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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.

Han Cen,1– 3 Qin-Wen Wen,4 Han-Qing Zhang,4 Hang Yu,4 Zhen Zeng,2 Ting Jin,2 Ting-Hui Wang,4 Wen Qin,4 Hua Huang,4 Xiu-Di Wu4 1Institute of Geriatrics, The Affiliated Hospital of Medical School, Ningbo University, Ningbo, Zhejiang, People’s Republic of China; 2Department of Preventive Medicine, Medical School of Ningbo University, Ningbo, Zhejiang, People’s Republic of China; 3Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, Zhejiang, People’s Republic of China; 4Department of Rheumatology, Ningbo First Hospital, Ningbo Hospital of Zhejiang University, Ningbo, Zhejiang, People’s Republic of ChinaCorrespondence: Xiu-Di Wu, Department of Rheumatology, Ningbo First Hospital, Ningbo Hospital of Zhejiang University, 59 Liuting Road, Ningbo, Zhejiang, 315010, People’s Republic of China, Tel +86 574 87085588, Fax +86 574 87291583, Email awu1100@aliyun.comPurpose: 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.Keywords: rheumatoid arthritis, methotrexate, transporter, single-nucleotide polymorphism, clinical response

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 hypothesi...

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

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.

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.

Background: Association of rs1344706 in the ZNF804A gene (2q32.1) with schizophrenia was first reported in a genome wide scan conducted in a sample of 479 cases and replicated in 6666 cases. Subsequently, evidence by replication was obtained in several samples with European- and Asian ancestral background. Methods: We report ascertainment, clinical characterization, quality control, and determination of ancestral background of a case control sample from Indonesia, comprising 1067 cases and 1111 ancestry matched controls. Genotyping was performed using a fluorescence-based allelic discrimination assay (TaqMan SNP genotyping assay) and a newly designed PCR-RFLP assay for confirmation of rs1344706 genotypes. Results: We confirmed association of the T-allele of rs1344706 with schizophrenia in a newly ascertained sample from Indonesia with Southeast Asian ancestral background (P = 0.019, OR = 1.155, 95%, CI 1.025-1.301). In addition, we studied several SNPs in the vicinity of rs1344706, for which nominally significant results had been reported. None of the association P values of the additional SNPs exceeded that of rs1344706. Conclusion: We provide additional evidence for association of the ZNF804A gene with schizophrenia. We conclude that rs1344706 or a yet unknown polymorphism in linkage disequilibrium is also involved in conferring susceptibility to schizophrenia in samples with different (Asian) ancestral backgrounds. Refereed/Peer-reviewed