Association Analysis of SLC6A20 Polymorphisms With Hirschsprung Disease.

PURPOSE: Hirschsprung disease (HSCR) is a congenital and heterogeneous disorder, which is caused by no neuronal ganglion cells in part or all of distal gastrointestinal tract. Recently, our genome-wide association study has identified solute carrier family 6, proline IMINO transporter, member 20 (SLC6A20) as one of the potential risk factors for HSCR development. This study performed a replication study for the association of SLC6A20 polymorphisms with HSCR and an extended analysis to investigate further associations for subgroups and haplotypes. METHODS: For the replication study, a total of 40 single nucleotide polymorphisms (SNPs) of SLC6A20 were genotyped in 187 HSCR subjects composed of 121 short-segment HSCR, 45 long-segment HSCR (L-HSCR), 21 total colonic aganglionosis, and 283 unaffected controls. Imputation was performed using genotype data from our genome-wide association study and this replication study. RESULTS: Imputed meta-analysis revealed that 13 SLC6A20 SNPs (minimum P = 0.0002 at rs6770261) were significantly associated with HSCR even after correction for multiple comparisons using false discovery rate (FDR) (minimum PFDR =  .005). In further subgroup analysis, SLC6A20 polymorphisms appeared to have increased associations with L-HSCR. Moreover, haplotype analysis also showed significant associations between 2 haplotypes (BL3_ht2 and BL4_ht2) and HSCR susceptibility (PFDR <  .05). CONCLUSIONS: Although further replications and functional evaluations are required, our results suggest that SLC6A20 may have roles in HSCR development and in the extent of aganglionic segment during enteric nervous system development.

Genome-wide association study with the risk of schizophrenia in a Korean population.

Schizophrenia is regarded as a multifactorial and polygenic brain disorder that is attributed to different combinations of genetic and environmental risk factors. Recently, several genome-wide association studies (GWASs) of schizophrenia have identified numerous risk factors, but the replication results remain controversial and ambiguous. To identify schizophrenia susceptibility loci in the Korean population, we performed a GWAS using the Illumina HumanOmni1-Quad V1.0 Microarray. We genotyped 1,140,419 single nucleotide polymorphisms (SNPs) in 350 Korea schizophrenia patients and 700 control subjects, and approximately 620,001 autosomal SNPs were passed our quality control. In the case-control analysis, the rs9607195 A>G on intergenic area 250 kb away from the ISX gene and the rs12738007 A>G on the intron of the MECR gene were the most strongly associated SNPs with the risk of schizophrenia (P = 6.2 × 10(-8) , OR = 0.50 and P = 3.7 × 10(-7) , OR = 2.39, respectively). In subsequent fine-mapping analysis, 6 SNPs of MECR were genotyped with 310 schizophrenia patients and 604 control subjects. The association of the MECR rs12738007, a top ranked-SNP in GWAS, was replicated (P = 1.5 × 10(-2) , OR = 1.53 in fine mapping analysis, P = 1.5 × 10(-6) , OR = 1.90 in combined analysis). The identification of putative schizophrenia susceptibility loci could provide new insights into genetic factors related with schizophrenia and clues for the development of diagnosis strategies.

A genome-wide association study identified new variants associated with the risk of chronic hepatitis B.

UNLABELLED: Hepatitis B virus (HBV) infection is the predominant risk factor for chronic hepatitis B (CHB), liver cirrhosis (LC) and hepatocellular carcinoma (HCC). Recently, several genome-wide association studies (GWASs) of CHB identified human leukocyte antigen (HLA) loci, including HLA-DP and HLA-DQ in Asian populations, as being associated with the risk of CHB. To confirm and identify the host genetic factors related to CHB infection, we performed another GWAS using a higher-density chip in Korean CHB carriers. We analyzed 1400 samples from Korean population (400 CHB cases and 1000 population controls) using a higher-density GWAS chip [1 140 419 single nucleotide polymorphisms (SNPs)]. In subsequent replication analysis, we further analyzed in an independent study of a Korean CHB cohort consisting of 2909 Korean samples (971 cases and 1938 controls). Logistic regression methods were used for statistical analysis adjusting for age and sex as covariates. This study identified two new risk-associated loci for CHB on the HLA region of chromosome 6, e.g. rs652888 on euchromatic histone-lysine-methyltransferase 2 (EHMT2, P = 7.07 × 10(-13)) and rs1419881 on transcription factor 19 (TCF19, P = 1.26 × 10(-18)). Conditional analysis with nearby HLA CHB loci that were previously known, confirmed the independent genetic effects of these two loci on CHB. CONCLUSION: The GWAS and the subsequent validation study identified new variants associated with the risk of CHB. These findings may advance the understanding of genetic susceptibility to CHB.

