Identification of additional EHMT2 variant associated with the risk of chronic hepatitis B by GWAS follow-up study.

Chronic hepatitis B (CHB) is a precursor to liver cirrhosis and hepatocellular carcinoma, caused by a Hepatitis B viral infection. Genome-wide association studies (GWASs) have been conducted to find genes associated with CHB risk. In previous GWAS, EHMT2 was identified as one of the susceptibility genes for CHB. To further characterize this association and discover possible causal variants, we conducted an additional association study. A total of 11 EHMT2 single-nucleotide polymorphisms (SNP) were selected and genotyped in 3902 subjects (1046 CHB patients and 2856 controls). An additional eight imputed SNPs were also included in further analysis. As a result, rs35875104 showed a strong association with the CHB, along with the previously reported genetic marker for CHB risk, rs652888 (odds ratio (OR) = 0.53, P = 2.20 × 10-8 at rs35875104 and OR = 1.58, P = 9.90 × 10-12 at rs652888). In addition, linkage disequilibrium and conditional analysis identified one SNP (rs35875104) as a novel genetic marker for CHB susceptibility. The GRSs (genetic risk scores) were calculated to visualize the combined genetic effects of all known CHB-associated loci, including EHMT2 rs35875104, which was additionally identified in this study. The findings from the present study may be useful for further understanding of the genetic etiology of CHB.

Functional Study of Haplotypes in UGT1A1 Promoter to Find a Novel Genetic Variant Leading to Reduced Gene Expression.

BACKGROUND: Uridine diphosphate glucuronyltransferase 1 family, A1 (UGT1A1) encodes for an enzyme that is a part of glucuronidation pathway, and a number of studies have shown that the promoter polymorphisms of UGT1A1 are associated with various diseases and drug response. In this study, we examined a possible association between UGT1A1 promoter haplotypes and the gene expression level. METHODS: To identify promoter haplotype structure population, we directly sequenced the promoter region of UGT1A1 in 192 healthy Korean to identify 10 UGT1A1 promoter single-nucleotide polymorphisms (SNPs). Then, we genotyped the 10 SNPs in additional 192 non-Korean samples comprised of Chinese, Japanese, European American, and African American, and constructed haplotype structures. Furthermore, we conducted luciferase assay for the promoter SNP haplotypes to examine a possible expression change. RESULTS: rs3755319C-rs2003569A-rs887829C-rs8175347(TA)6 (6.60 ± 0.15) and rs3755319A-rs2003569 G-rs887829C-rs8175347(TA)7 (2.79 ± 0.97) led to significantly lower gene expression when compared with rs3755319C-rs2003569 G-rs887829T-rs8175347(TA)6 (8.28 ± 0.60). CONCLUSIONS: Our result suggests that the haplotypes in UGT1A1 promoter region can affect the expression level of the gene and drug metabolism associated with UGT1A1. Furthermore, in addition to rs8175347, rs3755319 was found to induce lower gene expression of UGT1A1.

Screening of dihydropyrimidine dehydrogenase genetic variants by direct sequencing in different ethnic groups.

Dihydropyrimidine dehydrogenase (DPYD) is an enzyme that regulates the rate-limiting step in pyrimidine metabolism, especially catabolism of fluorouracil, a chemotherapeutic agent for cancer. In order to determine the genetic distribution of DPYD, we directly sequenced 288 subjects from five ethnic groups (96 Koreans, 48 Japanese, 48 Han Chinese, 48 African Americans, and 48 European Americans). As a result, 56 polymorphisms were observed, including 6 core polymorphisms and 18 novel polymorphisms. Allele frequencies were nearly the same across the Asian populations, Korean, Han Chinese and Japanese, whereas several SNPs showed different genetic distributions between Asians and other ethnic populations (African American and European American). Additional in silico analysis was performed to predict the function of novel SNPs. One nonsynonymous SNP (+199381A > G, Asn151Asp) was predicted to change its polarity of amino acid (Asn, neutral to Asp, negative). These findings would be valuable for further research, including pharmacogenetic and drug responses studies.

Genetic association analysis of ERBB4 polymorphisms with the risk of schizophrenia and SPEM abnormality in a Korean population.

