Chan-Bum Choi

Genome-Wide Association Study of Rheumatoid Arthritis in Koreans: Population-Specific Loci as Well as Overlap With European Susceptibility Loci

OBJECTIVE To perform a genome-wide association study (GWAS) in Koreans in order to identify susceptibility loci for rheumatoid arthritis (RA). METHODS We generated high-quality genotypes for 441,398 single-nucleotide polymorphisms (SNPs) in 801 RA cases and 757 controls. We then tested 79 markers from 46 loci for replication in an independent sample of 718 RA cases and 719 controls. RESULTS Genome-wide significance (P < 5 × 10(-08) ) was attained by markers from the major histocompatibility complex region and from the PADI4 gene. The replication data showed nominal association signals (P < 5 × 10(-02) ) for markers from 11 of the 46 replicated loci, greatly exceeding random expectation. Genes that were most significant in the replication stage and in the combined analysis include the known European RA loci BLK, AFF3, and CCL21. Thus, in addition to the previously associated STAT4 alleles, variants at these three loci may contribute to RA not only among Europeans, but also among Asians. In addition, we observed replication signals near the genes PTPN2, FLI1, ARHGEF3, LCP2, GPR137B, TRHDE, and CGA1. Based on the excess of small P values in the replication stage study, we estimate that more than half of these loci are genuine RA susceptibility genes. Finally, we systematically analyzed the presence of association signals in Koreans at established European RA loci, which showed a significant enrichment of European RA loci among the Korean RA loci. CONCLUSION Genetic risk for RA involves both population-specific loci as well as many shared genetic susceptibility loci in comparisons of Asian and European populations.

Replication of the genetic effects of IFN regulatory factor 5 (IRF5) on systemic lupus erythematosus in a Korean population

Recently, two studies provided convincing evidence that IFN regulatory factor 5 (IRF5) gene polymorphisms are significantly associated with systemic lupus erythematosus (SLE) in several white populations. To replicate the association with SLE in an Asian population, we examined the genetic effects in our SLE cohort from a Korean population. A total of 1,565 subjects, composed of 593 cases and 972 controls, were genotyped using the TaqMan® (Applied Biosystems, Foster City, CA, USA) method. The genetic effects of polymorphisms on the risk of SLE were evaluated using χ2 tests and a Mantel–Haenszel meta-analysis. Statistical analysis revealed results in the Korean population were similar to the previous reports from white populations. The rs2004640 T allele had a higher frequency in SLE cases (0.385) than controls (0.321; odds ratio (OR) = 1.32, P = 0.0003). In combined analysis, including all seven independent cohorts from the three studies so far, robust and consistent associations of the rs2004640 T allele with SLE were observed. The estimate of risk was OR = 1.44 (range, 1.34–1.55), with an overall P = 1.85 × 10-23 for the rs2004640 T allele. The haplotype (rs2004640T–rs2280714T) involved in both the alternative splice donor site and the elevated expression of IRF5 also had a highly significant association with SLE (pooled, P = 2.11 × 10-16). Our results indicate that the genetic effect on the risk of SLE mediated by IRF5 variants can be generally accepted in both white and Asian populations.

ARTS1 polymorphisms are associated with ankylosing spondylitis in Koreans

Objective To test the association between ARTS1 polymorphisms and Koreans with ankylosing spondylitis (AS). Methods All patients and controls were Korean. 872 patients with AS fulfilling the modified New York criteria and 403 healthy controls were genotyped for five single nucleotide polymorphisms (SNPs), rs27044, rs17482078, rs10050860, rs30107 and rs2287987, known to be associated with AS in Caucasians. Results SNPs rs27044 (p=9.37 × 10−7) and rs30187 (p=7.16 × 10−6) of ARTS1 were significantly associated with AS in Koreans. There was no significant association for rs17482078, rs10050860 and rs2287987. Two four-marker haplotypes were found to be associated with AS (GCCT: p=4.71×10−7, CCCC: p=8.56×10−6). Conclusions This is first confirmation in a non-Caucasian population that genetic polymorphisms in ARTS1 are associated with AS, implicating common pathogenetic mechanisms in Korean and Caucasian patients with AS.

Progress in defining clinically meaningful changes for clinical trials in nonrenal manifestations of SLE disease activity

Since the 2002 Dusseldorf meeting, one new agent, Benlysta, has been approved by the US Food and Drug Administration for systemic lupus erythematosus. Experiences from the field in conducting trials of all the agents tested during this period have provided valuable practical insights. There has been incremental progress in defining the minimal clinically important difference (MCID) of key disease manifestations and the view is largely that of the health care providers and not that of the person suffering the disease. This basic methodological work on the MCID should improve the efficiency and the clinical relevance of future trials and their design.