Association between TAAR6 polymorphisms and airway responsiveness to inhaled corticosteroids in asthmatic patients.

BACKGROUND: Genetic polymorphisms may be responsible for the wide variation in response to inhaled corticosteroids in asthmatic patients. We had previously reported that one polymorphism rs7772821, located on the 3'-UTR of trace amine-associated receptor 6 (TAAR6), is significantly associated with percentile changes in the forced expiratory volume in 1 s (%ΔFEV1) after inhaled corticosteroid treatment in asthmatics using a genome-wide association study. The aim of the present study was to validate the association between 15 single-nucleotide polymorphisms (SNPs) on the TAAR6 and airway responsiveness to inhaled corticosteroids in the asthmatics. METHODS: The %ΔFEV1 induced by 4 weeks' treatment with inhaled fluticasone propionate (1000 µg daily) was measured in 246 asthmatics. The 15 SNPs of TAAR6 were genotyped using a TaqMan assay. An association analysis between %ΔFEV1 and TAAR6 polymorphisms was carried out using a linear regression model controlling for age, sex, smoking status, presence of atopy, and baseline FEV1 as covariates. RESULTS: Among the 15 SNPs and seven haplotypes of TAAR6, rs7772821 (T>G) on the 3'-UTR showed the strongest correlation with inhaled corticosteroid-induced %ΔFEV1 (Pcorr=0.002 in the codominant model, Pcorr=0.03 in the dominant model, Pcorr=0.01 in the recessive model). The %ΔFEV1 of the rs7772821T>G minor homozygotes (60.77%) was higher than that of patients harboring either the rs7772821 T/G or T/T genotypes (21.32 and 31.60%, respectively). CONCLUSION: The TAAR6 rs7772821 polymorphism may be one of the important genetic factors for predicting the response to treatment with inhaled corticosteroids in asthmatics.

Association between ADH1B and ADH1C polymorphisms and the risk of head and neck squamous cell carcinoma.

Alcohol consumption is one of the major risk factors for head and neck squamous cell carcinoma (HNSCC), and the alcohol dehydrogenase (ADH) family proteins are key enzymes in ethanol metabolism. We examined the associations between single nucleotide polymorphisms (SNPs) of ADH1B and ADH1C and the risk of HNSCC. We analyzed six SNPS of ADH1B, namely -992C > G, -957C > A, +3170A>G, +3377G>T, +3491G>A, and +13543A>G, and five SNPs of ADH1C, namely -1064C>T, -325G>C, +5702A>G, +7462T>C, and +13044A>G, in 260 Korean HNSCC patients and 330 controls, using single base extension and the TaqMan assay. The odds ratios (ORs) and 95 % confidence intervals (95 % CIs) of the CG and GG genotypes of ADH1B -992C>G, the AA genotype of -957C>A, the GG genotype of +3170A>G, the GA genotype of +3491G>A, and +13543A>G were 0.51 (0.32-0.82), 0.63 (0.42-0.94), 1.84 (1.13-2.99), 1.77 (1.15-2.73), 2.34 (1.44-3.79), and 2.21 (1.23-3.95), respectively. The ORs of ADH1C +13044A>G were 1.94 (1.01-3.71) and 1.97 (1.05-3.71) in the dominant and co-dominant models, respectively. The ORs of the GC genotype of ADH1C -325G>C and the AG genotype of +5702A>G were 2.52 (1.51-4.21) and 2.43 (1.36-4.32), respectively. ADH1B +3170A>G and ADH1C +13044A>G were in strong linkage disequilibrium with the other SNPs of ADH1B and ADH1C, respectively. There were gene-environment interactions between ADH1B +3170A>G and ADH1C +13044A>G and alcohol consumption and smoking. ADH1B +3170A>G and ADH1C +13044A>G SNPs are associated with an increased risk of HNSCC, and they could be used as biomarkers for the high-risk group of HNSCC in Koreans.

