Hye-Soon Lee

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.

Smoking increases rheumatoid arthritis susceptibility in individuals carrying the HLA–DRB1 shared epitope, regardless of rheumatoid factor or anti–cyclic citrullinated peptide antibody status

OBJECTIVE Smoking is associated with rheumatoid arthritis (RA) in individuals with the HLA-DRB1 shared epitope (SE). SE alleles have been shown to be predominantly associated with anti-cyclic citrullinated peptide (anti-CCP)-positive RA. These risk factors have not been identified for anti-CCP-negative RA. The aim of this study was to investigate whether SE-containing HLA-DRB1 alleles, smoking, or the combination of these factors contributes to the development of RA, depending on the presence or absence of serologic markers, in a Korean population. METHODS All of the patients with RA (n =1,482) and all of the control subjects (n = 1,119) were Korean. Four-digit HLA-DRB1 typing was performed by a conventional polymerase chain reaction-sequence-based typing method. Information about smoking history was obtained through a questionnaire. The patients with RA were tested for anti-CCP antibodies and rheumatoid factor (RF). RESULTS The SE alleles had significant effects on anti-CCP antibody and RF formation. The DRB1*0901 allele was associated with the presence of anti-CCP antibodies (odds ratio [OR] 2.49) and RF (OR 2.09). SE alleles and smoking were associated with both anti-CCP-positive and anti-CCP-negative RA. The combination of smoking and double copies of the SE allele increased the risk of anti-CCP-positive RA 36.11-fold and increased the risk of anti-CCP-negative RA 12.29-fold, compared with the risk among nonsmokers not carrying SE alleles. Interactions between SE alleles and smoking were observed for both anti-CCP-positive and RF-positive RA, although the associations of RF-positive RA could be consequences of the underlying anti-CCP antibody status. CONCLUSION We demonstrated that the combination of SE alleles and smoking is associated with RA susceptibility regardless of anti-CCP antibody or RF status, but that the combination shows stronger effects in anti-CCP-positive/RF-positive patients with RA than in anti-CCP-negative/RF-negative patients with RA. The SE-smoking interactions were present in anti-CCP-positive and RF-positive RA.

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.

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.

Adult-onset Still's Disease with Disseminated Intravascular Coagulation and Multiple Organ Dysfunctions Dramatically Treated with Cyclosporine A

Severe systemic manifestations of adult onset Stills disease (AOSD) are often fatal and occasionally related to hemophagocytic syndrome (HS). We describe the case of a 49-yr-old woman with AOSD presenting with non-remitting high fever, confusion, jaundice, hepatosplenomegaly, serositis, azotemia, pancytopenia, coagulopathy with disseminated intravascular coagulation (DIC), hyperferritinemia, acute acalculous cholecystitis and ileocolitis noted in computed tomographic images. The patient had a history of herpes zoster developed prior to the admission, but there is no history of diarrhea or abdominal pain. Although bone marrow examination was not performed due to hemorrhagic diathesis, we suspected AOSD-associated HS on the basis of clinical course without detectable infectious agents in cultures or serologic studies. Intravenous immunoglobulin, pulse methylprednisolone, oral cyclosporine A (CsA) and ceftriaxone brought about transient improvement of fever and confusion, but the disease progressed. After increasing CsA dose, all previously mentioned abnormalities disappeared rapidly. Accordingly, we believe that DIC and multiple organ dysfunctions might have been the complications of HS but not that of sepsis, and that CsA can be used as a first-line therapy in case of life-threatening situations.

