Case-case genome-wide association analysis identifying genetic loci with divergent effects on Crohn's disease and ulcerative colitis.

Crohn's disease (CD) and ulcerative colitis (UC), two major subtypes of inflammatory bowel disease, show substantial differences in their clinical course and treatment response. To identify the genetic factors underlying the distinct characteristics of these two diseases, we performed a genome-wide association study (GWAS) between CD (n = 2359) and UC (n = 2175) in a Korean population, followed by replication in an independent sample of 772 CD and 619 UC cases. Two novel loci were identified with divergent effects on CD and UC: rs9842650 in CD200 and rs885026 in NCOR2. In addition, the seven established susceptibility loci [major histocompatibility complex (MHC), TNFSF15, OTUD3, USP12, IL23R, FCHSD2 and RIPK2] reached genome-wide significance. Of the nine loci, six (MHC, TNFSF15, OTUD3, USP12, IL23R and CD200) were replicated in the case-case GWAS of European populations. The proportion of variance explained in CD-UC status by polygenic risk score analysis was up to 22.6%. The area under the receiver-operating characteristic curve value was 0.74, suggesting acceptable discrimination between CD and UC. This CD-UC GWAS provides new insights into genetic differences between the two diseases with similar symptoms and might be useful in improving their diagnosis and treatment.

Identification of shared loci associated with both Crohn's disease and leprosy in East Asians.

Genome-wide association studies (GWAS) of Crohn's disease (CD) in European and leprosy in Chinese population have shown that CD and leprosy share genetic risk loci. As these shared loci were identified through cross-comparisons across different ethnic populations, we hypothesized that meta-analysis of GWAS on CD and leprosy in East Asian populations would increase power to identify additional shared loci. We performed a cross-disease meta-analysis of GWAS data from CD (1621 cases and 4419 controls) and leprosy (2901 cases 3801 controls) followed by replication in additional datasets comprising 738 CD cases and 488 controls and 842 leprosy cases and 925 controls. We identified one novel locus at 7p22.3, rs77992257 in intron 2 of ADAP1, shared between CD and leprosy with genome-wide significance (P = 3.80 × 10-11) and confirmed 10 previously established loci in both diseases: IL23R, IL18RAP, IL12B, RIPK2, TNFSF15, ZNF365-EGR2, CCDC88B, LACC1, IL27, NOD2. Phenotype variance explained by the polygenic risk scores derived from Chinese leprosy data explained up to 5.28% of variance of Korean CD, supporting similar genetic structures between the two diseases. Although CD and leprosy shared a substantial number of genetic susceptibility loci in East Asians, the majority of shared susceptibility loci showed allelic effects in the opposite direction. Investigation of the genetic correlation using cross-trait linkage disequilibrium score regression also showed a negative genetic correlation between CD and leprosy (rg [SE] = -0.40[0.13], P = 2.6 × 10-3). These observations implicate the possibility that CD might be caused by hyper-sensitive reactions toward pathogenic stimuli.

Characterization of Th17 tissue-resident memory cells in non-inflamed intestinal tissue of Crohn's disease patients.

Crohn's disease (CD) is a chronic inflammatory disorder affecting the bowel wall. Tissue-resident memory T (Trm) cells are implicated in CD, yet their characteristics remain unclear. We aimed to investigate the transcriptional profiles and functional characteristics of Trm cells in the small bowel of CD and their interactions with immune cells. Seven patients with CD and four with ulcerative colitis as controls were included. Single-cell RNA sequencing and paired T cell receptor sequencing assessed T cell subsets and transcriptional signatures in lamina propria (LP) and submucosa/muscularis propria-enriched fractions (SM/MP) from small bowel tissue samples. We detected 58,123 T cells grouped into 16 populations, including the CD4+ Trm cells with a Th17 signature and CD8+ Trm clusters. In CD, CD4+ Trm cells with a Th17 signature, termed Th17 Trm, showed significantly increased proportions within both the LP and SM/MP areas. The Th17 Trm cluster demonstrated heightened expression of tissue-residency marker genes (ITGAE, ITGA1, and CXCR6) along with elevated levels of IL17A, IL22, CCR6, and CCL20. The clonal expansion of Th17 Trm cells in CD was accompanied by enhanced transmural dynamic potential, as indicated by significantly higher migration scores. CD-prominent Th17 Trm cells displayed an increased interferon gamma (IFNγ)-related signature possibly linked with STAT1 activation, inducing chemokines (i.e., CXCL10, CXCL8, and CXCL9) in myeloid cells. Our findings underscored the elevated Th17 Trm cells throughout the small bowel in CD, contributing to disease pathogenesis through IFNγ induction and subsequent chemokine production in myeloid cells.

