Multiple polygenic risk scores can improve the prediction of systemic lupus erythematosus in Taiwan.

OBJECTIVE: To identify new genetic variants associated with SLE in Taiwan and establish polygenic risk score (PRS) models to improve the early diagnostic accuracy of SLE. METHODS: The study enrolled 2429 patients with SLE and 48 580 controls from China Medical University Hospital in Taiwan. A genome-wide association study (GWAS) and PRS analyses of SLE and other three SLE markers, namely ANA, anti-double-stranded DNA antibody (dsDNA) and anti-Smith antibody (Sm), were conducted. RESULTS: Genetic variants associated with SLE were identified through GWAS. Some novel genes, which have been previously reported, such as RCC1L and EGLN3, were revealed to be associated with SLE in Taiwan. Multiple PRS models were established, and optimal cut-off points for each PRS were determined using the Youden Index. Combining the PRSs for SLE, ANA, dsDNA and Sm yielded an area under the curve of 0.64 for the optimal cut-off points. An analysis of human leucocyte antigen (HLA) haplotypes in SLE indicated that individuals with HLA-DQA1*01:01 and HLA-DQB1*05:01 were at a higher risk of being classified into the SLE group. CONCLUSIONS: The use of PRSs to predict SLE enables the identification of high-risk patients before abnormal laboratory data were obtained or symptoms were manifested. Our findings underscore the potential of using PRSs and GWAS in identifying SLE markers, offering promise for early diagnosis and prediction of SLE.

Effects of Human Leukocyte Antigen DRB1 Genetic Polymorphism on Anti-Cyclic Citrullinated Peptide (ANTI-CCP) and Rheumatoid Factor (RF) Expression in Rheumatoid Arthritis (RA) Patients.

Rheumatoid arthritis (RA) is a systemic disease characterized by non-infectious inflammation of the joints and surrounding tissues, which can cause severe health problems, affect the patient's daily life, and even cause death. RA can be clinically diagnosed by the occurrence of blood serological markers, rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (anti-CCP). However, about 20% of RA patients exhibit negative results for both markers, which makes RA diagnosis difficult and, therefore, may delay the effective treatment. Previous studies found some evidence that human leukocyte antigen (HLA)-related genes might be the susceptibility genes for RA and their polymorphisms might contribute to varieties of susceptibility and disease severity. This study aimed for the genetic polymorphisms of the RA patient genome and their effects on the RA patient's serological makers, RF and anti-CCP. A total of 4580 patients' electronic medical records from 1992 to 2020 were retrieved from the China Medical University Hospital database. The most representative single-nucleotide polymorphisms (SNPs) were identified through a genome-wide association study (GWAS) followed by enzyme-linked immunosorbent assay (ELISA) validation using the blood from 30 additional RA patients. The results showed significant changes at the position of chromosome 6 with rs9270481 being the most significant locus, which indicated the location of the HLA-DRB1 gene. Further, patients with the CC genotype at this locus were more likely to exhibit negative results for RF and anti-CCP than those with the TT genotype. The C allele was also more likely to be associated with negative results for RF and anti-CCP. The results demonstrated that a genetic polymorphism at rs9270481 affected the expression of RF and anti-CCP in RA patients, which might indicate the necessity to develop a personalized treatment plan for each individual patient based on the genetic profile.

D2 Receptors and Sodium Ion Channel Blockades of the Basolateral Amygdala Attenuate Lithium Chloride-Induced Conditioned Taste Aversion Applying to Cancer Chemotherapy Nausea and Vomiting.

