J. S. Bae

Associations of CD6, TNFRSF1A and IRF8 polymorphisms with risk of inflammatory demyelinating diseases

Multiple sclerosis (MS) and neuromyelitis optica (NMO) are inflammatory autoimmune diseases that affect the central nervous system. Several genome‐wide and candidate gene studies have identified genetic polymorphisms associated with the risk of MS or NMO. In particular, two recently published studies of meta‐analysis in European‐origin populations have suggested associations of single‐nucleotide polymorphisms (SNPs) in CD6, TNFRSF1A and IRF8 with MS. The aim of our study was to assess the associations between SNPs in these three genes and the risk of inflammatory demyelinating disease (IDD) including MS and NMO. To the best of our knowledge, this is the first time such a study has been performed in an Asian population.

Association of CHRM2 polymorphisms with severity of alcohol dependence.

The cholinergic muscarinic 2 receptor (CHRM2) gene has been considered a candidate gene for the alcohol dependence in that it might underpin certain risk factors for this condition. This study examined variations in the CHRM2 between the patients with alcohol dependence and population controls in Korean and explored the associations between CHRM2 polymorphisms and severity of symptoms in the patients with alcohol dependence. One hundred and fifty‐five patients with alcohol dependence, defined by the Alcohol Use Disorders Identification Test (AUDIT) and the Alcohol Dependence Scale (ADS) to measure the severity of symptoms, and one hundred and ninety‐five population controls were drawn in the study. Three single nucleotide polymorphisms (SNPs) of CHRM2 were genotyped using the TaqMan assay and analyzed with the severity of symptoms of alcohol dependence. We found that although SNP rs324650 showed marginal association with the risk of alcohol dependence (P = 0.03), the significance of the result was not sustained after multiple corrections. SNP rs1824024 was significantly associated with the AUDIT and ADS scores in patients (P = 0.005 and 0.003, respectively). These findings suggested that the muscarinic acetylcholine function might be related not with alcohol dependence itself but with the severity of alcohol dependence in Korean population.

Possible association of SLC22A2 polymorphisms with aspirin-intolerant asthma.

Background: Aspirin-intolerant asthma (AIA) is a clinical syndrome characterized by acute bronchoconstriction following the ingestion of aspirin. Solute carrier family 22, member 2 (SLC22A2), also known as organic cation transporter 2 (OCT2), is predominantly expressed in the luminal membrane of airway epithelial cells and has been shown to mediate the transport of prostaglandins on the cyclooxygenase pathway which is regulated by aspirin blockage. Recently, SLC22A2-mediated uptake inhibition by several nonsteroidal anti-inflammatory drugs and decreased SLC22A2 transport activity by its genetic variants have been elucidated in asthma. Methods: To investigate the associations between AIA and genetic polymorphisms of the SLC22A2 gene, 18 variants were genotyped in 163 AIA subjects and 429 aspirin-tolerant asthma (ATA) controls. Logistic analyses were used to evaluate p values for the associations of SLC22A2 polymorphisms with AIA. Results: One common polymorphism in intron 5, i.e. rs316021, was significantly associated with susceptibility to AIA (p = 0.004, Pcorr = 0.05, OR = 0.60, 95% CI = 0.43–0.85 in a codominant model). The minor allele frequency of rs316021 in the AIA group was significantly lower than that in the ATA controls. In addition, a polymorphism in intron 4 (rs3912161) and a haplotype (SLC22A2-ht3) showed significantly stronger association signals with the FEV1 fall rate induced by aspirin provocation in AIA subjects compared with ATA controls (p = 0.004, Pcorr = 0.05). Conclusion: Our findings suggest that SLC22A2 could be a susceptibility gene for aspirin intolerance in asthmatics.

Putative association of transforming growth factor-α polymorphisms with clearance of hepatitis B virus and occurrence of hepatocellular carcinoma in patients with chronic hepatitis B virus infection.

Summary.u2002 Previous studies showed that several genetic polymorphisms might influence the clinical outcome of chronic hepatitis B virus (HBV) infection, including HBV clearance or development of hepatocellular carcinoma (HCC). The aim of this study was to determine whether polymorphisms of the transforming growth factor‐α (TGF‐α) gene are associated with clinical outcome of HBV infection. A total of 1096 Korean subjects having either present or past evidence of HBV infection were prospectively enrolled between January 2001 and August 2003. Among 16 genetic variants in TGFA gene, nine variants were genotyped using TaqMan assay and the genetic association with HBV clearance and HCC occurrence was analysed. Statistical analyses revealed that TGFA+103461T>C, TGFA+106151C>G and TGFA‐ht2 were marginally associated with clearance of HBV infection. However, only TGFA‐ht2 retained significance after multiple correction (ORu2003=u20030.39, Pcorru2003=u20030.007 in recessive model). Although no variants were significant after multiple correction, TGFA+88344G>A and TGFA+103461T>C were weakly associated in recessive model in the analysis of HCC occurrence. In addition, Cox relative hazards model also revealed that TGFA+88344G>A was associated with onset age of HCC occurrence in subjects (RHu2003=u20031.46, Pcorru2003=u20030.04). TGF‐α polymorphisms might be an important factor in immunity, progression of inflammatory process and carcinogenesis, which explains the variable outcome of HBV infection at least in part. Further biological evidence is warranted in the future to support these suggestive associations.