The HLA-DRβ1 amino acid positions 11–13–26 explain the majority of SLE–MHC associations

Genetic association of the major histocompatibility complex (MHC) locus is well established in systemic lupus erythematosus (SLE), but the causal functional variants in this region have not yet been discovered. Here we conduct the first fine-mapping study, which thoroughly investigates the SLE-MHC associations down to the amino acid level of major HLA genes in 5,342 unrelated Korean case-control subjects, taking advantages of HLA imputation with a newly constructed Asian HLA reference panel. The most significant association is mapped to amino acid position 13 of HLA-DRβ1 (P=2.48 × 10(-17)) and its proxy position 11 (P=4.15 × 10(-17)), followed by position 26 in a stepwise conditional analysis (P=2.42 × 10(-9)). Haplotypes defined by amino acid positions 11-13-26 support the reported effects of most classical HLA-DRB1 alleles in Asian and European populations. In conclusion, our study identifies the three amino acid positions at the epitope-binding groove of HLA-DRβ1 that are responsible for most of the association between SLE and MHC.

STAT4 polymorphism is associated with early-onset type 1 diabetes, but not with late-onset type 1 diabetes.

In an effort to discover non‐HLA genes affecting susceptibility to type 1 diabetes (T1D), we have investigated the association of polymorphisms in STAT4, an important signaling molecule of IL‐12, γIFN, and IL‐23, in a sample of 389 T1D patients and 152 nondiabetic controls in Korea. Four SNPs on chromosome 2q, which were recently found to be associated with rheumatoid arthritis, were examined for association and linkage disequilibrium. We found that neither alleles or genotypes among all four SNPs nor reconstructed haplotypes of the three SNPs within the same LD block (rs7574865, rs8179673, and rs10181656) were associated with susceptibility to T1D. When we stratified T1D patients into early‐onset and late‐onset subgroups on the basis of fewer or more than 7.8 years of age at diagnosis, however, the minor alleles of three SNPs (rs7574865, rs8179673, and rs10181656) showed a significant association with susceptibility to T1D in the early‐onset subgroup (i.e., rs7574865, OR = 1.44 [1.03–2.01], P < 0.05), but not in the late‐onset subgroup, suggesting that STAT4 is related to earlier development of T1D. The analysis of genotypes and haplotypes of the same SNPs (rs7574865, rs8179673, and rs10181656) showed very comparable degrees of risk for T1D. The age at diagnosis is lowest in the patients carrying the homozygotes of a minor allele, middle in the heterozygotes, and highest in the homozygotes of a major allele, suggesting the dosage effects of risk alleles on the age of onset of disease. Recognizing that only the early‐onset cases might represent the true autoimmune T1D in Asian populations, we see that STAT4 alleles and haplotype might influence cytokine signaling and, therefore, development of T1D.

Radiologic Changes of Cervical Spine in Ankylosing Spondylitis

Abstract Ankylosing spondylitis (AS) is characterised by its effects on the axial skeleton. The cervical spine is also vulnerable to the disease process. Our aim was to determine the frequency of radiologic changes to the cervical spine and their correlation with clinical variables. We also used the Bath Ankylosing Spondylitis Radiology Index (BASRI) system, which is one of the reliable scoring systems of radiography, to score the global radiologic changes to the cervical and lumbar spine and the hip joints in our AS cohort. There were 181 patients with anteroposterior and lateral full-flexion views on radiography of the cervical spine here included in the study. A radiologist examined the radiologic changes to all anatomical compartments of the cervical spine in detail and graded them according to the BASRI system. We used the clinical and demographic data of our AS cohort to determine their relation to the radiographic changes. Eighty-eight patients (48.6%) showed radiological changes to the cervical spine; to the discovertebral joint 35.9%; the apophyseal joint 26.0%; atlantoaxial articulation 22.1% (atlantoaxial subluxation 13.8%); the costovertebral joint 18.2%; and to the posterior ligamentous attachment 11.6%. Using the BASRI system, 73 patients (40.3%) showed radiologic changes to the cervical spine and were graded as score 1 (1.7%), 2 (22.7%), 3 (6.6%) or 4 (9.4%). Among those graded as normal by the BASRI system, 17 showed some changes to the cervical spine, such as atlantoaxial joint subluxation or narrowing, and severe osteoporosis with no other radiographic changes. Current age, disease duration, inflammatory back pain and cervical symptoms were associated with the radiographic changes to the cervical spine. The BASRI-cervical spine score correlated with the BASRI-lumbar spine and hip joint score, sacroiliitis, disease duration, and duration of inflammatory back pain and cervical symptoms. Our data suggest that radiographic changes to the cervical spine are frequent in AS, and can be predicted in the patients with old age, long duration of disease and inflammatory back pain, and cervical symptoms. Also, the BASRI scoring system showed similar results as a detailed assessment of the cervical spine in our study.