Cancer patients regularly suffer from the behavioral symptoms of chemotherapy-induced nausea and vomiting. Particularly, it is involved in Pavlovian conditioning. Lithium chloride (LiCl) was used as the unconditioned stimulus (US) and contingent with the tastant, for example, a saccharin solution (i.e., the conditioned stimulus; CS), resulted in conditioned taste aversion (CTA) to the CS intake. The present study employed an animal model of LiCl-induced CTA to imitate chemotherapy-induced nausea and vomiting symptoms. Recently, the basolateral amygdala (BLA) was shown to mediate LiCl-induced CTA learning; however, which brain mechanisms of the BLA regulate CTA by LiCl remain unknown. The present study was designed to test this issue, and 4% lidocaine or D2 blocker haloperidol were microinjected into BLA between the 0.1% saccharin solution intake and 0.15M LiCl. The results showed lidocaine microinjections into the BLA could attenuate the LiCl-induced CTA. Microinjections of haloperidol blunted the CTA learning by LiCl. Altogether, BLA via the sodium chloride ion channel and D2 receptors control LiCl-induced conditioned saccharin solution intake suppression. The findings can provide some implications and contributions to cancer chemotherapy-induced nausea and vomiting side effects, and will help to develop novel strategies to prevent the side effects of cancer chemotherapy.

Mirabegron is better tolerated than solifenacin in Sjogren's syndrome patients with overactive bladder symptoms-A randomized controlled trial.

OBJECTIVES: This study investigates the efficacy and adverse events of beta-3 agonists and antimuscarinic agents for managing overactive bladder syndrome in Sjogren syndrome. METHODS: Sjogren's syndrome patients with an Overactive Bladder Symptom Score (OABSS) >5 were enrolled and were randomly assigned to mirabegron 50 mg/day or solifenacin 5 mg/day. Patients were evaluated on the recruitment day and reassessed at Week 1, 2, 4, and 12. The study's primary endpoint was to have a significant change in OABSS at Week 12. The secondary endpoint was the adverse event and crossover rate. RESULTS: A total of 41 patients were included in the final analysis, with 24 in the mirabegron group and 17 in the solifenacin group. The study's primary outcome was a change of the OABSS at Week 12. We found that both mirabegron and solifenacin significantly reduce patients' OABSS after 12 weeks of treatment. The evolution of the OABSS was -3.08 for mirabegron and -3.71 for solifenacin (p = .56). Six out of 17 patients from the solifenacin group crossed over to the mirabegron arm due to severe dry mouth or constipation, while none from the mirabegron arm crossed over to the solifenacin group. Sjogren's syndrome-related pain was also improved in the mirabegron group (4.96-1.67, p = .008) compared to the solifenacin group (4.39-3.4, p = .49). CONCLUSIONS: Our study showed that mirabegron is equally effective as solifenacin in treating Sjogren's syndrome patients with overactive bladder. Mirabegron is superior to solifenacin in terms of treatment-related adverse events.

A Functional Polymorphism Downstream of Vitamin A Regulator Gene CYP26B1 Is Associated with Hand Osteoarthritis.

While genetic analyses have revealed ~100 risk loci associated with osteoarthritis (OA), only eight have been linked to hand OA. Besides, these studies were performed in predominantly European and Caucasian ancestries. Here, we conducted a genome-wide association study in the Han Chinese population to identify genetic variations associated with the disease. We recruited a total of 1136 individuals (n = 420 hand OA-affected; n = 716 unaffected control subjects) of Han Chinese ancestry. We carried out genotyping using Axiom Asia Precisi on Medicine Research Array, and we employed the RegulomeDB database and RoadMap DNase I Hypersensitivity Sites annotations to further narrow down our potential candidate variants. Genetic variants identified were tested in the Geisinger's hand OA cohort selected from the Geisinger MyCode community health initiative (MyCode®). We also performed a luciferase reporter assay to confirm the potential impact of top candidate single-nucleotide polymorphisms (SNPs) on hand OA. We identified six associated SNPs (p-value = 6.76 × 10-7-7.31 × 10-6) clustered at 2p13.2 downstream of the CYP26B1 gene. The strongest association signal identified was rs883313 (p-value = 6.76 × 10-7, odds ratio (OR) = 1.76), followed by rs12713768 (p-value = 1.36 × 10-6, OR = 1.74), near or within the enhancer region closest to the CYP26B1 gene. Our findings showed that the major risk-conferring CC haplotype of SNPs rs12713768 and rs10208040 [strong linkage disequilibrium (LD); D' = 1, r2 = 0.651] drives 18.9% of enhancer expression activity. Our findings highlight that the SNP rs12713768 is associated with susceptibility to and severity of hand OA in the Han Chinese population and that the suggested retinoic acid signaling pathway may play an important role in its pathogenesis.