Peptidyl arginine deiminase type IV (PADI4) haplotypes interact with shared epitope regardless of anti-cyclic citrullinated peptide antibody or erosive joint status in rheumatoid arthritis: a case control study

IntroductionAnti-cyclic citrullinated peptide autoantibodies (anti-CCP) are the most specific serologic marker for rheumatoid arthritis (RA). Genetic polymorphisms in a citrullinating (or deiminating) enzyme, peptidyl arginine deiminase type IV (PADI4) have been reproducibly associated with RA susceptibility in several populations. We investigated whether PADI4 polymorphisms contribute to anti-CCP-negative as well as -positive RA, whether they influence disease severity (erosive joint status), and whether they interact with two major risk factors for RA, Human Leukocyte Antigen-DRB1 (HLA-DRB1) shared epitope (SE) alleles and smoking, depending on anti-CCP and erosive joint status.MethodsAll 2,317 unrelated Korean subjects including 1,313 patients with RA and 1,004 unaffected controls were genotyped for three nonsynonymous (padi4_89, padi4_90, and padi4_92) and one synonymous (padi4_104) single-nucleotide polymorphisms (SNPs) in PADI4 and for HLA-DRB1 by direct DNA sequence analysis. Odds ratios (OR) were calculated by multivariate logistic regression. Interaction was evaluated by attributable proportions (AP), with 95% confidence intervals (CI).ResultsA functional haplotype of the three fully correlated nonsynonymous SNPs in PADI4 was significantly associated with susceptibility to not only anti-CCP-positive (adjusted OR 1.73, 95% CI 1.34 to 2.23) but also -negative RA (adjusted OR 1.75, 95% CI 1.15 to 2.68). A strong association with both non-erosive (adjusted OR 1.62, 95% CI 1.29 to 2.05) and erosive RA (adjusted OR 1.62, 95% CI 1.14 to 2.31) was observed for PADI4 haplotype. Gene-gene interactions between the homozygous RA-risk PADI4 haplotype and SE alleles were significant in both anti-CCP-positive (AP 0.45, 95% CI 0.20 to 0.71) and -negative RA (AP 0.61, 95% CI 0.29 to 0.92). Theses interactions were also observed for both non-erosive (AP 0.48, 95% CI 0.25 to 0.72) and erosive RA (AP 0.46, 95% CI 0.14 to 0.78). In contrast, no interaction was observed between smoking and PADI4 polymorphisms.ConclusionsA haplotype of nonsynonymous SNPs in PADI4 contributes to development of RA regardless of anti-CCP or erosive joint status. The homozygous PADI4 haplotype contribution is affected by gene-gene interactions with HLA-DRB1 SE alleles.

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.

Factors Influencing Discrepancies Between the QuantiFERON-TB Gold in Tube Test and the Tuberculin Skin Test in Korean Patients with Rheumatic Diseases

OBJECTIVES To estimate the positivity and agreement between QuantiFERON-tuberculosis (TB) gold in tube test (QFT-GIT) and tuberculin skin test (TST) according to underlying rheumatic diseases and to identify the influencing factors on discrepancies between the 2 tests. METHODS Among the 757 patients who underwent both QFT-GIT and TST simultaneously from September 2008 to November 2010, patients with indeterminate QFT-GIT results (n = 21), with active (n = 11) or suspicious (n = 1) findings for tuberculosis on a chest radiograph, were excluded. Finally, 724 patients were recruited for this study: 497 patients with rheumatoid arthritis (RA), 198 with ankylosing spondylitis (AS), and 29 with juvenile rheumatoid arthritis (JRA). The agreement between the 2 tests was estimated by Cohens κ and factors influencing discrepancies were identified using multivariate analysis. RESULTS The positivity of QFT-GIT was higher in RA than AS or JRA (30.2%, 16.2%, and 3.4%, respectively). In contrast, TST positivity was highest in AS compared to RA and JRA (45.5%, 28.2%, and 17.2%, respectively). The agreement between the 2 tests was low in all patients (κ = 0.285). The only predictor of a discrepancy between the 2 tests was older age. Factors associated with discordant QFT-GIT-negative/TST-positive results were female [odds ratio (OR) = 2.33, confidence interval (CI) 1.11 to 4.89] and AS (OR = 3.12, CI 1.44 to 6.79), whereas a discordant QFT-GIT-positive/TST-negative result was associated with glucocorticoid use (OR = 2.44, CI 1.24 to 4.81). CONCLUSIONS The agreement between the 2 tests is low; therefore, it would be better to perform both tests than to use any 1 test alone for the detection of LTBI in TB-endemic regions. Female and underlying AS are related to being QFT-GIT-negative/TST-positive, and the use of glucocorticoid is associated with being QFT-GIT-positive/TST-negative.