Transethnic analysis of the human leukocyte antigen region for ulcerative colitis reveals not only shared but also ethnicity-specific disease associations.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gut. Genetic association studies have identified the highly variable human leukocyte antigen (HLA) region as the strongest susceptibility locus for IBD and specifically DRB1*01:03 as a determining factor for ulcerative colitis (UC). However, for most of the association signal such as delineation could not be made because of tight structures of linkage disequilibrium within the HLA. The aim of this study was therefore to further characterize the HLA signal using a transethnic approach. We performed a comprehensive fine mapping of single HLA alleles in UC in a cohort of 9272 individuals with African American, East Asian, Puerto Rican, Indian and Iranian descent and 40 691 previously analyzed Caucasians, additionally analyzing whole HLA haplotypes. We computationally characterized the binding of associated HLA alleles to human self-peptides and analyzed the physicochemical properties of the HLA proteins and predicted self-peptidomes. Highlighting alleles of the HLA-DRB1*15 group and their correlated HLA-DQ-DR haplotypes, we not only identified consistent associations (regarding effects directions/magnitudes) across different ethnicities but also identified population-specific signals (regarding differences in allele frequencies). We observed that DRB1*01:03 is mostly present in individuals of Western European descent and hardly present in non-Caucasian individuals. We found peptides predicted to bind to risk HLA alleles to be rich in positively charged amino acids. We conclude that the HLA plays an important role for UC susceptibility across different ethnicities. This research further implicates specific features of peptides that are predicted to bind risk and protective HLA proteins.

CFH and VIPR2 as susceptibility loci in choroidal thickness and pachychoroid disease central serous chorioretinopathy.

Central serous chorioretinopathy (CSC) is a common disease affecting younger people and may lead to vision loss. CSC shares phenotypic overlap with age-related macular degeneration (AMD). As recent studies have revealed a characteristic increase of choroidal thickness in CSC, we conducted a genome-wide association study on choroidal thickness in 3,418 individuals followed by TaqMan assays in 2,692 subjects, and we identified two susceptibility loci: CFH rs800292, an established AMD susceptibility polymorphism, and VIPR2 rs3793217 (P = 2.05 × 10-10 and 6.75 × 10-8, respectively). Case-control studies using patients with CSC confirmed associations between both polymorphisms and CSC (P = 5.27 × 10-5 and 5.14 × 10-5, respectively). The CFH rs800292 G allele is reportedly a risk allele for AMD, whereas the A allele conferred risk for thicker choroid and CSC development. This study not only shows that susceptibility genes for CSC could be discovered using choroidal thickness as a defining variable but also, deepens the understanding of differences between CSC and AMD pathophysiology.

Amino acid position 37 of HLA-DRß1 affects susceptibility to Crohn's disease in Asians.

Crohn's disease (CD) and ulcerative colitis (UC) are the major types of chronic inflammatory bowel disease (IBD) characterized by recurring episodes of inflammation of the gastrointestinal tract. Although it is well established that human leukocyte antigen (HLA) is a major risk factor for IBD, it is yet to be determined which HLA alleles or amino acids drive the risks of CD and UC in Asians. To define the roles of HLA for IBD in Asians, we fine-mapped HLA in 12 568 individuals from Korea and Japan (3294 patients with CD, 1522 patients with UC and 7752 controls). We identified that the amino acid position 37 of HLA-DRß1 plays a key role in the susceptibility to CD (presence of serine being protective, P = 3.6 × 10-67, OR = 0.48 [0.45-0.52]). For UC, we confirmed the known association of the haplotype spanning HLA-C*12:02, HLA-B*52:01 and HLA-DRB1*1502 (P = 1.2 × 10-28, OR = 4.01 [3.14-5.12]).