Genetic contributions to female gout and hyperuricaemia using genome-wide association study and polygenic risk score analyses.

OBJECTIVES: To identify genetic variants and polygenic risk score (PRS) relating to female gout and asymptomatic hyperuricaemia (AH) in a genome-wide association study (GWAS). METHODS: Gout, AH and normouricemia controls were included from Taiwan biobank and China Medical University Hospital. All participants were divided into discovery and replication cohorts for GWAS. PRS was estimated according to whether the variant exhibited a protective effect on the phenotypes or not. Each cohort was separated into two groups by the age of 50 years old. RESULTS: A total of 59 472 females were enrolled, and gout and AH occupied 1.60% and 19.59%, respectively. Six variants located in genes SLC2A9, C5orf22, CNTNAP2 and GLRX5 were significantly predictors of female gout in those aged ≥50. For those aged <50 years old, only the variant rs147750368 (SPANXN1) on chromosome X was found. Most variants located in genes SLC2A9, ZNF518B, PKD2 and ABCG2 were found to be significantly related to AH in both age groups. The PRS could explain ∼0.59% to 0.89% of variance of gout in variants with protective effects, which showed 6.2 times of mean PRS in the risk variants, but only 1.2 times in the AH phenotype. Moreover, the PRS also revealed a dose-response trend between AH rates and quartile scores. CONCLUSION: The variants in gene SLC2A9 are the major genetic factors for females associated with gout in those aged ≥50. PRS can provide a more robust prediction of the gout/AH under a homogeneous selection of variants that show effects on the traits.

Single-cell RNA sequencing of immune cells in patients with acute gout.

Cell subpopulations in the blood and joint fluid of patients with gout are poorly understood. Single-cell RNA sequencing and bioinformatic tools were used to identify cell subsets and their gene signatures in blood and synovial fluid (SF) cells, determine their relationships, characterize the diversity, and evaluate interactions among specific cell types. We identified 34 subpopulations (5 types of B cells, 16 types of T and natural killer cells, 9 types of monocytes, and 4 other cell types) in the blood of five healthy subjects and seven patients with acute gouty, and the SF of three patients with acute gout. We found that naïve CD4 T cells and classical monocytes cell populations were enriched in patients with gout, whereas plasmacytoid dendritic cells and intermediate monocytes were more abundant in healthy subjects. SF was enriched in Th1/Th17 cells, effector memory CD8 T cells, mucosal-associated invariant T cells, and macrophages. Subclusters of these cell subpopulations showed different compositions between healthy subjects and those with acute gout, according to blood and SF samples. At the cellular level, the inflammation score of a subpopulation or subcluster was highest in SF, following by the blood of acute gout patients and healthy person, whereas energy score showed the opposite trend. We also detected specific cell-cell interactions for interleukin-1, tumor necrosis factor-α, and transforming growth factor-ß1 expression in the cells of patients with acute gout. Our study reveals cellular and molecular insights on inflammatory responses to hyperuricemia or uric crystal and may provide therapeutic guidance to improve treatments for gout.

Polygenic risk score trend and new variants on chromosome 1 are associated with male gout in genome-wide association study.

