Soo Ok Lee

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.

Identification of SNP markers for common CNV regions and association analysis of risk of subarachnoid aneurysmal hemorrhage in Japanese population

Copy number variation (CNV) is emerging as a new tool for understanding human genomic variation, but its relationship with human disease is not yet fully understood. The data for a total of 317,503 genotypes were collected for a genome-wide association study of subarachnoid aneurismal hemorrhage (SAH) in a Japanese population (cases and controls, n=497) using Illumina HumanHap300 BeadChip. To identify multi-allelic CNV markers, we visually inspected all genotype clusters of 317,503 SNP markers covering the whole genome using Illuminas BeadStudio 3.0 software. As a result, we identified 597 multi-allelic CNV markers for common (copy loss frequency>0.05) CNV regions in a Japanese population (n=497). The identified CNV markers shared the following characteristics: enrichment of Hardy-Weinberg disequilibria, Mendelian inconsistency among families, and high missing genotype rate. All annotated information for those markers is summarized in our database (http://www.snp-genetics.com/user/srch.htm). In addition, we performed case-control association analyses of identified multi-allelic CNV markers with the risk of subarachnoid aneurysmal hemorrhage. One SNP marker (rs1242541) within a CNV region neighboring the Sel-1 suppressor of lin-12-like protein (SEL1L) was significantly associated with a risk of SAH (P=0.0006). We also validated the CNV around rs1242541 using real-time quantitative polymerase chain reaction (PCR). Information and methods used in this study would be helpful for accurate genotyping of SNPs on CNV regions, which could be used for association analysis of SNP markers within CNV regions.

PUTATIVE ASSOCIATION OF FAS AND FASL GENE POLYMORPHISMS WITH CLINICAL OUTCOMES OF HEPATITIS B VIRUS INFECTION

Objective:Fas/FasL polymorphisms, which are related to apoptosis, might influence the clearance of hepatitis B virus (HBV) infection and the occurrence of hepatocellular carcinoma (HCC). This study was performed to determine whether Fas and FasL promoter polymorphisms are associated with clinical outcome in chronic HBV infection. Methods: A total of 1,095 Korean subjects were prospectively allocated to two different groups: ‘the chronic carrier group’ (CC; n = 666), who were repeatedly hepatitis B surface antigen (HBsAg)-positive, and ‘the spontaneous recovery group’ (SR; n = 429), who were HBsAg-negative with antibodies to HBsAg and hepatitis B core antigen. In addition, the CC group was subcategorized into chronic hepatitis and HCC subgroups. Fas promoter polymorphisms at –1377G>A and –670A>G and the FasL promoter polymorphism at –844C>T were analyzed for and the genotype distributions of subjects were compared. Results: There were no significant associations between Fas or FasL promoter polymorphism with the HBV clearance and HBeAg clearance. However, –1377G>A in Fas promoter region showed protective effect to HCC occurrence (RH = 0.70, p = 0.03). Conclusions:Fas–1377G>A polymorphisms might be involved in the pathogenesis of human HCC.

Different Genetic Effects of Interferon Regulatory Factor 5 (IRF5) Polymorphisms on Systemic Lupus Erythematosus in a Korean Population

Objective In an effort to replicate additional associations of interferon regulatory factor 5 (IRF5) polymorphisms with systemic lupus erythematosus (SLE) in an Asian population, we examined those genetic effects in a Korean SLE cohort. Methods Each IRF5 polymorphism was genotyped in 1565 subjects using the TaqMan method and examined to determine whether it could explain the association with SLE. Results Three single-nucleotide polymorphisms (IRF5-15-1, rs2070197, and rs10488631), which showed strong and/or independent association in Caucasian populations, were not polymorphic in our Korean population. Association analysis revealed different genetic effects in Koreans compared with Caucasian populations. In addition, conditional analysis suggested independent genetic effects of 3 variant groups in the Korean population. Conclusion We demonstrate different genetic effects of IRF5 polymorphisms on the risk of SLE according to ethnicity.

Association analysis of G72/G30 polymorphisms with schizophrenia in the Korean population.

Several studies examining the association between G72/G30 polymorphisms and schizophrenia in cohorts of various ethnic origins have recently been reported. The aim of the current study was to examine the genetic influence of the G72/G30 polymorphisms in the Korean population. Nine G72/G30 single-nucleotide polymorphisms (SNPs) were genotyped in 388 patients with schizophrenia and 367 normal controls from the Korean population. Based on statistical analyses, the positive associations of previous studies of other populations were not replicated in the present study. However, 2 of the 9 tested SNPs, rs778294 and rs947267, were found to be associated with the risk of schizophrenia after correction for multiple testing (P(cor)=0.03 and P(cor)=0.04, respectively). The rs778294 SNP, taken singly, had not been found to be associated with schizophrenia in previous studies, and the second SNP, rs947267, showed an opposite direction of genetic effect on schizophrenia risk here than in a previous study. Our association results were not consistent with those found in other populations, and, thus could be chance findings. Therefore, further studies with larger sample sizes are needed to confirm a risk allele for this gene if it exists.