Association of FUT2 and ABO with Crohn's disease in Koreans.

BACKGROUND AND AIM: Fucosyltransferase 2 (FUT2) at 19q13 is a well-established susceptibility locus for Crohn's disease (CD) in Caucasians. FUT2 encodes α-1,2-fucosyltransferase that regulates the secretion of the α-1-2-N-acetylgalactosaminyltransferase and α-1-3-galactosyltransferase (ABO) antigens in both the gastrointestinal mucosa and secretory glands. Given that CD is thought to arise from dysregulated mucosal immune responses to the gut flora and both the ABO blood group and the FUT2 secretor status affect the composition of the gut microbiota, the goal of this study was to evaluate the associations of variants of FUT2 and ABO with CD in Koreans. METHODS: Three single-nucleotide polymorphisms from the FUT2 and ABO genes were genotyped in 1735 patients with CD and 8074 healthy controls. RESULTS: The FUT2 non-secretor allele showed genome-wide significant association with CD in Koreans (rs1047781, odds ratio [OR] = 1.30, Pcombined  = 3.52 × 10-12 ). The ABO locus showed genome-wide significant association with CD in Asians (Pmeta  = 2.35 × 10-8 ). A moderate association was observed with the A and B groups (OR = 1.40, P = 2.26 × 10-6 ; and OR = 1.32, P = 1.92 × 10-4 , respectively) compared with the O group. Following stratification on the basis of FUT2 genotype, carriers of the secretor O blood group were significantly protective against CD than were those of the secretor non-O blood group (OR = 0.63, 95% confidence interval = 0.54-0.73, P = 2.86 × 10-9 ). CONCLUSIONS: These are the first results indicating that the O blood group and FUT2 secretor status are protective factors against CD in Asians.

Genome-wide association study of Parkinson's disease in East Asians.

Genome-wide association studies (GWAS) on Parkinson's disease (PD) have mostly been done in Europeans and Japanese. No study has been done in Han Chinese, which make up nearly a fifth of the world population. We conducted the first Han Chinese GWAS analysing a total of 22,729 subjects (5,125 PD cases and 17,604 controls) from Singapore, Hong Kong, Malaysia, Korea, mainland China and Taiwan. We performed imputation, merging and logistic regression analyses of 2,402,394 SNPs passing quality control filters in 779 PD cases, 13,227 controls, adjusted for the first three principal components. 90 SNPs with association P < 10-4 were validated in 9 additional sample collections and the results were combined using fixed-effects inverse-variance meta-analysis. We observed strong associations reaching genome-wide significance at SNCA, LRRK2 and MCCC1, confirming their important roles in both European and Asian PD. We also identified significant (P < 0.05) associations at 5 loci (DLG2, SIPA1L2, STK39, VPS13C and RIT2), and observed the same direction of associations at 9 other loci including BST1 and PARK16. Allelic heterogeneity was observed at LRRK2 while European risk SNPs at 6 other loci including MAPT and GBA-SYT11 were non-polymorphic or very rare in our cohort. Overall, we replicate associations at SNCA, LRRK2, MCCC1 and 14 other European PD loci but did not identify Asian-specific loci with large effects (OR > 1.45) on PD risk. Our results also demonstrate some differences in the genetic contribution to PD between Europeans and Asians. Further pan-ethnic meta-analysis with European GWAS cohorts may unravel new PD loci.

Effects of smoking on the association of human leukocyte antigen with ulcerative colitis.

