Chung-Jen Chen

Evidence for linkage of a candidate chromosome 1 region to human systemic lupus erythematosus.

Genetic susceptibility confers significant risk for systemic lupus erythematosus (SLE). The MHC region and other polymorphic loci have been associated with SLE. Because more compelling evidence for an involvement of a genetic locus includes linkage, we tested a candidate region homologous to a murine SLE susceptibility region in 52 SLE-affected sibpairs from three ethnic groups. We analyzed seven microsatellite markers from the human chromosome 1q31-q42 region corresponding to the telomeric end of mouse chromosome 1, the region where specific manifestations of murine lupus, including glomerulonephritis and IgG antichromatin, have been mapped. Comparing the mean allele sharing in affected sibpairs of each of these seven markers to their expected values of 0.50, only the five markers located at 1q41-q42 showed evidence for linkage (P = 0.0005-0.08). Serum levels of IgG antichromatin also showed evidence for linkage to two of these five markers (P = 0.04), suggesting that this phenotype is conserved between mice and humans. Compared to the expected random distribution, the trend of increased sharing of haplotypes was observed in affected sibpairs from three ethnic groups (P < 0.01). We concluded that this candidate 1q41-q42 region probably contains a susceptibility gene(s) that confers risk for SLE in multiple ethnic groups.

Association of a common complement receptor 2 haplotype with increased risk of systemic lupus erythematosus

A genomic region on distal mouse chromosome 1 and its syntenic human counterpart 1q23–42 show strong evidence of harboring lupus susceptibility genes. We found evidence of linkage at 1q32.2 in a targeted genome scan of 1q21–43 in 126 lupus multiplex families containing 151 affected sibpairs (nonparametric linkage score 2.52, P = 0.006). A positional candidate gene at 1q32.2, complement receptor 2 (CR2), is also a candidate in the murine Sle1c lupus susceptibility locus. To explore its role in human disease, we analyzed 1,416 individuals from 258 Caucasian and 142 Chinese lupus simplex families and demonstrated that a common three-single-nucleotide polymorphism CR2 haplotype (rs3813946, rs1048971, rs17615) was associated with lupus susceptibility (P = 0.00001) with a 1.54-fold increased risk for the development of disease. Single-nucleotide polymorphism 1 (rs3813946), located in the 5′ untranslated region of the CR2 gene, altered transcriptional activity, suggesting a potential mechanism by which CR2 could contribute to the development of lupus. Our findings reveal that CR2 is a likely susceptibility gene for human lupus at 1q32.2, extending previous studies suggesting that CR2 participates in the pathogenesis of systemic lupus erythematosus.

Gene-gene synergistic effect on atopic asthma: tumour necrosis factor-alpha-308 and lymphotoxin-alpha-NcoI in Taiwan's children.

Background Asthma is now known to be an inflammatory response caused by the release of inflammatory mediators and cytokines. Tumour necrosis factor (TNF) is a potent cytokine in the inflammation response of the airway, and the polymorphisms of TNF genes have been associated with asthma.

Associations between gout tophus and polymorphisms 869T/C and −509C/T in transforming growth factor β1 gene

OBJECTIVESnTo investigate the associations between gout tophus and polymorphisms 869T/C and -509C/T in TGF-beta1 gene.nnnMETHODSnThe polymorphisms 869T/C and -509C/T were determined in 73 gout patients and 114 healthy controls among male Taiwanese using the PCR-restriction fragment length polymorphism method. Each patient was matched with 1-2 controls by age within 1-2 yrs. The tophus number was measured from all the patients arms and legs.nnnRESULTSnNeither 869T/C nor -509C/T showed a significant association between patients and controls in the proportions of genotypes, allele frequency or dominant and recessive models. The mean number of tophi for all patients was 1.53 +/- 3.44, showing a significant difference in distribution among the genotypes at polymorphism 869T/C (P = 0.006), but not those in polymorphism -509C/T (P > 0.05). Those carrying genotype CC at polymorphism 869T/C have a mean number of tophi 0.35 (+/- 1.11), which is significantly lower than those carrying genotype TT (3.73 +/- 4.67; P < 0.05). Those with genotype TT at polymorphism 869T/C also had 11.06 times the likelihood of having at least one tophus compared with the genotype CC after adjustment of hyperuricaemia (95% CI = 1.84, 66.36; P = 0.009). However, except for the tophus number, these two polymorphisms did not show any significant association with the clinical characteristics or biochemical markers.nnnCONCLUSIONSnThe polymorphism 869T/C in TGF-beta1 gene has a significant association with the occurrence of tophus in gout patients.

