Yun Jung Kim

High‐density genotyping of STAT4 reveals multiple haplotypic associations with systemic lupus erythematosus in different racial groups

OBJECTIVE Systemic lupus erythematosus (SLE) is the prototypical systemic autoimmune disorder, with complex etiology and a strong genetic component. Recently, gene products involved in the interferon pathway have been under intense investigation in terms of the pathogenesis of SLE. STAT-1 and STAT-4 are transcription factors that play key roles in the interferon and Th1 signaling pathways, making them attractive candidates for involvement in SLE susceptibility. METHODS Fifty-six single-nucleotide polymorphisms (SNPs) across STAT1 and STAT4 on chromosome 2 were genotyped using the Illumina platform, as part of an extensive association study in a large collection of 9,923 lupus patients and control subjects from different racial groups. DNA samples were obtained from the peripheral blood of patients with SLE and control subjects. Principal components analyses and population-based case-control association analyses were performed, and the P values, false discovery rate q values, and odds ratios with 95% confidence intervals were calculated. RESULTS We observed strong genetic associations with SLE and multiple SNPs located within STAT4 in different ethnic groups (Fishers combined P = 7.02 x 10(-25)). In addition to strongly confirming the previously reported association in the third intronic region of this gene, we identified additional haplotypic association across STAT4 and, in particular, a common risk haplotype that is found in multiple racial groups. In contrast, only a relatively weak suggestive association was observed with STAT1, probably due to its proximity to STAT4. CONCLUSION Our findings indicate that STAT4 is likely to be a crucial component in SLE pathogenesis in multiple racial groups. Knowledge of the functional effects of this association, when they are revealed, might improve our understanding of the disease and provide new therapeutic targets.

Possible Reactivation of Potential Hepatitis B Virus Occult Infection by Tumor Necrosis Factor-α Blocker in the Treatment of Rheumatic Diseases

Objective. To assess the safety of anti-tumor necrosis factor (TNF-α) therapy in patients with rheumatic diseases in terms of the reactivation of potential hepatitis B virus (HBV) occult infection. Methods. Patients who had taken anti-TNF-α for the treatment of rheumatic diseases from January 2002 to May 2008 were included in the study. In this patient group, we retrospectively investigated a series of serum aminotransferase levels, HBV serologic status, the type of anti-TNF-α therapy, duration of the anti-TNF-α treatment, and concurrent use of hepatotoxic drugs. Results. A total of 266 cases were documented using 3 serologic markers for HBV infection: HBV surface antigen (HBsAg), HBV surface antibody (HBsAb), and HBV core IgG Ab (HBcAb). Of these, 8 cases had chronic hepatitis B (HBsAg+), 170 cases were HBcAb-negative, and 88 cases were identified as having potential HBV occult infections represented by HBsAg-negative and HBcAb-positive, irrespective of the status of the HBsAb. The frequency of clinically significant (> 2 times normal value) and persistent increase (> 2 consecutive tests) of aminotransferase levels was significantly higher in the group with a potential HBV occult infection compared to the HBcAb-negative group. In the multiple logistic regression analysis controlling for various potential confounding factors such as prophylactic anti-tuberculosis medication, methotrexate, nonsteroidal antiinflammatory drugs, and the type of anti-TNF-α therapy, only potential HBV occult infection was a significant risk factor for abnormal liver function test (LFT). Conclusion. All rheumatic patients who plan to take anti-TNF-α treatment should undergo a test for HBV serology, including HBcAb, and have a close followup with an LFT test during therapy. Further prospective studies for hepatitis B viral load using HBV-polymerase chain reaction in patients who are HbcAb positive are needed to identify whether the abnormal LFT comes from the reactivation of occult HBV infection.