The human receptor tyrosine-protein kinase erbB-4 (ERBB4) gene mediates neuregulin 1 (NRG1) signaling, and is involved in neuronal migration and differentiation. Despite the potential significance of ERBB4 in the development of schizophrenia, relatively few genetic studies for the association of ERBB4 with schizophrenia were performed in the populations including Ashkenazi Jews, Americans including Caucasians and African Americans, and Han Chinese. In this study, differences in ERBB4 variations were investigated to determine association with schizophrenia and smooth pursuit eye movement (SPEM) abnormality in a Korean population. Seven polymorphisms in ERBB4 gene were genotyped in 435 schizophrenia cases and 390 unrelated healthy controls. In order to investigate the relationship between ERBB4 and the risk of schizophrenia and SPEM abnormality, differences in SNP and haplotype distribution were analyzed using logistic and multiple regression analyses. However, we failed to replicate the associations reported by previous studies in other populations. Although statistically not significant, the tendency towards associations between ERBB4 polymorphisms and the risk of schizophrenia and SPEM abnormality in this study from a Korean population would be helpful for further genetic etiology studies in schizophrenia.

Potential association of DDR1 genetic variant with FEV1 decline by aspirin provocation in asthmatics.

BACKGROUND: The discoidin domain receptor tyrosine kinase 1 (DDR1) is positioned within the major histocompatibility complex (MHC) region which plays an important role in the immune system. In addition, DDR1 has been elucidated to be downregulated during the epithelial-mesenchymal transition of bronchial epithelium. OBJECTIVE: To investigate the potential genetic associations between DDR1 and aspirin-exacerbated respiratory disease (AERD), this study conducted association studies of DDR1 single nucleotide polymorphisms (SNPs) with AERD and the obstructive symptom of forced expiratory volume in 1 s (FEV(1)) decline after aspirin provocation. METHODS: Nine common SNPs were genotyped in 93 AERD patients and 96 aspirin-tolerant asthma (ATA) controls. The genotype distributions of all loci were in Hardy-Weinberg equilibrium (HWE; p > .05). Results. In the results of logistic analyses using age, sex, smoking status, and atopy as covariates, DDR1 rs1264320 in the intronic region showed a potent association signal with FEV(1) decline by aspirin provocation in asthmatics of this study even after corrections for multiple testing (p = .003 and corrected p = .01). However, the variants of DDR1 were not significantly associated with the AERD development (corrected p > .05). On further comparison of FEV(1) decline by aspirin provocation between AERD and ATA, the variant rs1264320 was found to be associated with the FEV(1) decline of ATA rather than AERD. CONCLUSION: Despite the need for further functional evaluations and replications, we conclude that DDR1 polymorphisms are not likely to contribute to predispositions of AERD, but may be potentially associated with FEV(1) decline by aspirin provocation in asthmatics.

Association study between TRIM26 polymorphisms and risk of aspirin-exacerbated respiratory disease.

Aspirin-exacerbated respiratory disease (AERD) is a clinical syndrome that is characterized by nasal polyposis, general symptoms of asthma and sensitive response to non-steroidal anti-inflammatory drugs (NSAIDs). Although the exact function of tripartite motif-containing 26 (TRIM26) still remains unknown, the gene functions in the immune response. Thus, we hypothesized that TRIM26 polymorphisms may affect aspirin-induced bronchospasm and explored whether the gene can be a marker for diagnosis of AERD. To investigate our hypothesis that TRIM26 may serve as a genetic marker for diagnosis of AERD, this study focused on demonstrating the associations between single nucleotide polymorphisms (SNPs) of the TRIM26 gene and AERD. We genotyped 18 polymorphisms of TRIM26 in a total of 189 asthmatics and examined their associations with the risk of AERD. We performed logistic analysis for obtaining P-values and regression analysis for demonstrating an association between the phenotype with FEV1 and the genotype. We observed no associations between polymorphisms in TRIM26 and the risk of AERD in both logistic and regression analyses. Although our results reveal a lack of association, the suggested functional role of TRIM26 makes it a putative candidate gene for AERD. Thus, replications in other populations using larger samples may provide valuable information for AERD etiology.

Genetic analysis of complement component 9 (C9) polymorphisms with clearance of hepatitis B virus infection.

