover, 12 genetic polymorphisms were found to be significantly associated with ΔDAS28-ESR >0.6. With adjustment for corresponding confounders, SLC19A1 TGAA haplotype consisting of rs1051266, rs1131596, rs12659 and rs3788200 was significantly associated with EULAR good and moderate response and ΔDAS28-ESR >0.6 compared with the most common haplotype CAGG. The ABCC2 haplotype TTT composed of rs717620, rs4148396 and rs3740066 was significantly associated with EULAR good and moderate response and ΔDAS28-ESR >0.6 compared with the most common haplotype CCC. Conclusion: Our results highlight the potential of genetic polymorphisms within transporter genes, particularly SLC19A1 and ABCC2, as predictors of clinical response to MTX in Chinese RA patients.

Assessment of genetic polymorphisms within nuclear factor-κB signaling pathway genes in rheumatoid arthritis: Evidence for replication and genetic interaction.

OBJECTIVE: This study was performed to replicate the associations of genetic polymorphisms within nuclear factor-κB (NF-κB) signaling pathway genes with rheumatoid arthritis (RA), and to further examine genetic interactions in a Chinese population. METHODS: A total of eleven single-nucleotide polymorphisms (SNPs) were genotyped in 594 RA patients and 604 healthy controls. RESULTS: Genetic association analysis revealed that NFKBIE rs2233434, TNIP1 rs10036748 and BLK rs13277113 were significantly associated with RA, cyclic citrullinated peptide (CCP)-positive RA and rheumatoid factor (RF)-positive RA, and TNFAIP3 rs2230926 was significantly associated with CCP-positive RA. Significant additive interaction was observed between NFKB1 rs28362491 and IKBKE rs12142086 (RERI = 0.76, 95% CI 0.13-1.38; AP = 0.57, 95% CI 0.11-1.03), NFKBIE rs2233434 and BLK rs13277113 (RERI = 1.41, 95% CI 0.88-1.94; AP = 0.85, 95% CI 0.50-1.20), NFKBIL rs2071592 and TNIP1 rs10036748 (RERI = 0.59, 95% CI 0.17-1.02; AP = 0.46, 95% CI 0.05-0.87), UBE2L3 rs5754217 and TNFSF4 rs2205960 (RERI = 0.50, 95% CI 0.16-0.84; AP = 0.57, 95% CI 0.09-1.05). Significant multiplicative interaction was detected between BLK rs13277113 and UBE2L3 rs5754217 (p = 0.02), BLK rs13277113 and TNFSF4 rs2205960 (p = 0.03). CONCLUSIONS: Our results lent further support to the role of NF-κB signaling pathway in the pathogenesis of RA from a genetic perspective.

Genetic association analysis of ATG16L1 rs2241880, rs6758317 and ATG16L2 rs11235604 polymorphisms with rheumatoid arthritis in a Chinese population.

OBJECTIVE: This study was performed to test whether ATG16L1 rs2241880, rs6758317 and ATG16L2 rs11235604 polymorphisms were associated with RA and further examine the genetic interaction between ATG16L1 and ATG16L2 in RA among a Chinese population. METHODS: A total of 594 RA patients and 604 healthy controls were included, and the genetic polymorphisms were genotyped based on HI-SNP technology. RESULTS: Significant associations of ATG16L1 rs2241880 polymorphism with RA (T/T versus C/T + C/C, OR = 1.32, 95% CI 1.04-1.67, P = 0.02), cyclic citrullinated peptide (CCP)-positive RA (genotype comparison, P = 5.38 × 10-3; T/T versus C/T + C/C, OR = 1.45, 95% CI 1.12-1.87, P = 4.86 × 10-3) and rheumatoid factor (RF)-positive RA (genotype comparison, P = 0.03; T versus C, OR = 1.23, 95% CI 1.01-1.49, P = 0.04; T/T versus C/T + C/C, OR = 1.44, 95% CI 1.10-1.88, P = 7.62 × 10-3) were found. Significant genetic interaction between ATG16L1 rs2241880 and ATG16L2 rs11235604 was associated RA (P = 0.03), and significant genetic interaction between ATG16L1 rs6758317 and ATG16L2 rs11235604 was associated with RA (P = 7.57 × 10-3), CCP-positive RA (P = 0.01) and RF-positive RA (P = 0.01). Consistently, stratification analysis found that significant associations of RA with ATG16L1 rs2241880, rs6758317 polymorphisms were only detected among individuals carrying C/T genotype of the ATG16L2 rs11235604 polymorphism. CONCLUSIONS: Our results indicated that ATG16L1 rs2241880 polymorphism was associated with RA in Chinese population, and provided evidence for genetic interaction between ATG16L1 and ATG16L2 in determing the development of RA, highlighting the involvement of autophagy in the pathogenesis of RA.

Associations of genetic polymorphisms within MALAT1, UCA1, FAM211A-AS1 and AC000111.6 with genetic susceptibility to rheumatoid arthritis.