Gout and Type 2 diabetes have a mutual inter-dependent effect on genetic risk factors and higher incidences

OBJECTIVEnTo explore the causal relationship between gout and Type 2 diabetes based on genetic evidence and national outpatient database.nnnMETHODSnTwenty male gout patients with early-onset, gout family history, without a habit of alcohol consumption or obesity before the first attack of gout were selected from hospital in 2010; and 42 unrelated male Chinese subjects were selected from HapMap as controls for genome-wide analysis study (GWAS). The comorbid diseases with gout were revealed by applying the significant single nucleotide polymorphisms (SNPs) to MetaCore platform, and the comorbid relationship was analysed by standardized incidence ratio (SIR) from outpatient database.nnnRESULTSnA total of 334 SNPs were significantly related to gout in GWAS (Pu2009<u200910(-7)), and Type 2 diabetes was the most significantly associated disease with gout as recognized by 36 gene symbols correspondent to the above significant SNPs. The analysis of national outpatient database showed that the overall incident Type 2 diabetes was 1.50 cases per 1000 person-months among gout patients, which was higher than the overall incident gout (1.06 cases) among Type 2 diabetes. The age-adjusted SIR of incident Type 2 diabetes among gout was 2.59 (95% CI 2.42, 2.78), whereas the age-adjusted SIR for incident gout among Type 2 diabetes was 1.61 (95% CI 1.48, 1.74).nnnCONCLUSIONnAfter excluding obesity and alcohol consumption behaviour, this study showed that patients with gout and Type 2 diabetes shared the common genetic factors most, and that there existed a mutual inter-dependent effect on higher incidences.

Arginase Levels are Increased in Patients with Rheumatoid Arthritis

Arginase and nitric oxide synthase (NOS) compete for the same substrate, L-arginine. The reciprocal regulation of arginase and NOS in L-arginine-metabolizing pathways has recently been demonstrated. Since NOS is involved in the inflammation of human arthritides, we hypothesized that this reciprocal regulation might also occur within the inflamed synovium. The present study shows that both serum arginase activity and protein levels were significantly higher in patients with rheumatoid arthritis (RA) than in patients with systemic lupus erythematosus (SLE) or osteoarthritis (OA) or in healthy controls. Arginase protein concentrations in supernatants of monocyte cultures from RA patients were also significantly higher than in those from SLE or OA patients or healthy controls. In RA patients, there was a significant correlation between the serum concentrations of arginase protein and rheumatoid factor (r = 0.82, p < 0.0001). These data indicate that increased arginase production is seen in RA patients, but not in other immune-related diseases, suggesting that increased arginase production is unique to, and may play an important role in, the pathogenesis of RA disease.

Monocyte-derived cytokine--IL-12, TGF-beta 1 and TNF-alpha in patients with tuberculosis.

Pulmonary tuberculosis is an infectious disease caused by Mycobacterium tuberculosis (MTB). This microorganism is capable of inducing a delayed hypersensitivity in the lung, with subsequent expression of the disease. This reaction depends on the presence of different cytokines that exert specific functions. To study the variability of different cytokine responses after MTB antigenic challenge, we used antigens derived from MTB to stimulate the monocytes from both normal healthy contact and the patients with active tuberculosis. We found in the resting state monocytes from healthy contact secreted higher amounts of IL-12 than those from patients. After stimulation with MTB antigen, the secretion of IL-12 did not increase in normal healthy contact, but in patients with tuberculosis the secretion increased. After MTB antigen stimulation, monocytes from patients with active tuberculosis secreted a higher amount of TNF-alpha. In summary, the patterns of monocyte-derived cytokine secretion upon mycobacterial antigen challenge were different in these two groups.