BACKGROUND: Gout is a highly hereditary disease, but not all those carrying well-known risk variants have developing gout attack even in hyperuricemia status. We performed a genome-wide association study (GWAS) and polygenic risk score (PRS) analysis to illustrate the new genetic architectures of gout and asymptomatic hyperuricemia (AH). METHODS: GWAS was performed to identify variants associated with gout/AH compared with normouricemia. The participants were males, enrolled from the Taiwan Biobank and China Medical University, and divided into discovery (n=39,594) and replication (n=891) cohorts for GWAS. For PRS analysis, the discovery cohort was grouped as base (n=21,814) and target (n=17,780) cohorts, and the score was estimated by grouping the polymorphisms into protective or not for the phenotypes in the base cohort. RESULTS: The genes ABCG2 and SLC2A9 were found as the major genetic factors governing gouty and AH, and even in those carrying the rs2231142 (ABCG2) wild-genotype. Surprisingly, variants on chromosome 1, such as rs7546668 (DNAJC16), rs10927807 (AGMAT), rs9286836 (NUDT17), rs4971100 (TRIM46), rs4072037 (MUC1), and rs2974935 (MTX1), showed significant associations with gout in both discovery and replication cohorts (all p-values < 1e-8). Concerning the PRS, the rates of gout and AH increased with increased quartile PRS in those SNPs having risk effects on the phenotypes; on the contrary, gout/AH rates decreased with increased quartile PRS in those protective SNPs. CONCLUSIONS: We found new variants on chromosome 1 significantly relating to gout, and PRS predicts the risk of developing gout/AH more robustly based on the SNPs' effect types on the trait.

Exploring RNA modifications, editing, and splicing changes in hyperuricemia and gout.

Hyperuricemia and gout are two of the most common metabolic disorders worldwide; their incidence is increasing with changes in lifestyle, and they are correlated with many diseases, including renal and cardiovascular diseases. The majority of studies on hyperuricemia and gout have focused on the discovery of the associated genes and their functions and on the roles of monocytes and neutrophils in the development of gout. Virtually no studies investigating the epigenomics of gout disease or exploring the clinical significance of such research have been conducted. In this study, we observed that the expression of enzymes involved in RNA modifications or RNA editing was affected in uric acid (UA)- or monosodium urate (MSU)-treated cell lines. RNA alternative splicing and splicing factors were also affected by UA or MSU treatment. We used transcriptome sequencing to analyze genome-wide RNA splicing and RNA editing and found significant changes in RNA splicing and RNA editing in MSU- or UA-treated THP-1 and HEK293 cells. We further found significant changes of RNA modifications, editing, and splicing in patients with gout. The data indicate that RNA modifications, editing, and splicing play roles in gout. The findings of this study may help to understand the mechanism of RNA splicing and modifications in gout, facilitating the development of new diagnostic and therapeutic strategies.

Hypothyroidism risk associated with rheumatoid arthritis: A population-based retrospective cohort study.

ABSTRACT: Studies on the thyroid disease risk in patients with rheumatoid arthritis (RA) associated with comorbidities are limited. This population-based retrospective cohort study investigated the hypothyroidism risk in patients with RA and the role of comorbidities.We used Taiwan National Health Insurance Research Database to identify 16,714 RA patients newly diagnosed in 2000 to 2008 and 66,856 control persons without RA, frequency matched by sex, age, and index year. Incidence and the RA group to controls hazard ratio of hypothyroidism were estimated.The hypothyroidism incidence was 1.74-fold higher in the RA group than in controls (16.6 vs 9.52 per 10,000 person-years), with the Cox method estimated adjusted hazard ratio of 1.67 (95% confidence interval = 1.39-2.00) after controlling for covariates. Near 75% of the study population were women, with the incidence 3.6-time higher than men in both groups. The hypothyroidism incidence increased with age, from 12.1 per 1000 person-years in 20 to 39 years to 20.0 per 1000 person-years in 60+ years in RA patients, higher than that in controls (7.17 vs 10.0 per 1000 person-years, respectively by age). Each comorbidity was related to an increased incidence and higher in the RA group than in controls. Among all comorbidities, stroke exerted the greatest impact in the RA group with an adjusted hazard ratio of 3.85 (95% confidence interval = 1.24-12.0).RA patients have an increased risk of developing hypothyroidism; this risk was pronounced in women and the elderly. RA patients should be closely monitored to prevent the development of hypothyroidism.

Production performances and antioxidant activities of laying hens fed Aspergillus oryzae and phytase co-fermented wheat bran.