Neuregulin 3 does not confer risk for schizophrenia and smooth pursuit eye movement abnormality in a Korean population

Located on chromosome 10q22‐q23, the human neuregulin3 (NRG3) is considered to be a strong positional and functional candidate gene for schizophrenia pathogenesis. Several case–control studies examining the association of polymorphisms in NRG3 with schizophrenia and/or related traits such as delusion have been reported recently in cohorts of Han Chinese, Ashkenazi Jews, Australians and white Americans of Western European ancestry. Thus, this study aimed to comprehensively investigate the association of NRG3 genetic variations with the risk of schizophrenia and smooth pursuit eye movement (SPEM) abnormality in a Korean population. Using TaqMan assay, six single‐nucleotide polymorphisms (SNPs) in the intronic region of NRG3 were genotyped and two major haplotypes were identified in 435 patients with schizophrenia as cases and 393 unrelated healthy individuals as controls. A total of 113 schizophrenia patients underwent an eye tracking task, and degree of SPEM abnormality was measured using the logarithmic values of the signal/noise (Ln S/N) ratio. Differences in frequency distributions were analyzed using logistic and regression models following various modes of genetic inheritance and controlling for age and sex as covariates. Subsequent analysis revealed that the frequency distributions of NRG3 polymorphisms and haplotypes were similar between schizophrenia patients and healthy controls of Korean ethnicity. Furthermore, no significant differences were observed between the genetic variants tested for SPEM abnormality. By elucidating a lack of association in a Korean population, findings from this study may contribute to the understanding of the genetic etiology focusing on the role of NRG3 in schizophrenia pathogenesis.

Identification of genetic polymorphisms in bovine mitochondrial deoxyribonucleic acid.

In this study, the intent was to identify genetic polymorphisms of mitochondrial (mt) DNA in Korean cattle (Bos taurus coreana) and to analyze the genetic relationship between Korean cattle and other breeds. Whole mtDNA genomes (16,338 bp) of 26 animals (16 Korean cattle and 10 Holsteins) were directly sequenced. Multiple alignments, including 26 whole-mtDNA sequences obtained by direct sequencing and 10 mtDNA sequences from a public database (National Center for Biotechnology Information), revealed 393 mtDNA polymorphisms (382 SNP, 3 heteroplasmies, and 8 insertion-deletion polymorphisms). Estimated gene diversity of mtDNA was 0.00198 among these 36 animals. Phylogenic analysis with mtDNA polymorphisms revealed a distinct genetic difference between Bos taurus (Korean, Japanese Black, Holstein, and Fleckvieh breeds) and Bos indicus (Nellore and Zwergzebu breeds). The genetic information regarding mtDNA polymorphisms identified in this study would be useful for further investigation of mtDNA in other breeds.

Association analysis of PDE4B polymorphisms with schizophrenia and smooth pursuit eye movement abnormality in a Korean population.

Schizophrenia is a debilitating mental disorder with a high heritability rate. Located on chromosome 1p31.3, the human cAMP-specific 3,5-cyclic phosphodiesterase 4B (PDE4B) gene has been considered as an important candidate gene for the risk of schizophrenia. Several genetic association studies reported the association between PDE4B polymorphisms and the risk of schizophrenia in Caucasian, African American, Indian, and Japanese populations. The aim of this study is to examine the association of PDE4B variations with schizophrenia and smooth pursuit eye movement (SPEM) abnormality in a Korean population. A case-control association analysis was carried out by comparing the genotype distribution of eight PDE4B polymorphisms between 457 schizophrenia patients and 386 normal healthy subjects. Differences in the frequency distribution of PDE4B single nucleotide polymorphisms (SNPs) and haplotypes were analyzed by logistic regression analyses controlling for age as a covariate. Statistical analyses revealed nominal significant associations of rs1040716, rs472952, rs1321177, and rs2144719 with the risk of schizophrenia (p = 0.02~0.05). The rs11208756 polymorphism showed a nominal significant association with SPEM abnormality (p = 0.05). In a meta-analysis with Japanese and Korean populations, three SNPs (rs472952, rs1040716, and rs2180335) revealed significant associations with schizophrenia (meta-p value = 0.0038~0.019). Our results support previously reported association of PDE4B variations with schizophrenia in other populations. The findings in this study add a new evidence for the involvement of PDE4B gene in schizophrenia etiology.

Lack of association between GTF2H4 genetic variants and AERD development and FEV1 decline by aspirin provocation

Aspirin‐exacerbated respiratory disease (AERD) is prevalent in about 10% of asthma patients and is characterized by a severe decline in forced expiratory volume in 1‐s (FEV1), an important phenotype for total lung capacity, upon ingestion of aspirin. The general transcription factor IIH subunit 4 (GTF2H4) is positioned at 6p21.33, a part of the major histocompatibility complex (MHC) class II region that contains a number of genes that play an important role in the immune system. In addition, genetic variants in another general transcription factor IIH gene have revealed significant association with lung disease. To investigate whether GTF2H4 genetic variants could be a causative factor for AERD development and FEV1 decline by aspirin provocation, five common single‐nucleotide polymorphisms (SNPs) were genotyped in 93 patients with AERD and 96 aspirin‐tolerant asthma (ATA) controls. As a result, when adjusted for age, gender, smoking status and atopy as covariates, the rs1264307 variant and two haplotypes showed nominal signals in the association with AERD (Pu2003=u20030.02–0.04), but the significances disappeared after corrections for multiple testing (corrected Pu2003>u20030.05). In further multiple regression analysis, no genetic variants of GTF2H4 showed significant associations with FEV1 decline by aspirin provocation in asthmatics (Pu2003>u20030.05). Despite the need for replications in larger cohorts, our preliminary findings suggest that GTF2H4 variants may not be associated with susceptibility to AERD and obstructive symptoms in asthmatics.