Association of VARS2-SFTA2 polymorphisms with the risk of chronic hepatitis B in a Korean population.

BACKGROUND & AIMS: Hepatitis B virus (HBV) infection is the most serious risk factor for chronic hepatitis B (CHB), cirrhosis, and hepatocellular carcinoma. Recently, several genome-wide association studies (GWASs) identified important variants associated with the risk of CHB in Asian populations. Specifically, our previous GWAS identified the VARS2-SFTA2 gene region as one of the genetic risk loci for CHB. METHODS: To further characterize this association and to isolate possible causal variants within it, we performed an additional association study by genotyping more SNPs in the vicinity of the VARS2 and SFTA2 genes. In all, 14 SNPs of VARS2-SFTA2 were analysed among a total of 3902 subjects (1046 cases and 2856 controls). RESULTS: Logistic regression analysis revealed that six SNPs, including the previously reported rs2532932, were significantly associated with the risk of CHB (P = 1.7 × 10(-10) ~0.002). Further linkage disequilibrium and conditional analysis identified two variants (rs9394021 and rs2517459) as new markers of genetic risk factors for CHB rather than the reported SNP from our previous study (rs2532932). To evaluate the cumulative risk for CHB based on all known genetic factors, genetic risk score (GRS) were calculated. As anticipated, the distribution of the number of risk alleles in cases vs. controls clearly differed according to the GRS. Similarly, the odds ratios (ORs) were increased (OR = 0.32-3.97). CONCLUSION: Our findings show that common variants in the VARS2-SFTA2 gene region are significantly associated with CHB in a Korean population, which may be useful in further understanding genetic susceptibility to CHB.

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.

Functional polymorphism in aldehyde dehydrogenase-2 gene associated with risk of tuberculosis.

BACKGROUND: The well-known genetic polymorphisms in ADH1B(His47Arg) and ALDH2(Glu487Lys) have dramatic effects on the rate of metabolizing alcohol and acetaldehyde. We investigated possible involvement of these functional polymorphisms in other common complex-trait diseases. METHODS: The genetic effects of these two polymorphisms on hepatitis, asthma, type-2 diabetes mellitus (T2DM), and tuberculosis (TB) were examined in a Korean population. RESULTS: We demonstrated that the well-known functional polymorphism of a primary alcohol-metabolizing enzyme (ALDH2 Glu487Lys) has a strong genetic association with the risk of TB. The frequency of the minor allele (ALDH2*487Lys) was found to be much lower in TB patients (freq. = 0.099/n = 477) than among controls (freq. = 0.162/n = 796) (P = 0.00001, OR (95% confidential interval) = 0.57 (0.45-0.74)). Our data may indicate that TB was once an endemic disease, which exerted selection pressure for higher frequencies of ALDH2*487Lys in Asian populations. In addition, the calculated attributable fraction (AF) indicates that 39.5% of TB patients can attribute their disease to the detrimental effects of ALDH2Glu487Glu. CONCLUSION: Our results suggest that this polymorphism is one of the genetic components of TB, at least in the Korean population.

Association study of DKK2 polymorphisms with alcohol dependence and alcohol-related harm.