OBJECTIVE: Wheat bran (WB) was co-fermented with Aspergillus oryzae and phytase (Phy) to determine whether co-fermentation improve WB phosphorus and fiber utilization in Isa-brown layers. METHODS: A total of 112 Isa brown layer were randomly divided into 7 treatments with 8 replicates per a treatment and 2 hens per a replicate. The treatments included basal diet (control), basal diet supplemented with 250 unit/kg Phy (control+Phy), diet with 10% WB (10% WB), diet with 5% WB and 250 unit/kg Phy (5% WB+Phy) diet with 10% WB and 250 unit/kg Phy (10% WB+Phy), diet with 5% fermented WB supplemented with molasses and phy (PCFWH) and 125 unit/kg Phy (5% PCFWH), and diet with 10% PCFWH (10% PCFWH). The intestinal microbial population, intestinal morphology, serum antioxidant enzyme activities, and excreta phosphorus content were assessed. RESULTS: In PCFWH, spore counts, protease activity, xylanase activity, and ferulic acid were 8.50 log/g dry matter (DM), 190 unit/g DM, 120 unit/g DM, and 127 µg/g, respectively. Xylobiose and xylotriose were released in PCFWH, while they were not detectable in WB. Antioxidant capacity was also enhanced in PCFWH compared to WB. The 10% WB+Phy and 10% PCFWH groups produced higher egg mass, but hens fed 5% WB+Phy had the lowest amount of feed intake. Eggs from 10% PCFWH had better eggshell weight, eggshell strength, and eggshell thickness. Birds fed with 10% PCFWH also had higher serum superoxide dismutase and catalase activities. Compare to control, 10% PCFWH significantly reduced excreta phosphorus content. CONCLUSION: Diet inclusion of 10% PCFWH improved egg quality, antioxidant status, and excreta phosphorus content of laying hens.

Laying Diet Supplementation with Ricinus communis L. leaves and Evaluation of Productive Performance and Potential Modulation of Antioxidative Status.

This study evaluated the antioxidant capacity of Ricinus communis L. (RC) leaves and powder when used as a feed additive for laying hens. Results showed that the total phenolic content of the aqueous leaf extract of Ricinus communis L. (RCE) was 48.39 mg gallic acid equivalent (GAE) per gram dry weight (DW). The flavonoid content was 9.76 mg quercetin dihydrate equivalent (QE)/g DW. Ferrous chelating activity was approximately 56.2% with an RCE concentration of 1 mg/mL; the highest chelating activity was 91.2% with 4 mg/mL extract. The reducing power of 1 mg/mL RC was 1.17 times better than 1 mg/mL butylated hydroxytoluene (BHT). The Trolox equivalent antioxidant capacity (TEAC) value of 12.5 mg/mL RCE was equivalent to 3.09 mg/mL Trolox. RCE (10 mg/mL) had a lipid oxidative inhibition capacity of 35.3%. A total of 80 ISA brown laying hens at twenty-nine weeks of age were randomly allocated into the control or 1 of 3 treatment groups; the latter received 0.5%, 1% or 2% of RC, respectively, for 12 weeks. Results showed that the RC supplementation improved the feed conversion rate and 0.5% RC generated the best results. Additionally, the egg yolk score was significantly increased in all RC-supplemented groups. Moreover, there was no significant difference in serum characteristics between the treatment groups. Serum antioxidant enzyme activity showed that superoxide dismutase (SOD) activity increased in the RC-supplemented groups relative to the control but was not significantly different. mRNA expression levels of the antioxidant regulatory genes GCLC, GST, HO-1, SOD1, and SOD2 were significantly increased with 2% RC supplementation. In summary, RC is a suitable feed additive for laying hens and the addition of 0.5% RC leaf powder resulted in the greatest benefits.

Evaluation of the Combined Use of Saccharomyces Cerevisiae and Aspergillus Oryzae with Phytase Fermentation Products on Growth, Inflammatory, and Intestinal Morphology in Broilers.