Recently, several long non-coding RNAs (lncRNAs) including MALAT1, UCA1, ENST00000483588, and ENST00000456270 have been implicated in the pathogenesis of rheumatoid arthritis (RA), and we hypothesized that polymorphisms within these lncRNA genes might be genetic modifiers for the development of RA. A total of 10 potentially functional single-nucleotide polymorphisms (SNPs) were selected and genotyped in 1198 participants, including 594 RA patients and 604 healthy controls. Significant associations of FAM211A-AS1 rs2882581 (G vs. A, OR = 1.31, 95%CI 1.07-1.62, p = .01; G/G + A/G vs. A/A, OR = 1.40, 95%CI 1.08-1.83, p = .01), rs3744281 (T vs. A, OR = 1.25, 95%CI 1.02-1.54, p = .03; T/T vs. A/T + A/A, OR = 1.69, 95%CI 1.01-2.82, p = 4.59 × 10-2), and rs3760235 (A vs. G, OR = 1.32, 95%CI 1.04-1.68, p = .02; A/A vs. A/G + G/G, OR = 1.32, 95%CI 1.00-1.74, p = 4.89 × 10-2) with RF-positive RA were found. Functional annotation results indicated that these identified polymorphisms might regulate the expression of FAM211A-AS1 and nearby genes via impacting on transcription factor binding. Taken together, our results indicated that FAM211A-AS1 rs2882581, rs3744281, and rs3760235 were involved in the genetic background of RF-positive RA.

Plasma Long Non-Coding RNA Expression Profiles in Patients with Rheumatoid Arthritis.

BACKGROUND: Recently, long non-coding RNAs (lncRNAs) have attracted substantial attention owing to their unforeseen critical roles in a wide range of biological processes. The aim of our study was to provide an overview of lncRNA expression profiles in plasma of RA patients. METHODS: The Agilent LncRNA + mRNA Human Gene Expression Microarray V4.0 was employed to determine differentially expressed (DE) lncRNAs and mRNAs in plasma of four female newly diagnosed and DMARD-naïve RA patients and four female age-matched healthy controls. The KOBAS (KEGG Orthology Based Annotation System) software was applied to determine the gene ontology (GO) terms and pathway in which the DE mRNAs were enriched. Furthermore, a lncRNA-mRNA co-expression network was constructed according to the correlation between DE lncRNAs and mRNAs. RESULTS: Compared with healthy controls, a total of 289 DE lncRNAs (169 up-regulated and 120 down-regulated) and 468 DE mRNAs (280 up-regulated and 188 down-regulated) were found in the plasma of patients with RA. Bioinformatics analysis indicated that the DE mRNAs might be involved in the pathogenesis of RA mainly through platelets. In addition, a co-expression network composed of 229 network nodes and 340 connections between 116 lncRNAs and 113 mRNAs was constructed. CONCLUSIONS: We characterized the plasma lncRNA expression profiles in RA patients for the first time. Our results could shed new light on the pathogenesis of RA and help identify lncRNAs as novel diagnostic biomarkers and therapeutic targets for RA.

The clinical value of hematological markers in rheumatoid arthritis patients treated with tocilizumab.

BACKGROUND: Emerging evidence indicates that some hematological markers have critical value in evaluating treatment response. This study was performed to determine the clinical value of hemoglobin (Hb), platelet (Plt), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) in rheumatoid arthritis (RA) patients treated with tocilizumab (TCZ). METHODS: Fifty-two RA patients receiving TCZ were recruited and followed for 6 months. The values of abovementioned hematological markers were collected. Clinical disease activity index (CDAI) and disease activity score based on 28 joints (DAS28)-ESR were calculated. Correlation analysis was conducted by calculating Pearson's correlation coefficient. The change in disease activity between groups according to the baseline level of hematological markers was compared by t test. RESULTS: Significant correlation between change in NLR (△NLR), change in PLR (△PLR), and change in CDAI (△CDAI) was found (△NLR: r = 0.30, P = 0.03; △PLR: r = 0.31, P = 0.03). The change in Plt (△Plt) was correlated with change in DAS28-ESR (△DAS28-ESR) (r = 0.36, P = 8.24 × 10-3 ). Greater improvement in CDAI was seen in patients categorized into Plt high group (t = 2.06, P = 0.04), NLR high group (t = 2.15, P = 0.04), and PLR high group (t = 2.41, P = 0.02) compared with the contrast group. CONCLUSION: Our study demonstrated that △Plt, △NLR, and △PLR could be used to monitor the clinical response to TCZ. RA patients with high baseline levels of Plt, NLR, and PLR achieved more improvement, indicating these hematological markers might be utilized to guide TCZ treatment.

Body Mass Index and Clinical Response to Tocilizumab in Patients With Rheumatoid Arthritis.

OBJECTIVES: This study aims to determine whether baseline body mass index (BMI) affects clinical response to tocilizumab (TCZ) after six months of treatment in rheumatoid arthritis (RA) patients. PATIENTS AND METHODS: In this prospective study, a total of 52 RA patients (10 males, 42 females; mean age 50.6±12.2 years; range, 23 to 73 years) receiving intravenous TCZ were consecutively recruited and followed-up for six months. BMI was calculated before initiation of TCZ treatment. The primary clinical response criterion was clinical disease activity index (CDAI) low disease activity (LDA) and the secondary clinical response criteria included CDAI remission, disease activity score based on 28 joints (DAS28)-erythrocyte sedimentation rate (ESR) LDA, DAS28-ESR remission, European League Against Rheumatism (EULAR) good response, and decreased DAS28-ESR (ΔDAS28-ESR)≥1.2. RESULTS: The number of RA patients classified as normal weight, overweight, and obese according to baseline BMI was 38 (73.1%), eight (15.4%), and six (11.5%), respectively. Similar baseline BMI median levels were found between RA patients reaching CDAI LDA and non-LDA: 21.11 (18.94-23.72) versus 20.78 (20.03-22.29) (p=0.98), and non-significant difference in the proportion of responders between normal weight and overweight/obese RA patients was found (p=0.47). No significant difference was found when the secondary clinical response criteria were applied. CONCLUSION: Our study demonstrates that BMI is not associated with clinical response to TCZ among RA patients and TCZ may be used to treat RA patients regardless of BMI levels.