Clinical and genetic risk factors of herpes zoster in patients with systemic lupus erythematosus

ObjectiveThe aim of this study was to determine the clinical and genetic risk factors that influence herpes zoster occurrence in patients with systemic lupus erythematosus (SLE).MethodsThree hundred three SLE patients meeting the American College of Rheumatology criteria were enrolled in this study. Herpes zoster was diagnosed when classic grouped vesicles were noted. Medical records were reviewed retrospectively to collect clinical information. For Fc gamma receptor IIa (FcγRIIa) and FcγRIIIa genotyping, polymerase chain reaction (PCR) using allele-specific primers was performed. The PCR sequence-specific oligonucleotide probe method was utilized in human HLA-DRB1 genotyping.ResultsForty-two cases (13.9%) of zoster occurred among 303 SLE patients. The incidence of zoster in patients with SLE was 32.5/1,000 patients per year. Patients who developed zoster had higher rates of lupus nephritis (P=0.018) and positive anti-Sm antibody (P=0.019). However, FcγRIIa and FcγRIIIa polymorphism and the HLA-DRB1 genotype did not influence herpes zoster occurrence.ConclusionSystemic lupus erythematosus patients with lupus nephritis or anti-Sm antibody are at higher risk of herpes zoster. FcγRIIa (H/R131), FcγRIIIa (F/V176), and HLA-DRB1 genetic polymorphisms did not influence the occurrence of herpes zoster in these patients.

Deletion variants of RABGAP1L, 10q21.3, and C4 are associated with the risk of systemic lupus erythematosus in Korean women.

OBJECTIVE Several copy number variations (CNVs) have been found to be associated with systemic lupus erythematosus (SLE) through the target gene approach. However, genome-wide features of CNVs and their role in the risk of SLE remain unknown. The aim of this study was to identify SLE-associated CNVs in Korean women. METHODS Genome-wide assessments of CNVs were performed in 382 SLE patients and 191 control subjects, using an Illumina HumanHap610 BeadChip genotyping platform. SLE-associated CNV regions that were identified by genome-wide association study (GWAS) were replicated in quantitative polymerase chain reaction (PCR) and deletion-typing PCR analyses in an independent sample set comprising 564 SLE patients and 511 control subjects. RESULTS Of 144 common CNV regions, 3 deletion-type CNV regions in 1q25.1, 8q23.3, and 10q21.3 were found to be significantly associated with SLE by GWAS analysis. In the independent replication, the CNV regions in 1q25.1 (RABGAP1L) and 10q21.3 were successfully replicated (odds ratio [OR] 1.30, P=0.038 and OR 1.90, P=3.6×10(-5), respectively), and the associations were confirmed again by deletion-typing PCR. The CNV region in the C4 gene, which showed a potential association in the discovery stage, was included in the replication analysis and was found to be significantly associated with the risk of SLE (OR 1.88, P=0.01). Through deletion-typing PCR, the exact sizes and breakpoint sequences of the deletions were defined. Individuals with the deletions in all 3 loci (RABGAP1L, 10q21.3, and C4) had a much higher risk of SLE than did those without any deletions in the 3 loci (OR 5.52, P=3.9×10(-4)). CONCLUSION These CNV regions can be useful to identify the pathogenic mechanisms of SLE, and might be used to more accurately predict the risk of SLE by taking into consideration their synergistic effects on disease susceptibility.