Polymorphisms in interleukin 8 and its receptors (IL8, IL8RA and IL8RB) and association of common IL8 receptor variants with peripheral blood eosinophil counts

AbstractAirway inflammation is a major factor in the pathogenesis of asthma. Interleukin 8 (IL8) is a potent proinflammatory cytokine that interacts with its receptors, IL8RA and IL8RB. We investigated the genetic polymorphisms in IL8, IL8RA, and IL8RB for any association with risk of asthma and peripheral blood eosinophil counts in a Korean population. By carrying out direct sequencing in 24 individuals, we identified 20 sequence variants within exons and their flanking regions, including the 1.5 kb promoter regions of IL8, IL8RA, and IL8RB. Among them, seven common single-nucleotide polymorphisms (SNPs) were selected for genotyping in our asthma cohort (n = 1,439). Two common haplotypes in IL8 and three in IL8RA and IL8RB (defined as one block) were identified. Although none of the polymorphisms showed a significant association with risk of asthma, IL8RA-B ht2 showed a significant association with the peripheral blood eosinophil counts (%) among asthma patients, e.g., lower eosinophil levels among individuals with the homozygous IL8RA-B ht2 (3.55 ± 3.39%) than among other asthmatic patients (5.52 ± 5.55%; Pcorr = 0.018). Our findings suggest that polymorphisms and haplotypes in IL8RA and IL8RB might be among the genetic factors underlying production of peripheral blood eosinophil.

Putative association of RUNX1 polymorphisms with IgE levels in a Korean population.

RUNX1, a member of the runt domain gene family of transcription factors, encodes a heterodimeric transcription factor and regulates the expression of various genes related to hematopoiesis and myeloid differentiation. RUNX1 has been one of the target genes for research into various autoimmune diseases due to its properties as a transcription factor and functional distribution for chromosomal translocation. In an effort to identify additional gene polymorphisms in which variants have been implicated in asthma, we investigated the genetic polymorphisms in RUNX1 to evaluate it as a potential candidate gene for a host genetic study of asthma and IgE production. We identified 19 sequence variants by direct DNA sequencing in 24 individuals of which four common variants were selected for genotyping in our asthma cohort (1,055 asthmatic patients, 384 normal controls). Using logistic regression analysis for association with the risk of asthma, while controlling for age, gender, and smoking status as covariates, no significant associations with the risk of asthma were detected. However, two polymorphisms in the promoter region (-2084G>C and -1282G>A) showed a marginal association with total IgE levels (0.03 and 0.03 in recessive models, respectively). Our findings suggest that polymorphisms in RUNX1 might be one of the genetic factors for the regulation of IgE production.

MYLK polymorphism associated with blood eosinophil level among asthmatic patients in a Korean population

The myosin light chain kinase (MYLK) gene encodes both smooth muscle and nonmuscle cell isoforms. Recently, polymorphisms in MYLK have been reported to be associated with several diseases. To examine the genetic effects of polymorphisms on the risk of asthma and related phenotypes, we scrutinized MYLK by re-sequencing/genotyping and statistical analysis in Korean population (n = 1,015). Seventeen common polymorphisms located in or near exons, having pairwise r2 values less than 0.25, were genotyped. Our statistical analysis did not replicate the associations with the risk of asthma and log-transformed total IgE levels observed among African descendant populations. However, two SNPs in intron 16 (+89872C > G and +92263T >C), which were in tight LD (|D′| = 0.99), revealed significant association with log-transformed blood eosinophil level even after correction multiple testing (P = 0.002/Pcorr= 0.01 and P = 0.002/Pcorr = 0.01, respectively). The log-transformed blood eosinophil levels were higher in individuals bearing the minor alleles for +89872C > G and +92263T > C, than in those bearing other allele. In additional subgroup analysis, the genetic effects of both SNPs were much more apparent among asthmatic patients and atopic asthma patients. Among atopic asthma patients, the log-transformed blood eosinophil levels were proportionally increased by gene-dose dependent manner of in both +89872C > G and +92263T > C (P = 0.0002 and P = 0.00007, respectively). These findings suggest that MYLK polymorphisms might be among the genetic factors underlying differential increases of blood eosinophil levels among asthmatic patients. Further biological and/or functional studies are needed to confirm our results.