BACKGROUND: The complement component 9 (C9), a major cytolytic protein in the complement system, plays an important role in the immunological process. However, associations between genetic variations of the complement factor and chronic hepatitis B virus infection still need to be investigated. AIMS: We hypothesized that genetic variations in the complement component 9 gene can influence the clearance of chronic hepatitis B virus infection, hepatocellular carcinoma occurrence, and onset age of hepatocellular carcinoma. To investigate the relationship between complement component 9 variations and these disease phenotypes, we performed a case-control association analysis in a Korean population. METHODS: Genetic variations were identified through direct DNA sequencing and genotyped using TaqMan assay (n = 1,103). In order to investigate the relationship of complement component 9 with chronic hepatitis B virus clearance and hepatocellular carcinoma occurrence, differences in SNP and haplotype frequency distributions were analyzed using logistic and multiple regression analyses with adjusted age and gender as covariates. RESULTS: Although +23189C>T polymorphism in exon 4 and C9_ht2 [T-G-C-A-C] were significantly associated with clearance of chronic hepatitis B virus infection and hepatocellular carcinoma occurrence, the association signals were not retained after multiple testing corrections. CONCLUSIONS: We conclude that variations in the complement component 9 gene are unlikely to influence clearance of chronic hepatitis B virus infection and hepatocellular carcinoma occurrence. Although this preliminary result provides meaningful information, further functional investigations in other genetic factors for pathway analyses are required.

No associations of polymorphisms in ADPRT with hepatitis B virus clearance and hepatocellular carcinoma occurrence in a Korean population.

AIM: The human adenosine diphosphate ribosyl transferase (ADPRT) gene might significantly affect cancer by encoding poly(ADP-ribose) polymerase 1 enzyme (PARP-1) and promoting an important role in cellular responses to DNA damage, genomic stabilization and regulation of tumor suppressor genes. We explored whether polymorphisms of ADPRT affect clearance of hepatitis B virus (HBV) infection or risk of hepatocellular carcinoma (HCC) occurrence in a Korean HBV cohort. METHODS: Genotyping was performed in a total of 1066 subjects composed of 434 spontaneously recovered (SR) subjects as normal controls and 632 chronic carriers (CC) of HBV who were further classified into 325 patients with liver cirrhosis (LC)/chronic hepatitis (CH) and 307 patients with HCC. RESULTS: Logistic analyses of six common single nucleotide polymorphisms (SNP) and their haplotypes revealed that none of the polymorphisms were significantly associated with clearance of HBV infection and HCC occurrence, except for nominal evidence of association between haplotype 2 (ht2) with HBV clearance (P = 0.05). In the analysis of age of HCC occurrence which is an important factor in disease progression to HCC, results from Cox proportional hazards showed that none of the variants were significantly associated with onset age of HCC occurrence, although a nominal signal in ht4 (P = 0.03, but P(corr) > 0.05) was initially detected. CONCLUSION: Although ADPRT is an important gene for cellular responses and tumor regulations, our study provides evidence that ADPRT variations do not affect HBV clearance and HCC occurrence.

Putative association of SMAPIL polymorphisms with risk of aspirin intolerance in asthmatics.

BACKGROUND: Aspirin-intolerant asthma (AIA), as a clinical syndrome caused by aspirin, is characterized by lung inflammation and reversible bronchoconstriction. Recently, the altered trafficking and diminished airway reactivity have been implicated in allergic airway remodeling. The stromal membrane-associated protein 1-like (SMAP1L) exerts common and distinct functions in vesicle trafficking including endocytosis. The disturbance of pulmonary surfactant synthesis has been elucidated to be associated with asthma experimentally. Moreover, in alveolar type II (ATII) cells that synthesize pulmonary surfactant, alterations of clathrin-dependent endocytosis cause disturbance at the surfactant function, suggesting that SMAP1L, which directly interacts with clathrin, could be associated with asthma and related phenotypes. OBJECTIVE: To verify our hypothesis that SMAP1L could play a role in the development of AIA, this study investigated associations between single-nucleotide polymorphisms (SNPs) of the SMAP1L gene and AIA. METHODS: We conducted an association study between 19 SNPs of the SMAP1L gene and AIA in a total of 592 Korean subjects including 163 AIA and 429 aspirin-tolerant asthma (ATA) patients. Associations between polymorphisms of SMAP1L and AIA were analyzed with sex, smoking status, atopy, and body mass index as covariates. RESULTS: Logistic analyses revealed that three common polymorphisms, rs2982510, rs2294752, and rs446738, were putatively associated with the increased susceptibility to AIA (p = .003, p(corr) = .004, OR = 0.24, 95% CI = 0.09-0.62 for rs2982510 and rs2294752; p = .008, p(corr) = .03, OR = 0.44, 95% CI = 0.24-0.80 for rs446738, in the recessive model). In addition, rs2982510 and rs2294752 were significantly associated with the fall of forced expiratory volume in 1 s (FEV1) by aspirin provocation (p = .001, p(corr) = .04 in the recessive model for both SNPs). CONCLUSIONS: Our findings suggest that SMAP1L might be a susceptible gene to AIA, providing a new strategy for the control of aspirin intolerance.