Saccharomyces cerevisiae and Aspergillus oryzae are both ancient probiotic species traditionally used as microbes for brewing beer and soy sauce, respectively. This study investigated the effect of adding these two probiotics with phytase fermentation products to the broilers diet. Fermented products possess protease and cellulase, and the activities were 777.1 and 189.5 U/g dry matter (DM) on S. cerevisiae fermented products (SCFP) and 190 and 213.4 U/g DM on A. oryzae fermented products (AOFP), respectively. Liposaccharides stimulated PBMCs to produce nitric oxide to 120 µmol. Both SCFP and AOFP reduced lipopolysaccharides stimulated peripheral blood mononuclear cells (PBMCs) nitric oxide release to 40 and 60 µmol, respectively. Nevertheless, in an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, SCFP and AOFP also increased the survival rate of lipopolysaccharides stimulated PBMCs by almost two-fold compared to the negative control. A total of 240 broilers were divided into four groups as Control, SCFP 0.1% (SCFP), SCFP 0.05% + AOFP 0.05% (SAFP), and AOFP 0.1% (AOFP) groups, respectively. Each group had 20 broilers, and three replicate pens. The results showed that the addition of SCFP, SAFP, and AOFP groups did not affect the growth performances, but increased the jejunum value of villus height and villus: crypt ratio on SAFP and AOFP groups compared to the control and SCFP groups. Furthermore, adding SCFP, SAFP, and AOFP significantly reduced the number of Clostridium perfringens in ileum chyme. SCFP, SAFP, and AOFP significantly reduced the amount of interleukin-1ß, inducible nitric oxide synthases, interferon-γ, and nuclear factor kappa B mRNA expression in PBMCs, especially in the AOFP group. In summary, all the SCFP, SAFP, and AOFP groups can be suggested as a functional feed additive since they enhanced villus: crypt ratio and decreased inflammation-related mRNA expression, especially for AOFP group in broilers.

LncRNA-Jak3:Jak3 coexpressed pattern regulates monosodium urate crystal-induced osteoclast differentiation through Nfatc1/Ctsk expression.

LncRNA transcripts have been emerged as gene regulators through transcriptional and posttranscriptional regulation. Monosodium urate monohydrate (MSU) elicits inflammatory response and a critical regulator of bone erosion in gout. The aim of this study is to clarify the pro-osteogenic role of LncRNA in MSU-induced osteoclast differentiation. We performed microarray analysis to identify stage specific expressions of LncRNA and mRNA during osteoclast differentiation in RAW264.7 cells. Among the 314 pairs of LncRNA-mRNA coexpressed patterns in the osteoclast lineage, 22 pairs revealed to have inflammatory function. Importantly, LncRNA-Jak3 and Jak3 co-expression patterns were significantly upregulated in the osteoclasts. In specific, Jak3 contributes to MSU-induced osteoclasts differentiation by positively regulating expression of the osteoclast factor, nuclear factor of activated T-cells 1 (Nfatc1). Mechanistically, LncRNA-Jak3-mediated Nfatc1 activation upregulated cathepsin K (Ctsk) expressions. LncRNA-Jak3 knockdown abolished formation of MSU-induced mature osteoclasts. In addition, we found that gout patients showed increased levels of LncRNA-Jak3 in the mononuclear cells. Our data demonstrate that the critical functional role of LncRNA-Jak3 in osteoclast differentiation via Jak3/Nfatc1/Ctsk axis. Finally, characterization of these regulatory networks is likely to reveal novel drug targets and opportunities for therapeutic intervention in bone erosion.

Retrospective cohort study on risk of hearing loss in patients with rheumatoid arthritis using claims data.