BACKGROUND AND AIM: Tobacco smoking is a risk factor for gastrointestinal disorders, causing mucosal damage and impairing immune responses. However, smoking has been found to be protective against ulcerative colitis (UC). Human leukocyte antigen (HLA) is a major susceptibility locus for UC, and HLA-DRB1*15:02 has the strongest effect in Asians. This study investigated the effects of smoking on the association between HLA and UC. METHODS: The study enrolled 882 patients with UC, including 526 never, 151 current, and 205 former smokers, and 3091 healthy controls, including 2124 never, 502 current, and 465 former smokers. Smoking-stratified analyses of HLA data were performed using a case-control approach. RESULTS: In a case-control approach, HLA-DRB1*15:02 was associated with UC in never smokers (ORnever smokers  = 3.20, Pnever smokers  = 7.88 × 10-23 ) but not in current or former smokers (Pcurrent smokers  = 0.72 and Pformer smokers  = 0.33, respectively). In current smokers, HLA-DQB1*06 was associated with UC (ORcurrent smokers  = 2.59, Pcurrent smokers  = 6.39 × 10-12 ). No variants reached genome-wide significance in former smokers. CONCLUSIONS: An association between UC and HLA-DRB1*15:02 was limited to never smokers. Our findings highlight that tobacco smoking modifies the effects of HLA on the risk of UC.

Association of TRAP1 with infliximab-induced mucosal healing in Crohn's disease.

BACKGROUND AND AIM: Anti-tumor necrosis factor (TNF) agents, such as infliximab (IFX), have been increasingly used to induce and maintain disease remission in patients with Crohn's disease (CD). Despite a considerable non-response rate, little is known about the genetic predictors of response to anti-TNF therapy in CD. Our aim in this study was to investigate the genetic factors associated with response to anti-TNF therapy in patients with CD. METHODS: We performed a two-stage genome-wide association study (GWAS) to identify loci influencing the response to IFX among Korean patients with CD, comprising 42 good responders with mucosal healing and 70 non-responders. The achievement of mucosal healing was assessed by endoscopy and imaging. The functional significance of TRAP1 (TNF receptor associated protein 1) was examined using dextran sodium sulfate-induced colitis model in TRAP1 transgenic mice. RESULTS: The GWAS identified rs2158962, an intronic single nucleotide polymorphism (SNP) of TRAP1, significantly associated with mucosal healing (odds ratio = 4.94; Pcombined  = 1.35 × 10-7 ). In the dextran sodium sulfate-induced acute colitis, TRAP1 transgenic mice showed a better response to IFX than the wild-type mice. CONCLUSIONS: The TRAP1 gene is associated with mucosal healing in CD patients following IFX therapy. Identifying the genetic predictors of mucosal healing to anti-TNF therapy can prevent patients from exposure to ineffective therapies.

FOLD: a method to optimize power in meta-analysis of genetic association studies with overlapping subjects.

MOTIVATION: In genetic association studies, meta-analyses are widely used to increase the statistical power by aggregating information from multiple studies. In meta-analyses, participating studies often share the same individuals due to the shared use of publicly available control data or accidental recruiting of the same subjects. As such overlapping can inflate false positive rate, overlapping subjects are traditionally split in the studies prior to meta-analysis, which requires access to genotype data and is not always possible. Fortunately, recently developed meta-analysis methods can systematically account for overlapping subjects at the summary statistics level. RESULTS: We identify and report a phenomenon that these methods for overlapping subjects can yield low power. For instance, in our simulation involving a meta-analysis of five studies that share 20% of individuals, whereas the traditional splitting method achieved 80% power, none of the new methods exceeded 32% power. We found that this low power resulted from the unaccounted differences between shared and unshared individuals in terms of their contributions towards the final statistic. Here, we propose an optimal summary-statistic-based method termed as FOLD that increases the power of meta-analysis involving studies with overlapping subjects. AVAILABILITY AND IMPLEMENTATION: Our method is available at http://software.buhmhan.com/FOLD. CONTACT: mail: buhm.han@amc.seoul.kr. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Association of CDKN2A/CDKN2B with inflammatory bowel disease in Koreans.