Association of CACNG6 polymorphisms with aspirin-intolerance asthmatics in a Korean population.

BACKGROUND: Aspirin-intolerant asthma (AIA) occurs in the lower and upper airways through excessive production of leukotrienes upon administration of non-steroidal anti-inflammatory drugs (NSAIDs). One of the three symptoms of AIA is nasal polyposis, a chronic inflammatory disease that is related to the function of calcium ion in recruitment of immune cells during airway inflammation. It has been implicated that bronchodilation in the airway is related to Ca(2+) regulation. The calcium channel, voltage-dependent, gamma subunit 6 (CACNG6) gene encodes a protein that stabilizes the calcium channel. METHODS: To study the associations between AIA and polymorphisms in CACNG6 gene, eight variants were genotyped in 102 AIA cases and 429 aspirin-tolerant asthma (ATA) controls. Logistic analyses were used to evaluate the associations of CACNG6 polymorphisms with AIA. RESULTS: Statistical analyses revealed that a single nucleotide polymorphism (SNP; rs192808C > T; P = 0.0004, Pcorr = 0.0029, OR = 2.88 in co-dominant model; P = 0.0005, Pcorr = 0.0036, OR = 2.99 in dominant model) in intron and a haplotype unique to this variant (CACNG6_BL1_ht6; P = 0.003, Pcorr = 0.02, OR = 2.57 in co-dominant model, P = 0.001, Pcorr = 0.0087, OR = 2.81 in dominant model) were significantly associated with the risk of AIA. CONCLUSIONS: Our results suggest that the CACNG6 variants might be associated with the risk of AIA in a Korean population.

Positive association between aspirin-intolerant asthma and genetic polymorphisms of FSIP1: a case-case study.

BACKGROUND: Aspirin-intolerant asthma (AIA), which is caused by non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, causes lung inflammation and reversal bronchi reduction, leading to difficulty in breathing. Aspirin is known to affect various parts inside human body, ranging from lung to spermatogenesis. FSIP1, also known as HDS10, is a recently discovered gene that encodes fibrous sheath interacting protein 1, and is regulated by amyloid beta precursor protein (APP). Recently, it has been reported that a peptide derived from APP is cleaved by alpha disintegrin and metalloproteinase 33 (ADAM33), which is an asthma susceptibility gene. It has also been known that the FSIP1 gene is expressed in airway epithelium. OBJECTIVES: Aim of this study is to find out whether FSIP1 polymorphisms affect the onset of AIA in Korean population, since it is known that AIA is genetically affected by various genes. METHODS: We conducted association study between 66 single nucleotide polymorphisms (SNPs) of the FSIP1 gene and AIA in total of 592 Korean subjects including 163 AIA and 429 aspirin-tolerant asthma (ATA) patients. Associations between polymorphisms of FSIP1 and AIA were analyzed with sex, smoking status, atopy, and body mass index (BMI) as covariates. RESULTS: Initially, 18 SNPs and 4 haplotypes showed associations with AIA. However, after correcting the data for multiple testing, only one SNP showed an association with AIA (corrected P-value = 0.03, OR = 1.63, 95% CI = 1.23-2.16), showing increased susceptibility to AIA compared with that of ATA cases. Our findings suggest that FSIP1 gene might be a susceptibility gene for aspirin intolerance in asthmatics. CONCLUSION: Although our findings did not suggest that SNPs of FSIP1 had an effect on the reversibility of lung function abnormalities in AIA patients, they did show significant evidence of association between the variants in FSIP1 and AIA occurrence among asthmatics in a Korean population.