OBJECTIVES: Population studies on hearing loss (HL) associated with rheumatoid arthritis (RA) are lacking. This study investigated the risk of developing HL in patients with RA using a nationwide population cohort. SETTING: The population-based insurance claims data in the Taiwan National Health Insurance Research Database. DESIGN: Retrospective cohort study followed up RA cohort and control cohort without RA frequency matched by sex, age and diagnosis year. STUDY POPULATION: 18 267 patients with RA newly diagnosed in 2000-2006 and 73 068 controls without RA. MAIN OUTCOMES: Incidences of HL by the end of 2011 and the RA cohort to non-RA cohort HRs after adjusting for sex, age and comorbidities. RESULTS: The HL incidence was higher in the RA cohort than in the non-RA cohort (3.08 vs 1.62 per 1000 person-years), with an adjusted HR (aHR) of 1.91 (95% CI 1.70 to 2.14) for the RA cohort relative to the non-RA cohort after controlling for age, sex and comorbidities. Men and the elderly are at a higher risk. Cardiovascular comorbidities were associated with a further increased HL risk for patients with RA. Medications were associated with reduced HL incidence; patients with RA who used non-steroidal anti-inflammatory drugs (NSAIDs) had an aHR of 0.12 (95% CI 0.07 to 0.20), compared with non-users. CONCLUSIONS: This study demonstrates that patients with RA are at an increased risk of developing HL. Findings highlight the need of disease-modifying treatment and scheduled auditory examinations for HL prevention and early detection for patients with RA.

Variants of ALPK1 with ABCG2, SLC2A9, and SLC22A12 increased the positive predictive value for gout.

We investigated the interactions of ALPK1 variants and the loci of ABCG2, SLC2A9, and SLC22A12 on gout risk. We conducted two case-control studies. Participants were recruited from hospitals (n = 410; 104 gout cases and 306 controls) and communities (n = 678; 373 gout cases and 305 controls) in Taiwan. The genotypes of ALPK1 (rs11726117 M861T, rs231247 R1084R, and rs231253 3' UTR), ABCG2 (rs2231142 Q141K and rs2231137 V12M), SLC2A9 (rs3733591 R265H and rs1014290), and SLC22A12 (rs3825016 H86H, rs11231825 H142H, and rs475688) were genotyped. Under a recessive model, the joint effects of ALPK1 variants and the SNPs rs2231142 of ABCG2, rs1014290 of SLC2A9, or rs475688 and rs3825016 of SLC22A12 were associated with gout. The rs11726117 [CC] of ALPK1 and rs2231142 [TT] of ABCG2 with the sequential addition of the rs1014290 [AA] of SLC2A9 and rs3825016 [CC] of SLC22A12 were associated with gout risk (odds ratio (OR): 13.01, 15.11, and 55.00 and positive predictive value (PPV): 56%, 69%, and 99% in the Han group, respectively; OR: 3.76, 5.78, and 12.30 and PPV: 74%, 80%, and 81% in the aboriginal group, respectively). Combined exposure to the four high-risk genotypes of ALPK1 and the uric-acid-related loci of ABCG2, SLC2A9, and SLC22A12 was associated with an increased gout risk and a high PPV for gout.

Rheumatoid arthritis is associated with rs17337023 polymorphism and increased serum level of the EGFR protein.

OBJECTIVE: We have previously described the association of rheumatoid arthritis (RA) prevalence and two epidermal growth factor receptor (EGFR) SNPs (rs17337023 and rs2227983) among the Taiwanese population. This present study aimed to elucidate whether the SNPs can alter the expression of EGFR in the progression of RA. METHODS: The cohort study included 366 Taiwan's Han Chinese RA patients and 326 age and gender matched healthy controls. Blood samples collected from the participants were analyzed to determine their serum EGFR levels and to identify EGFR SNPs from their genomic DNA. Genotyping for EGFR SNPs was performed by restriction fragment length polymorphism (RFLP) assay. The relationship between EGFR SNP and the clinical manifestations of RA was evaluated. RESULTS: Our results showed that a statistically significant difference in genotype frequency distributions at rs17337023 SNP for RA patients and controls (p ˂ 0.05). In addition, compared with the haplotype frequencies between case and control groups, the RA patient with the GT haplotype appeared to be a significant "protective" haplotype compared with other haplotypes (OR: 0.73, 95% CI: 0.59-0.91; p = 0.005). Furthermore, the increased serum level of EGFR was also observed in RA patients (p ˂ 0.001). CONCLUSION: Our study showed that RA is associated with rs17337023 SNP in EGFR gene and increased serum level of the EGFR protein. These findings suggest EGFR is worthy of further investigation as a therapeutic target for RA.

Association of inflammatory cytokines with mortality in peritoneal dialysis patients.

