Search

A recent study in the North American White population has documented the association of a common STAT4 haplotype (tagged by rs7574865) with risk for rheumatoid arthritis (RA) and systemic lupus erythematosus. To replicate this finding in the Korean population, we performed a case-control association study. We genotyped 67 single nucleotide polymorphisms (SNPs) within the STAT1 and STAT4 regions in 1123 Korean patients with RA and 1008 ethnicity-matched controls. The most significant four risk SNPs (rs11889341, rs7574865, rs8179673, and rs10181656 located within the third intron of STAT4) among 67 SNPs are identical with those in the North American study. All four SNPs have modest risk for RA susceptibility (odds ratio 1.21-1.27). A common haplotype defined by these markers (TTCG) carries significant risk for RA in Koreans [34 percent versus 28 percent, P=0.0027, OR (95 percent CI)=1.33 (1.10-1.60)]. By logistic regression analysis, this haplotype is an independent risk factor in addition to the classical shared epitope alleles at the HLA-DRB1 locus. There were no significant associations with age of disease onset, radiographic progression, or serologic status using either allelic or haplotypic analysis. Unlike several other risk genes for RA such as PTPN22, PADI4, and FCRL3, a haplotype of the STAT4 gene shows consistent association with RA susceptibility across Whites and Asians, suggesting that this risk haplotype predates the divergence of the major racial groups.

Objective: Recently, Swedish members of the Epidemiological Investigation of Rheumatoid Arthritis (EIRA) provided evidence that smoking may trigger RA-specific immune reactions to citrullinated protein in carriers of HLA-DR shared epitope alleles. In an effort to confirm this interaction between smoking and shared epitope alleles, we performed a case-only analysis of 3 North American RA cohorts., Methods: A total of 2,476 white patients with RA were studied, 1,105 from the North American Rheumatoid Arthritis Consortium (NARAC) family collection, 753 from the National Inception Cohort of Rheumatoid Arthritis Patients (Inception Cohort), and 618 from the Study of New Onset Rheumatoid Arthritis (SONORA). All patients were HLA-DRB1 typed, and tested for anti-cyclic citrullinated peptide (anti-CCP) and rheumatoid factor. Information about smoking history was obtained by questionnaire., Results: A significant association was found between smoking and the presence of anti-CCP in the NARAC and the Inception Cohort, but not in the SONORA. The shared epitope alleles consistently correlated with anti-CCP in all 3 populations. Using multiple logistic regression analyses, shared epitope alleles were still the most significant risk factor for anti-CCP positivity. Weak evidence of gene-environment interaction between smoking and shared epitope alleles for anti-CCP formation was found only in the NARAC., Conclusion: Unlike the EIRA data, we could not confirm a major gene-environment interaction for anti-CCP formation between shared epitope alleles and smoking in 3 North American RA cohorts. Our data indicate a need for further studies to address the full range of environmental factors other than smoking that may be associated with citrullination and RA.

The 620W allelic variant of the intracellular tyrosine phosphatase, PTPN22, is associated with a number of different autoimmune disorders, and this provides direct evidence for common mechanisms underlying many of these diseases. The associated allele appears to influence thresholds for T cell receptor signaling, and a variety of disease models involving both central and peripheral tolerance can be proposed. However, given the fact that PTPN22 is expressed in a variety of immunologically relevant cell types, the precise mechanisms for these associations remain unclear. In general, the PTPN22 620W allele appears to play a role in autoimmune disorders that have a prominent humoral component, suggesting that further investigation of PTPN22 activity in B cells will be useful. From a genetic perspective, the data highlights the genetic heterogeneity underlying autoimmunity in different ethnic groups.

Objective: Anticitrullinating autoantibodies are specific markers for rheumatoid arthritis (RA). A functional haplotype of 4 exonic single-nucleotide polymorphisms (SNPs) in a citrullinating enzyme, peptidylarginine deiminase 4 (PADI4), was shown to be associated with susceptibility to RA in a Japanese population and was shown to increase the stability of PADI4 messenger RNA. However, the association was not confirmed in 4 subsequent studies involving Caucasian RA patients living in the UK, a French Caucasian population, and a Spanish population. The aim of the current study was to investigate the association of SNPs in the PADI4 gene with RA in a Korean population., Methods: Four exonic SNPs of the PADI4 gene (padi4_89, padi4_90, padi4_92, and padi4_104) were genotyped in 545 unrelated patients with RA and 392 controls, using the MassArray SNP genotyping system. Allelic, genotypic, and haplotypic associations of the SNPs with RA susceptibility were examined using the chi-square test and multivariate logistic regression analyses., Results: Increased RA susceptibility was significantly associated with the minor alleles of padi4_89 (P = 2.3 x 10(-5)), padi4_90 (P = 2.3 x 10(-5)), padi4_92 (P = 2.1 x 10(-5)), and padi4_104 (P = 1.1 x 10(-3)) and the haplotype carrying the 4 minor alleles (P = 1.0 x 10(-4)). Genotypes carrying the minor alleles and HLA-DRB1 shared epitope (SE) alleles (P = 9.4 x 10(-21)) were also associated with increased RA susceptibility. The genotypic associations were sustained among individuals who did not carry any SE alleles, except in the case of padi4_104. Individuals carrying the risk SNPs and/or SE alleles were more susceptible to RA than were individuals carrying neither risk SNPs nor SE alleles., Conclusion: The PADI4 SNPs and haplotypes are associated with RA susceptibility in Koreans. Thus, the association of PADI4 with RA may depend on genetic heterogeneity between Asians and Europeans.