BACKGROUND: Alcohol dependence (AD) is a common disorder with both environmental and genetic factors. Previous studies have shown that the genomic region from chromosome 4q22-q32 is closely associated with AD. Furthermore, a study with Irish subjects revealed that the polymorphisms of Dickkopf WNT signaling pathway inhibitor (DKK2), located at 4q25, showed a significant association with AD. METHODS: We conducted a replication study of the association between DKK2 polymorphisms and AD with 459 alcoholics and 444 normal controls, all of Korean descendent. To rank the AD of the subjects, Alcohol Use Disorders Identification Test (AUDIT) was utilized. Using the TaqMan assay, 21 single-nucleotide polymorphisms (SNPs) of DKK2 were genotyped. RESULTS: Our analysis showed that rs17037102 (Q146R) was significantly associated with overall AUDIT score (p = 0.003, p(corr)  = 0.05 in dominant model). Further analysis showed that the SNP was significantly associated with alcohol-related harm (p = 0.001, p(corr)  = 0.02 in co-dominant model). Several other SNPs, including the 3 SNPs which were associated with AD in European population, showed marginal associations that were erased when corrections for multiple testing was applied. Furthermore, rs17037102 was in linkage disequilibrium with the nonexonic DKK2 SNPs which showed associations with AD in the previous study with Irish population, which suggests that rs17037102 may be the causal SNP. CONCLUSIONS: We found 1 DKK2 SNP to be significantly associated with alcohol-related harm in alcoholic subjects. The SNP might be the causal SNP which led its linked SNPs to show associations in previous studies.

Association between HTR7 genetic polymorphisms and alcohol dependence, using the alcohol use disorders identification test (AUDIT).

BACKGROUND: A recent genome-wide association study has identified 5-hydroxytrytamine (serotonin) receptor 7, adenylate cyclase-coupled (HTR7) as a risk gene for alcohol dependence. In addition, the serotonergic system has been considered as a modulator that plays an important role in alcohol use disorders. Functional, pharmacological, and genetic studies of serotonin neurotransmission have revealed that serotonin receptors are potential targets for the treatment of alcohol use disorders. The aim of this study is to investigate whether associations between HTR7 genetic polymorphisms and alcohol dependence could be replicated. METHODS: This study genotyped a total of 22 common single nucleotide polymorphisms (SNPs) in 459 alcoholic patients and 444 nonalcoholic controls. RESULTS: Logistic regression analysis of the case-control study, controlling for age and sex as covariates, showed nominal associations of 7 SNPs (p = 0.02 to 0.04; odds ratio = 0.60 to 1.35). In further linear regression analysis based on the Alcohol Use Disorders Identification Test score for alcohol dependence, 8 SNPs and 3 haplotypes showed relatively significant associations with alcohol dependence (minimum p = 0.001; p(corr) = 0.02). CONCLUSIONS: Although further replications and functional evaluations are needed, our findings suggest that genetic variations of HTR7 may contribute to the predisposition for alcohol dependence.

Association analysis of FABP1 gene polymorphisms with aspirin-exacerbated respiratory disease in asthma.

Previously, we used a proteomic approach to demonstrate that the protein level of fatty acid-binding protein 1 (FABP1) is increased in nasal polyps in patients with aspirin-exacerbated respiratory disease (AERD). To reveal the genetic effect of FABP1 variants, we evaluated the association of FABP1 polymorphisms with the risk of AERD in 207 asthmatics with AERD and 1019 aspirin-tolerant asthmatics (ATA). Seven polymorphisms of FABP1 were selected from the National Center for Biotechnology Information (build 36) using minor allele frequency and linkage disequilibrium criteria. The genotype and haplotype distributions were not significantly different between the AERD and ATA groups in all of the genetic models. The percent decline of forced expiratory volume in 1 second (FEV1) after the oral aspirin challenge (OAC) test did not differ according to single-nucleotide polymorphism (SNP) genotypes. In haplotype analysis, asthmatic patients who were BL2ht2 homozygotes showed a greater decline in FEV1 after the OAC test than subjects who possessed 1 or no copy of BL2ht2 (P = 0.035). However, these observations were not significant after correction for multiple comparisons (corrected P value = 1.00). Neither genotype nor haplotype was associated with the presence of nasal polyposis in the study subjects. Although we did not find a significant association between the FABP1 polymorphisms and AERD, our data suggest that the 7 SNPs are not associated with the increased expression of FABP1 in asthmatic patients with AERD. Further studies of epigenetic factors that may contribute to the increased expression of FABP1 in AERD should be performed.