AIMS: Previous study on association between pro-inflammatory cytokines and mortality in PD population is limited. We aimed to investigate here. METHODS: Total 50 patients who underwent incident PD were enrolled in this study. We measured the titers of pro-inflammatory cytokines Interleukin-18(IL-18), Interleukin-6 (IL-6), and Interleukin-1ß (IL-1ß). Study outcomes were all-cause mortality, cardiovascular-related mortality, and infection-caused mortality. Cox-regression model was used. RESULTS: In this 7 year prospective study, IL-18 ≥ 804.3pg/ml, IL-6 ≥ 3.92 pg/ml, IL-1ß ≥ 0.86pg/ml, age ≥ 50 years-old, and existence of diabetes could be used as individual significant predictors for mortality in PD patients. Higher titers of IL-6 were associated with lower averaging albumin levels within 1st year of PD. Increasing numbers of these risk markers of mortality was associated with decreasing survival advantages (P = 0.001). CONCLUSION: Age ≥ 50 years-old, diabetes, and inflammatory cytokines profiles at the start of PD therapy could predict for 7-year mortality in PD population.

Polymorphism and protein expression of MUTYH gene for risk of rheumatoid arthritis.

BACKGROUND: We have previously described the association between rheumatoid arthritis (RA) prevalence and the two mutY Homolog (E. coli) (MUTYH) SNPs (rs3219463 and rs3219476) among the Taiwanese population. This present study will aim to elucidate whether the SNPs can alter the expression of EGFR in the progression of RA. METHODS: The cohort study included 368 Taiwan's Han Chinese RA patients and 364 healthy controls. Blood samples collected from the participants were analyzed to determine their serum MUTYH levels and to identify rs3219463 SNP of MUTYH from their genomic DNA. RESULTS: Our data resulted in a statistically significant difference in genotype frequency distributions at rs3219463 for RA patients and controls (p < 0.0002). Also, the patients with G carrier at rs3219463 were less likely to suffer from painful joints (p < 0.006) and DAS28 scores (p < 0.003). Furthermore, the increase in serum level of MUTYH was also observed in RA patients (p < 0.005). CONCLUSIONS: Our study showed that RA is associated with rs3219463 SNP in EGFR gene and an increased serum level of the MUTYH protein. These findings suggest MUTYH is worthy of further investigation as a therapeutic target for RA.

URAT1 inhibition by ALPK1 is associated with uric acid homeostasis.

Objective: The aim of this study was to identify a protein for urate transporter 1 (URAT1) regulation. Methods: The clinical dataset consisted of 492 case-control samples of Han Chinese (104 gout and 388 controls). Three alpha kinase 1 ( ALPK1 ) and SLC22A12 loci associated with high gout risk and uric acid levels were genotyped. The overexpression of ALPK1 on URAT1 protein expression was evaluated in vivo in h ALPK1 transgenic mice. The in vitro protein levels of ALPK1 and URAT1 in ALPK1 small interfering RNA-transfected human kidney-2 cells with MSU crystal stimulation were examined. Results: ALPK1 , which is a single nucleotide polymorphism (SNP) of rs11726117 (M861T; T), reduced the risk of gout via the SLC22A12 gene SNPs rs3825016 and rs475688, as compared with the subject of ALPK1 rs11726117 (C) allele {rs11726117 [CT + TT] vs rs3825016, odds ratio [OR] 0.39 [95% confidence interval (CI) 0.23, 0.67]; rs11726117 [CT + TT] vs rs475688, OR 0.39 [95% CI 0.23, 0.67]}. ALPK1-overexpressed mice demonstrated lower levels of URAT1 protein ( P = 0.0045). Mouse endogenous ALPK1 proteins were detected in renal proximal tubule cells. MSU crystals inhibited URAT1 expressions through an upregulation of ALPK1 in human kidney-2 cells. Conclusion: Elevated ALPK1 expression decreased URAT1 expression. ALPK1 might prevent the impact of urate reuptake via SLC22A12 and appeared to be negatively associated with gout. ALPK1 is a potential repressor of URAT1 protein expression.