Putative Role of Functional Interferon Regulatory Factor 5 (IRF5) Polymorphism in Rheumatoid Arthritis in a Korean Population

Objective Recent studies suggest that polymorphisms of interferon regulatory factor 5 (IRF5) are significantly associated with systemic lupus erythematosus in several populations. The effect of IRF5 polymorphism on susceptibility to rheumatoid arthritis (RA) has been investigated, and the results were inconsistent. We analyzed the genetic effects of IRF5 polymorphisms on RA in a Korean population. Methods Eight single-nucleotide polymorphisms (SNP) and 2 insertion-deletion polymorphisms in IRF5 were genotyped in 2183 subjects (1204 RA cases and 979 controls) using the TaqMan® method. The genetic effects of SNP on the risk of RA were evaluated using chi-square tests and multivariate logistic regression, controlling for age, sex, and shared epitope (SE), and we then performed conditional analysis by SE status and anti-cyclic citrullinated peptide (anti-CCP) antibody (Ab) status. Data from a Mantel-Haenszel metaanalysis of odds ratios (OR) were subsequently combined in a separate analysis with the results of the association of rs2004640 with RA from a previous study. Results Two of the IRF5 polymorphisms, CGGGGindel (OR 1.38, 95% CI 1.09–1.76, pcorr = 0.04) and rs2004640 (OR 1.36, 95% CI 1.09–1.68, pcorr = 0.03), and one haplotype, including the rs2004640 and the CGGGGindel, ht3 (A-Del-T-C-del-A-T) (OR 1.39, 95% CI 1.09–1.79, pcorr = 0.04) were significantly associated with an increased risk of RA. After stratification according to anti-CCPAb and SE status, rs2004640 SNP was associated with the anti-CCPAb-positive (OR 1.47, 95% CI 1.15–1.88, pcorr = 0.01) or SE-positive group (OR 1.54, 95% CI 1.14–2.09, pcorr = 0.03). A combined analysis including all 3 independent cohorts from the previous study revealed an association of the rs2004640 with RA (pooled OR 1.21, 95% CI 1.07–1.38, pooled p = 0.0031 in dominant model). Conclusion Our results suggest that the IRF5 polymorphism is associated with genetic susceptibility to RA at least in a Korean population, and that it may contribute to disease susceptibility in SE-positive or anti-CCP Ab-positive patients with RA.

Genetic studies of systemic lupus erythematosus in Asia: where are we now?

There have been many genetic studies of systemic lupus erythematosus (SLE) in Asia, but the status of SLE in Asia remains unclear. Genes that have been associated with SLE in Caucasians have shown both consistent and inconsistent results in Asians. This prompted us to review studies of SLE-associated genes and compare the degree of consistency according to ethnicity in Asia. We searched PubMed and the national databases in Korea and Japan for SLE genetic studies. A total of 755 articles were found and after applying various exclusion criteria, 442 studies including 17 linkage studies, 2 genome-wide association studies and 423 candidate-gene analyses were reviewed. Nine linkage loci were confirmed to be associated with SLE susceptibility in non-Asians, but the risk locus (16q12) has been identified in only one Asian study. A total of 156 candidate genes were analyzed, of which 92 were studied in Asians. Although there were allelic (HLA-DRB1 and IRF5) or genetic heterogeneity (FCGR gene family), HLA-DRB1, the FCGR gene family, IRF5, STAT4 and MECP2 showed consistent associations with SLE susceptibility across ethnicities. In conclusion, genetic associations often vary with ethnicity, requiring validation in different ethnic groups, and hence future SLE genetic studies will require strong worldwide collaborations.

Lack of association between interleukin 23 receptor gene polymorphisms and rheumatoid arthritis susceptibility

The recent discovery of interleukin 23 (IL-23), its receptor, and the underlying signal transduction pathway has improved our understanding of cellular immunity. Several studies suggest that IL-23 is an essential promoter of chronic joint inflammation. In this report, we assess the possible association of interleukin 23 receptor (IL23R) polymorphisms and haplotypes with rheumatoid arthritis (RA). The study was conducted on 1,204 RA patients and 979 healthy controls. Seven polymorphisms were selected from previous IBD reports. The seven SNPs (rs1004819, rs7517847, rs10489629, rs2201841, rs1343151, rs11209032 and rs1495965) were genotyped using the TaqMan assay. Comparison of RA and control subjects revealed no statistically significant differences in the distribution of the IL23R genotypes and haplotypes. Our results clearly indicate that IL23R gene polymorphisms do not play a significant role in susceptibility to RA in the Korean population. Accordingly, we conclude that IL23R gene polymorphisms cannot be applied as an effective genetic marker for RA susceptibility.