BACKGROUND AND AIM: CDKN2A/CDKN2B locus on 9p21 is reported to be associated with various diseases, including cancer and cardiovascular and inflammatory diseases. Significant downregulation of CDKN2B-AS1 in inflamed colon tissue of inflammatory bowel disease (IBD) cases was reported in Europeans. This study aimed to confirm the suggestive association of CDKN2A/CDKN2B with IBD identified in our recent genome-wide association study (GWAS). METHODS: We examined the association of CDKN2A/CDKN2B locus with IBD in an additional sample of 574 IBD cases and 542 controls, totaling 4068 cases and 8074 controls. In silico study was performed at various levels for functional annotation of the causal variant. Co-localization of the GWAS association signals and the corresponding expression quantitative trait loci in IBD-related tissues was evaluated using eCAVIAR. RESULTS: An expanded GWAS showed genome-wide significant association of rs3731257 at 9p21 with IBD (odds ratio = 1.17, 95% confidence interval = 1.12-1.22, Pcombined  = 5.68 × 10-9 ) and Crohn's disease (odds ratio = 1.22, 95% confidence interval = 1.15-1.28, Pcombined  = 8.85 × 10-9 ) in the Korean population. Co-localization study suggested that both CDKN2B-AS1 and CDKN2A might be functionally associated with the locus in the small intestine. CONCLUSIONS: rs3731257 in CDKN2A/CDKN2B is an IBD-susceptible locus in Koreans, with a suggestive role for small intestine-specific gene regulation. Our findings suggested that alterations of the CDKN2A/CDKN2B locus could affect the pathophysiology of IBD.

An observational study of the optimal placement of a cerebral oximeter probe to avoid the frontal sinus in children.

The frontal sinus is an airspace behind the brow ridge in the skull and can affect the accuracy of the regional cerebral oxygen saturation measurements. We evaluated the optimal location for placement of a cerebral oximeter probe while avoiding the frontal sinus in pediatric patients. This retrospective observational study included 203 pediatric patients aged 3-17 years who had undergone brain computed tomography from November 2010 to December 2015. The patients were divided into five subgroups based on their age. The frontal sinus height was measured from the superior orbital rim. Pneumatization of the frontal sinus was not visible in 78% (3-5 years) and 22% (6-8 years) of the patients. The mean (SD) of the frontal sinus height was 5.9 (3.4), 9.5 (4.1), 14.0 (6.2) 18.6 (8.4), and 21.1 (7.9) mm in the 3-5, 6-8, 9-11, 12-14, and 15-17 year age-groups, respectively. Age was positively correlated with the frontal sinus height (r = 0.61, P < 0.001, 95% confidence interval [CI] 0.513-0.688). A frontal sinus height shorter than 1, 2, and 3 cm were seen in 10 of 11 (91%), 69 of 74 (94%), and 108 of 118 (90%) patients aged 3-5, 6-10, and 11-17 years, respectively. When oximeter probes are applied in pediatric patients, placement based on age can help avoid the frontal sinus.

Identification of Loci at 1q21 and 16q23 That Affect Susceptibility to Inflammatory Bowel Disease in Koreans.

Recent genome-wide association studies have identified more than 200 regions that affect susceptibility to inflammatory bowel disease (IBD). However, identified common variants account for only a fraction of IBD heritability and largely have been identified in populations of European ancestry. We performed a genome-wide association study of susceptibility loci in Korean individuals, comprising a total of 1505 IBD patients and 4041 controls. We identified 2 new susceptibility loci for IBD at genome-wide significance: rs3766920 near PYGO2-SHC1 at 1q21 and rs16953946 in CDYL2 at 16q23. In addition, we confirmed associations, in Koreans, with 28 established IBD loci (P < 2.16 × 10-4). Our findings support the complementary value of genetic studies in different populations.

Genome-wide association study of gastric adenocarcinoma in Asia: a comparison of associations between cardia and non-cardia tumours.