Allopurinol and the incidence of bladder cancer: a Taiwan national retrospective cohort study.

Our aim is to investigate the risk association between allopurinol use and cancer incidence among gout patients using clinical evidence. Newly diagnosed male patients with gout, 20 years or older, were included after excluding those who had a diagnosis of type 2 diabetes, and were followed up for 12 years in a retrospective cohort study of one million outpatients of a national database. The gout patients were matched to male controls by age and first diagnosis date of gout disease. We then estimated the risk associations between incident cancers and duration of allopurinol use by Cox hazard regression, age-adjusted standardized incidence ratio, and incidence per 1000 person-years. A total of 24u2009050 gout patients and 76u2009129 controls were included. The incidence of all-cause cancers for gout patients and controls was 8.26 cases and 7.49 cases/1000 person-years, respectively; it was markedly increased in gout patients who used allopurinol for over 90 days. The hazard ratio of all-cause cancers was 1.21 (95% confidence interval=1.03–1.42, P=0.019) after adjustment for age and 2.26 for bladder cancer (95% confidence interval=1.32–3.87, P=0.003) on comparing those who used allopurinol for over 90 days with nonusers. Meanwhile, other cancers did not show the same significant result. We concluded that those who used allopurinol for a long duration had a higher occurrence of both bladder cancer and all-cause cancers in clinical evidence.

HLA-DQA 1 Genotyping in Patients with Rheumatoid Arthritis in Taiwan

To investigate the role of HLA-DQA1 genotypes and their interaction with HLA-DRB1 in the pathogenesis of rheumatoid arthritis (RA) in Taiwan, HLA-DQA1 was determined in 71 patients with RA and 108 healthy controls by SSP-PCR method. HLA-DRB1 and HLA-DQA1 were simultaneously detected in 55 RA patients and 101 healthy controls. PCR/SSOP method was used to determine the HLA-DRB1 genotypes, and the subtypes of HLA-DR4 were determined by cloning and sequencing. The phenotypic frequency of HLA-DQA1*0301 was significantly lower in RA than in controls, and, in contrast, the HLA-DQA1*0302 and DQA1*0303 were significantly higher in RA than in controls. The associations of DQA1*0301, *0302, and *0303 with RA were independent of DR4 and DRB1*0405. Moreover, the interactions between HLA-DR4 and HLA-DQA1*0302 or DQA1*0303 could enhance the development of RA. We also found that the prevalence of bone erosion and seropositivity of rheumatoid factor (RF) were significantly higher in HLA-DQA1*0303 positive RA patients than in healthy controls. HLA-DQA1*0302 and DQA1*0303 are the risk factors for susceptibility to RA, while HLA-DQA1*0301 is a protective factor. A synergistic effect for the susceptibility to RA can be found between HLA-DR4 and HLA-DQA1*0302 or DQA1*0303. We also found that the HLA-DQA1*0303 was related to bone erosion and seropositivity of RF in RA patients.

Systemic Lupus Erythematosus Complicated by Recurrent Spontaneous Pneumothorax- a Case Report

Despite frequent pleuro-pulmonary involvement, spontaneous pneumothorax is rare in patients with systemic lupus erythematosus (SLE). Here, we report a 17-year-old female patient with SLE, complicated by multiple organs involvement. She initially presented with interstitial pneumonitis and pulmonary hemorrhage, followed by spontaneous pneumothorax and CNS involvement. The patient was treated with immunosuppressive agents, including steroid and cyclophosphamide pulse therapies. Spontaneous pneumothorax happened to her once again at a different location during treatment. After aggressive therapy, the disease activity of SLE gradually diminished, and pneumothorax had not recurred during the further follow-up. Therefore, the pneumothorax may occur in SLE patients with high disease activity.