A regulatory SNP at position −899 in CDKN1A is associated with systemic lupus erythematosus and lupus nephritis

The CDKN1A gene encoding a cell cycle inhibitor, p21(WAF1/CIP1), is located in the systemic lupus erythematosus (SLE) susceptibility locus on chromosome 6p21.2. Decreased cellular levels of p21 are associated with SLE. Here, we examine four single-nucleotide polymorphisms (SNPs) within the promoter and two in the first intron of CDKN1A for association with SLE susceptibility. A comparison of 742 Korean SLE patients with 1017 controls disclosed that one SNP (rs762624 C>A at position −899), located at a putative Myb-binding site in the promoter, was associated with SLE susceptibility (P=0.00047). This association was independent of the SLE-association signal of HLA-DRB1 on 6p21.3, as it was significant after adjustment for SLE-risk DRB1 alleles (P=0.0012). The same SNP was associated with lupus nephritis (P=0.000014). The risk allele-carrying promoter sequence displayed ∼15% lower activity than the non-risk sequence upon fusion to the luciferase gene (P=0.025). Endogenous CDKN1A mRNA levels measured in Epstein–Barr virus-transformed B cells established from 16 control subjects were linearly correlated with a decreasing copy number of the risk allele (P=0.024). Accordingly, we conclude that the minor allele A at −899 of CDKN1A is associated with increased susceptibility to SLE and lupus nephritis, and decreased cellular levels of p21.

Analysis of single nucleotide polymorphisms in Toll-like receptor 4 shows no association with ankylosing spondylitis in a Korean population

The role of microbial triggers in the pathogenesis of the ankylosing spondylitis (AS) has remained an active area of clinical and basic research but remains unresolved. We have recently found evidence of an important role for TLR4 in experimental reactive arthritis, raising the question to be addressed whether genetic polymorphisms in TLR4 affects susceptibility to AS. Innate immune responses to Gram-negative bacteria involve in a central role the binding of lipopolysaccharide to TLR4. Two commonly occurring SNPs in the human TLR4 gene (Asp299Gly and Thr399Ile) have been shown to be associated with increased risk of Gram-negative bacteremia in sepsis patients and with susceptibility to inflammatory bowel disease. It remains unresolved whether these SNPs are associated with AS and we have addressed this in a relatively genetically homogeneous population in Korea. A cohort of 200 Korean AS patients and 197 ethnically matched controls were studied. All patients were native Koreans with AS satisfying the modified New York criteria. Korean controls were examined and confirmed to be unaffected by AS. All subjects were genotyped for two functional SNPs in the TLR4 gene: Asp299Gly (A/G polymorphism) and TLR-4 (Thr399Ile) (C/T polymorphism) The Sequenom MassARRAY system was used for genotyping (Sequenom Inc., San Diego, CA, USA). All cases and controls were homozygous for the (A) allele for 299 variant and similarly for the 399 variant all cases and controls were homozygous for the (C) allele. Genetic-environmental interactions figure prominently in current concepts of the pathogenesis of AS. Our findings indicate that the polymorphisms in the TLR4 gene cannot be regarded as major contributors to AS susceptibility in the Korean population.

Adverse events in analgesic treatment with tramadol associated with CYP2D6 extensive-metaboliser and OPRM1 high-expression variants

Tramadol, alone or in combination with paracetamol, is an effective analgesic that relieves the moderate to severe pain that accompanies various disorders (including osteoarthritis) and follows surgical operations. However, this synthetic atypical opioid frequently evokes various adverse events (AEs), and the most frequent are nausea and vomiting.1 Although the mode of tramadol-induced nausea/vomiting is unclear, opioid receptors on the chemoreceptor trigger zone in the human brain can bind opioids to cause nausea/vomiting.2 A major pathway of tramadol metabolism is demethylation to O -desmethyltramadol by cytochrome P450 enzyme 2D6 (CYP2D6),3 and O -desmethyltramadol has an orders of magnitude higher affinity for the μ-opioid receptor (OPRM1) than tramadol and other metabolites.4 Because many genetic variations in CYP2D6 confer large interindividual differences in enzyme activity,5 and several variations in OPRM1 substantially affect expression level,6 this study examined genotype–phenotype associations between functional polymorphisms in CYP2D6 …