ADAM33 gene polymorphisms are associated with the risk of idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is characterized by progressive dyspnea and worsening lung function due to remodeling of the lung, including epithelial mesenchymal transition. ADAM33 is a disintegrin and metalloprotease domain-containing protein, which may be related to lung fibrosis by exerting angiogenesis and remodeling of the lung. Thus, we evaluated the association of single-nucleotide polymorphisms (SNPs) of ADAM33 with the risk of IPF. METHODS: A total of 237 patients with IPF and 183 healthy subjects participated in the present study. Nine polymorphisms were selected. Genotyping was performed by single-base extension. Polymorphisms and haplotypes were analyzed for associations with the risk of IPF using multiple logistic regression models controlling for age, gender, and smoking status as covariates. RESULTS: All SNPs were in Hardy-Weinberg equilibrium. The minor allele frequency (MAF) of rs628977G>A in intron 21 was significantly lower in subjects with surgical IPF than in normal controls in the recessive model [33.2 vs. 38.0 %, p = 0.02, OR = 0.40 (0.19-0.84)]. When the subjects with clinical IPF were included, the difference in MAF persisted with a p value of 0.03 [OR = 0.50 (0.27-0.94)]. CONCLUSIONS: ADAM33 rs628977G>A was marginally associated with a decreased risk of IPF in a recessive model.

Association analysis of melanocortin 3 receptor polymorphisms with the risk of pulmonary tuberculosis.

PURPOSE: Melanocortin 3 Receptor (MC3R) is one of the families of seven-transmembrane G-protein-coupled receptors, and a recent study showed that MCR3 promoter polymorphism was significantly associated with the susceptibility of tuberculosis (TB) in South African population. METHODS: We analyzed six MC3R polymorphisms to examine the genetic effects on the risk of pulmonary TB in Korean subjects by using TaqMan assays and case-control analyses. RESULTS: Using statistical analyses, one common promoter polymorphism (MC3R rs11575886 T > C) was found to be associated with an increased risk of pulmonary TB. The frequency of the C-bearing genotype of rs11575886 was higher in pulmonary TB patients than in normal controls (p = 0.03, OR = 1.46) although the significance was not retained after correction. In silico analysis for the difference of transcription binding factor (TF), motif between C and T allele demonstrated that the TF motif and its threshold scores of C allele were lower than those of T allele. CONCLUSIONS: The C allele of rs11575886 could be a risk allele for the pulmonary TB by affecting the binding of TF. Our findings suggest that polymorphisms in MC3R might be one of genetic factors for the risk of pulmonary TB development in Korean subjects.

Association analysis of tapasin polymorphisms with aspirin-exacerbated respiratory disease in asthmatics.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is characterized by the development of airway obstruction in asthmatic individuals following the ingestion of aspirin or other nonsteroidal anti-inflammatory drugs. TAPBP (TAP-binding protein, tapasin) is upregulated by eicosanoids, which act as potent inflammatory molecules in aspirin-related reactions. Thus, functional alterations in the TAPBP gene may contribute toward AERD. OBJECTIVES: We examined the relationship between the single nucleotide polymorphisms on the TAPBP gene and AERD. MATERIALS AND METHODS: A group of asthmatic patients (n=1252) underwent the oral aspirin challenge. Oral aspirin challenge reactions were categorized into two groups as follows: 15% or greater decreases in forced expiratory volume in 1 s or naso-ocular and skin reactions (AERD), or 15% or less decreases in forced expiratory volume in 1 s without naso-ocular and skin reactions (aspirin-tolerant asthma). Five single nucleotide polymorphisms of the TAPBP gene were genotyped. RESULTS: Logistic regression analysis showed that the minor allele frequencies of TAPBP rs2071888 C>G (Thr260Arg) on exon 4 (P>0.05), which was in absolute linkage disequilibrium with rs1059288 T>C on 3'UTR, were significantly higher in the AERD group than in the aspirin-tolerant asthma group, and the P values remained significant after multiple comparisons (Pcorr=0.006, odds ratio: 1.37, 95% confidence interval: 1.11-1.69, additive model; Pcorr=0.009, odds ratio: 1.52, 95% confidence interval: 1.14-2.03, dominant model). Alpha-helical wheel plotting showed that 260Arg had greater hydrophilic helical property than 260Thr. CONCLUSION: TAPBP polymorphisms may play a role in the development of AERD.