OBJECTIVE: Genome-wide association studies (GWAS) of gastric cancer have reported differences in single-nucleotide polymorphism (SNP) associations for tumour subtypes, particularly when divided by location into the gastric cardia versus the non-cardia. DESIGN: Here we present results for a GWAS using 2350 East Asian gastric cancer cases divided as 1189 gastric cardia and 1027 gastric non-cardia cases and 2708 controls. We also included up to 3042 cardia cases, 4359 non-cardia cases and 7548 controls for replication from two Chinese studies and one Korean study. From the GWAS, we selected 12 top SNPs for each gastric cancer subtype, 4 top SNPs for total gastric cancer and 1 SNP in MUC1 for replication testing. RESULTS: We observed genome-wide significant associations for rs10074991 in PRKAA1 at 5p13.1 for cardia (p=7.36×10(-12)) and non-cardia cancers (p=2.42×10(-23)) with per allele OR (95% CI) for the combined endpoint of 0.80 (0.77 to 0.83). At 6p21.1, rs2294693 near UNC5CL was significantly associated with gastric non-cardia cancer risk (p=2.50×10(-8)), with OR (95% CI) of 1.18 (1.12 to 1.26), but there was only a nominal association for cardia cancer (p=1.47×10(-2)). We also confirmed a previously reported association for rs4072037 in MUC1 with p=6.59×10(-8) for total gastric cancer and similar estimates for cardia and non-cardia cancers. Three SNPs in PSCA previously reported to be associated with gastric non-cardia cancer showed no apparent association for cardia cancer. CONCLUSIONS: Our results suggest that associations for SNPs with gastric cancer show some different results by tumour location in the stomach.

Analysis of non-synonymous-coding variants of Parkinson's disease-related pathogenic and susceptibility genes in East Asian populations.

To evaluate the contribution of non-synonymous-coding variants of known familial and genome-wide association studies (GWAS)-linked genes for Parkinson's disease (PD) to PD risk in the East Asian population, we sequenced all the coding exons of 39 PD-related disease genes and evaluated the accumulation of rare non-synonymous-coding variants in 375 early-onset PD cases and 399 controls. We also genotyped 782 non-synonymous-coding variants of these genes in 710 late-onset PD cases and 9046 population controls. Significant enrichment of LRRK2 variants was observed in both early- and late-onset PD (odds ratio = 1.58; 95% confidence interval = 1.29-1.93; P = 8.05 × 10(-6)). Moderate enrichment was also observed in FGF20, MCCC1, GBA and ITGA8. Half of the rare variants anticipated to cause loss of function of these genes were present in healthy controls. Overall, non-synonymous-coding variants of known familial and GWAS-linked genes appear to make a limited contribution to PD risk, suggesting that clinical sequencing of these genes will provide limited information for risk prediction and molecular diagnosis.

Linking a genome-wide association study signal to a LRRK2 coding variant in Parkinson's disease.

BACKGROUND: Genome-wide association studies have identified several loci associated with Parkinson's disease (PD). Whole-exome sequencing detects rare coding variants, but their links with PD genome-wide association study loci are unknown. Our objective was to investigate whether nonsynonymous variants in LRRK2 can explain associations at the PD-associated locus tagged by rs1994090. METHODS: We sequenced all coding exons of LRRK2 in 453 East Asian samples and evaluated linkage disequilibrium between each nonsynonymous variant and rs1994090. We then tested selected variants and haplotypes for association with PD in 13,581 East Asian samples. RESULTS: Of all the nonsynonymous variants, only p.Gly2385Arg was in moderate linkage disequilibrium with rs1994090 and was observed on haplotypes tagged by the rs1994090-C risk allele. Conditional analyses showed that associations at these 2 variants are not independent. CONCLUSIONS: LRRK2 p.Gly2385Arg can explain most if not all of the PD association at rs1994090 in East Asians, but other nonsynonymous variants are independent. © 2015 International Parkinson and Movement Disorder Society.

Influences of XDH genotype by gene-gene interactions with SUCLA2 for thiopurine-induced leukopenia in Korean patients with Crohn's disease.