A promoter nucleotide variant of the dendritic cell-specific DCNP1 associates with serum IgE levels specific for dust mite allergens among the Korean asthmatics

Dendritic cells (DCs), the most abundant antigen-presenting cells in the lung, have been drawing attention for their roles in specific allergic responses to aeroallergens with support of Th lymphocytes, and in persistent inflammatory changes in allergic asthma. To identify genetic factors that may be involved in the asthma susceptibility and development of the disease phenotypes, we examined association of DC-specific DCNP1 polymorphisms with the disease risk. The case–control study revealed association of the nucleotide variants with serum immunoglobulin E (IgE) levels specific for Dermatophagoides farinae (Der f 1) and Dermatophagoides pteronyssinus (Der p 1), major aeroallergens of dust mites, among subjects with asthma. In particular, the T-allele-carrying genotype frequencies for one of the variants (c.−1289C>T) located in the promoter region were found increased in the asthmatic group with low levels of the mite-specific IgE (odds ratio (OR)=0.63 (0.48–0.83) for Der p 1). Results from functional analyses indicated that the promoter variant would affect the gene expression by modulating DNA–protein interaction. We propose that the genetic polymorphism of DCNP1 may influence production of specific IgE by altering DC functions in the mite allergen presenting and/or processing. The functional relevance of the genetic variation would provide an important insight into the genetic basis of allergic response to the mite antigens.

Mortality and Incidence of Malignancy in Korean Patients with Rheumatoid Arthritis

Objective. To determine the standardized mortality ratio (SMR) and standardized incidence ratio (SIR) for malignancy in Korean patients with rheumatoid arthritis (RA). Methods. We enrolled 1534 patients with RA who fulfilled the American College of Rheumatology criteria, from October 2001 to December 2007. Baseline assessment included sociodemographic variables, laboratory findings including rheumatoid factor, anticitrullinated protein antibody, functional class, radiological stage, medication, and the Korean version of the Health Assessment Questionnaire. We used the national mortality rate from 2001 to 2007 from the Korean National Statistical Office (KNSO) and the incidence rate from the Korean Central Cancer Registry (KCCR) from 2001 to 2007 as comparison data for estimates of SMR and SIR. Confidence intervals were calculated based on the Poisson distribution. Results. There were 57 deaths in 6683 person-years of followup. The number of expected deaths (derived from the KNSO) was 42.33 and the SMR for patients with RA was 1.35 (95% CI 1.02–1.74). The main causes of death were malignancy, cardiovascular disease, and respiratory disease. In the cause-specific SMR, deaths from respiratory disease, especially from interstitial lung disease (ILD) and pneumonia, were significantly higher than expected: 4.66 (95% CI 2.13–8.85) for all respiratory disease, 18.18 (95% CI 2.20–65.64) for ILD, and 10.26 (95% CI 2.79–26.26) for pneumonia. Thirty malignancies had occurred in 1501 patients. The number of expected malignancies derived from the KCCR was 34.91, yielding a SIR for cancer of 0.86 (95% CI 0.58–1.23). Conclusion. Our study demonstrates that the SMR was slightly higher in patients with RA, but the incidence rates of malignancies were not significantly different from the general population. But deaths from respiratory diseases were significantly higher.

Common promoter polymorphism in monocyte differentiation antigen CD14 is associated with serum triglyceride levels and body mass index in non-diabetic individuals

Aims  Growing evidence supports the hypothesis that chronic low‐grade inflammation related to innate immunity may play an important role in the pathophysiology of Type 2 diabetes mellitus (T2DM). The monocyte differentiation antigen CD14 gene (CD14) acts as the receptor for lipopolysaccharide (LPS) and augments monocyte/macrophage inflammatory responses.