Extended genetic effects of ADH cluster genes on the risk of alcohol dependence: from GWAS to replication.

Alcohol dependence (AD) is a multifactorial and polygenic disorder involving complex gene-to-gene and gene-to-environment interactions. Several genome-wide association studies have reported numerous risk factors for AD, but replication results following these studies have been controversial. To identify new candidate genes, the present study used GWAS and replication studies in a Korean cohort with AD. Genome-wide association analysis revealed that two chromosome regions on Chr. 4q22-q23 (ADH gene cluster, including ADH5, ADH4, ADH6, ADH1A, ADH1B, and ADH7) and Chr. 12q24 (ALDH2) showed multiple association signals for the risk of AD. To investigate detailed genetic effects of these ADH genes on AD, a follow-up study of the ADH gene cluster on 4q22-q23 was performed. A total of 90 SNPs, including ADH1B rs1229984 (H47R), were genotyped in an additional 975 Korean subjects. In case-control analysis, ADH1B rs1229984 (H47R) showed the most significant association with the risk of AD (p = 2.63 × 10(-21), OR = 2.35). Moreover, subsequent conditional analyses revealed that all positive associations of other ADH genes in the cluster disappeared, which suggested that ADH1B rs1229984 (H47R) might be the sole functional genetic marker across the ADH gene cluster. Our findings could provide additional information on the ADH gene cluster regarding the risk of AD, as well as a new and important insight into the genetic factors associated with AD.

Genome-wide association study of aspirin-exacerbated respiratory disease in a Korean population.

Aspirin-exacerbated respiratory disease (AERD) is a nonallergic clinical syndrome characterized by a severe decline in forced expiratory volume in one second (FEV1) following the ingestion of non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin. The effects of genetic variants have not fully explained all of the observed individual differences to an aspirin challenge despite previous attempts to identify AERD-related genes. In the present study, we performed genome-wide association study (GWAS) and targeted association study in Korean asthmatics to identify new genetic factors associated with AERD. A total of 685 asthmatic patients without AERD and 117 subjects with AERD were used for the GWAS of the first stage, and 996 asthmatics without AERD and 142 subjects with AERD were used for a follow-up study. A total of 702 SNPs were genotyped using the GoldenGate assay with the VeraCode microbead. GWAS revealed the top-ranked variants in 3' regions of the HLA-DPB1 gene. To investigate the detailed genetic effects of an associated region with the risk of AERD, a follow-up targeted association study with the 702 single nucleotide polymorphisms (SNPs) of 14 genes was performed on 802 Korean subjects. In a case-control analysis, HLA-DPB1 rs1042151 (Met105Val) shows the most significant association with the susceptibility of AERD (p = 5.11 × 10(-7); OR = 2.40). Moreover, rs1042151 also shows a gene dose for the percent decline of FEV1 after an aspirin challenge (p = 2.82 × 10(-7)). Our findings show that the HLA-DPB1 gene polymorphism may be the most susceptible genetic factor for the risk of AERD in Korean asthmatics and confirm the importance of HLA-DPB1 in the genetic etiology of AERD.

Association of genetic polymorphisms in CD40 with susceptibility to SLE in the Korean population.

OBJECTIVE: The aim of this study was to examine the association of CD40 polymorphisms with the risk of SLE in the Korean population. METHODS: A total of 601 Korean SLE patients and 984 healthy controls were enrolled. We selected seven CD40 gene SNPs based on previous results of CD40 gene sequencing in the Korean population. Statistical analysis was carried out by logistic regression, controlling for age and sex as covariates. Odds ratios (ORs) and P-values in co-dominant, dominant and recessive models were also calculated. RESULTS: SNP rs3765456 showed significant association with risk of SLE (OR = 1.34, P = 0.007, Pcorr = 0.03) in the dominant model. SNPs rs1883832 and rs4810485, and haplotype 2 (GTTCTAA) were also associated with the risk of SLE in the dominant model, but statistical significance disappeared after correction for multiple testing. Haplotype 2 had a protective effect on LN (OR = 0.47, P = 0.01, Pcorr = 0.05) in the recessive model while rs73115010, rs6074028 and haplotype 3 (ACGTCGG) resulted in increased risk of arthritis in the recessive model (OR = 2.87, 2.76 and 2.46, P = 0.002, 0.004 and 0.01, Pcorr = 0.009, 0.02 and 0.05, respectively). CONCLUSION: CD40 gene polymorphisms are possible risk factors for SLE development, especially rs3765456 in the dominant model. CD40 polymorphisms are also associated with SLE clinical manifestation, mainly nephritis and arthritis. Further replication with larger numbers, and populations of different ethnicities, are needed to confirm our findings.