Objective: The 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)., Methods: Three 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 (Fc gamma RIIa) and Fc gamma RIIIa 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., Results: Forty-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, Fc gamma RIIa and Fc gamma RIIIa polymorphism and the HLA-DRB1 genotype did not influence herpes zoster occurrence., Conclusion: Systemic lupus erythematosus patients with lupus nephritis or anti-Sm antibody are at higher risk of herpes zoster. Fc gamma RIIa (H/R131), Fc gamma RIIIa (F/V176), and HLA-DRB1 genetic polymorphisms did not influence the occurrence of herpes zoster in these patients.

DNase II is an important enzyme for DNA fragmentation and degradation during programmed cell death and, consequently, a potential candidate gene for genetic study of systemic lupus erythematosus (SLE). Genetic associations of DNase II with SLE and related phenotypes were examined in Korean patients with SLE. A total of 350 Korean SLE patients and 330 healthy subjects were enrolled. Direct DNA sequencing and TaqMan were employed. Logistic regression analyses were performed to examine the genetic association with SLE and related phenotypes. Through direct sequencing in 24 Korean individuals, six sequence variants were identified: one in the 5' flanking region, four in exons (including one nonsynonymous), and one in the 3' flanking region. Four of these polymorphisms were selected for a larger-scale genotyping (350 SLE patients and 330 normal controls). No significant associations with the risk of SLE were detected. However, further analyses of association with the risk of renal disorder among SLE patients revealed several positive associations. One promoter SNP (-1066G>C), +2630T>C (Ser145Ser), +6235G>C and one haplotype showed weak associations with the risk of nephritis among SLE patients.

Objective: To investigate the association of susceptibility and protective HLA-DRB1 alleles with rheumatoid arthritis (RA) and its clinical markers in an Asian population., Methods: All RA patients (n = 574) and control subjects (n = 392) were Korean. HLA-DRB1 typing and further subtyping of all alleles was performed by polymerase chain reaction, sequence-specific oligonucleotide probe hybridization, and direct DNA sequencing analysis. We used a relative predispositional effects (RPEs) method and a false discovery rate correction method for multiple comparisons., Results: The DRB1*0405 and *0901 alleles showed the most significant associations with RA (P = 7.83 x 10(-24), odds ratio [OR] 4.40 [95% confidence interval (95% CI) 3.24-5.99], and P = 3.76 x 10(-9), OR 2.47 [95% CI 1.82-3.36], respectively). The RPEs test showed that the DRB1*0401 and *0410 alleles conferred susceptibility and that the DRB1*0701, *0802, *1301, *1302, *1403, and *1405 alleles showed significant protective effects. Susceptibility and protective alleles both showed a pattern consistent with additive genetic effects, and each influenced RA independently of the other. The compound heterozygote DRB1*0405/*0901 was associated with the highest risk of RA (corrected P = 1.81 x 10(-11), OR 58.2 [95% CI 7.95-425.70]). The mean age at disease onset was approximately 4 years earlier or was 3 years earlier, respectively, in patients with at least 1 copy of the DRB1*0405 or the DRB1*0901 allele. Radiographic changes (stages II-IV) were more frequent in patients with at least 1 copy of DRB1*0405 (P = 0.032, 92.6% versus 84.3%, OR 2.33 [95% CI 1.24-4.39])., Conclusion: The DRB1*0405/*0901 heterozygote has the strongest association with RA, suggesting that this heterozygote enhances the susceptibility to RA in Koreans.

DNase I could be the most important nuclease for the removal of DNA from nuclear antigens at sites of high cell turnover, and thus may also prevent systemic lupus erythematosus (SLE). Sixteen SNPs were identified by direct DNA sequencing, among which six were selected for genotyping in a larger investigation on the basis of linkage disequilibria among SNPs, their frequency, location and haplotype tagging status. Genetic associations of polymorphisms in DNase I with the risk of SLE and the production of common autoantibodies were examined in a Korean population (350 SLE patients and 330 controls). Although no significant associations with the risk of SLE were found, logistic regression analyses revealed that one non-synonymous SNPs in exon 8, +2373A>G(Gln244Arg), was significantly associated with an increased risk of the production of anti-RNP and anti-dsDNA antibodies among SLE patients. The frequency of the homozygous minor allele (Arg/Arg) was much higher in patients who had the anti-RNP antibody (31.3%) than in patients who did not have this antibody (14.4%) (P=0.0006, OR=2.86). In addition, the A/T mutation in exon 2 of DNase reported in two Japanese SLE patients was not present in SLE patients (n=350) or controls (n=330) in our Korean population, which combined with the results of previous reports strongly suggests that the mutation is not present in three major ethnic groups: Caucasian, African and Asian.