Angiotensin-converting enzyme (ACE) gene polymorphisms are associated with idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is characterized by progressive dyspnea and worsening lung function. ACE is increased in the bronchoalveolar lavage fluid from patients with IPF, suggesting the role of ACE in the pathogenesis of IPF. We evaluated the role of single-nucleotide polymorphisms (SNPs) in the development risk of IPF. METHODS: Two-hundred twenty patients with IPF and 456 healthy subjects were included in this study. Eleven polymorphisms were selected among those reported previously. Genotype was performed by single base extension. RESULTS: Although absolute LD (|D'|= 1 and r(2 )= 1) was not present, 11 SNPs showed tight LDs. The logistic analysis of the all of 11 SNPs on the ACE genes between patients with IPF and healthy subjects were found to be related with the risk of IPF in recessive type. However, in patients with IPF diagnosed by surgical lung biopsy, only two SNP of -5538T>C and +21288_insdel SNPs were related with the risk of IPF in co-dominant type, and there were no SNPs related with the risk of IPF in dominant type. In patients with IPF diagnosed by clinical criteria or surgical lung biopsy, four SNPs on promoter (-5538T>C, -5508A>C, -3927T>C, -115T>C), one on intron (+15276A>G), one on exon (+21181G>A), and one in three prime region (+21288_insdel) were related with the risk of IPF. CONCLUSIONS: This study showed a newly discovered SNP of ACE associated with the risk of development of IPF. ACE -5538T>C and -5508A>C significantly associated with risk of IPF in Korea.

Putative association between UBE2E2 polymorphisms and the risk of gestational diabetes mellitus.

We hypothesized that ubiquitin-conjugating enzyme E2 E2 (UBE2E2) may be associated with gestational diabetes mellitus (GDM) and conducted association analyses. A total of 2071 subjects were recruited for the study, with 1104 cases and 967 controls. Two UBE2E2 single-nucleotide polymorphisms rs6780569 and rs7612463, and their haplotypes were analyzed for the study. As a result, rs7612463 showed a significant association with GDM in the recessive model. In addition, the regression analyses for the phenotypes showed that rs6780569. rs7612463 and ht2 showed significant associations with fasting plasma glucose (FPG) in recessive models, while ht1 showed an association in the dominant model. Our results show that the genetic variants of UBE2E2 are associated with GDM and FPG, which could be an important preliminary result for future studies.

Lack of association between CD226 genetic variants and inflammatory demyelinating diseases in Korean population.

OBJECTIVE: This study was conducted to find the possible association between CD226 polymorphisms and inflammatory demyelinating diseases in Korean population. METHODS: A total of 14 CD226 SNPs were selected based on their linkage disequilibrium, minor allele frequency, and location. Then, the SNPs were genotyped in 178 IDD patients and 237 healthy controls. Subsequently, we conducted logistic analysis to find possible associations RESULTS: Statistical analyses revealed only a marginal signal for a common SNP rs1788229 with inflammatory demyelinating disease (p=0.05), while other SNPs failed to show associations with any diseases. However, the significance of rs1788229 disappeared after a multiple testing correction of the data (p>0.05). Interestingly, rs763361, which showed significant associations with multiple sclerosis in several previous studies, did not show any association at all. CONCLUSIONS: While prior studies have found CD226 polymorphisms to be significantly associated with inflammatory demyelinating diseases, our results indicate the CD226 polymorphisms to be not associated with the diseases in Korean population. However, our results suggest that the causal genes for inflammatory demyelinating diseases may vary depending on the population.