BACKGROUND: The impact of genetic variation in the thiopurine S-methyltransferase (TPMT) gene on thiopurine-induced leukopenia has been well demonstrated. Although xanthine dehydrogenase (XDH) is the second major contributor to azathioprine breakdown, polymorphisms in XDH have rarely been studied in IBD patients. We aim to access association between XDH variants and thiopurine-induced leukopenia by gene-gene interaction in a Crohn's disease (CD) population. STUDY: A total of 964 CD patients treated with thiopurines were recruited from a tertiary referral center. The association between four XDH variants (p.Gly172Arg, p.Asn1109Thr, p.Arg149Cys, and p.Thr910Lys) and thiopurine-induced leukopenia was analyzed in cases with early leukopenia (n = 66), late leukopenia (n = 264), and in controls without leukopenia (n = 632). Three non-synonymous SNPs, which we previously reported association with thiopurine-induced leukopenia, NUDT15 (p.Arg139Cys), SUCLA2 (p.Ser199Thr), and TPMT *3C were selected for epistasis analysis with the XDH variants. RESULTS: There was no significant association for two variants of XDH and thiopurine-induced leukopenia. In the epistasis analysis, only XDH (p.Asn1109Thr) * SUCLA2 (p.Ser199Thr) showed a statistically significant association with early leukopenia [odds ratio (OR) = 0.16; p = 0.03]. After genotype stratification, a positive association on the background of SUCLA2 wild-type (199Ser) between the XDH (p.Asn1109Thr) and early leukopenia (OR = 4.39; p = 0.01) was detected. CONCLUSION: Genes associated with thiopurine-induced leukopenia can act in a complex interactive manner. Further studies are warranted to explore the mechanisms underlying the effects of the combination of XDH (p.Asn1109Thr) and SUCLA2 (199Ser) on thiopurine-induced leukopenia.

Validation study of candidate single nucleotide polymorphisms associated with left ventricular hypertrophy in the Korean population.

BACKGROUND: Left ventricular hypertrophy (LVH) is a valid predictor for cardiovascular mortality and morbidity regardless of age, gender, and race. The HyperGEN study conducted a genome-wide association study and identified twelve single nucleotide polymorphisms (SNPs) associated with LVH. The aim of this study was to validate these candidate SNPs in the Korean population. METHODS: Among 1637 individuals from the Korean Multi-Rural Communities Cohort Study (MRCohort) of the Korean Genome Epidemiology Study (KoGES), we carried out a linear regression analysis with left ventricular mass index (LVMI) and a logistic regression analysis for LVH status. RESULTS: The rs4129218 on chromosome 12 tended to be associated with LVM/body surface area (adjusted ß = -0.023; p = 0.036) and LVM/height(2.7) (adjusted ß = -0.027; p = 0.016), and was marginally protective against LVH after adjustment for age, sex, body mass index, serum creatinine, systolic blood pressure, heart rate and antihypertensive medication (adjusted odds ratio = 0.766 and 0.731; p = 0.027 and 0.007 according to indexation by BSA and height(2.7), respectively). CONCLUSIONS: In the Korean population, the minor allele of rs4129218 had borderline association with lower LVM. This study suggests that rs4129218 on chromosome 12 showed consistent tendency of possibly related loci for LVH independent of ethnic background.

Association of TNFSF15 polymorphisms in Korean children with Crohn's disease.

BACKGROUND: Genome-wide association studies have identified tumor necrosis factor superfamily member 15 (TNFSF15) as a Crohn's disease (CD)-related gene. The aim of this study was to evaluate the association between five TNFSF15 polymorphisms and CD in Korean children and analyze their genotypes in relation to phenotype. METHODS: Five single-nucleotide polymorphisms of TNFSF15 (rs3810936, rs6478108, rs6478109, rs7848647, rs7865494) were genotyped in 108 CD patients and in 599 healthy controls. Risk allele, genotype, and haplotype were analyzed in CD patients and controls, and genotype-phenotype relationships were studied. RESULTS: There were significant associations of rs3810936, rs6478108, rs6478109, rs7848647 with CD in Korean pediatric patients (P = 6.5×10(-8), P = 1.3×10(-8), P = 3.7×10(-8), P = 2.9×10(-8), respectively). The adjusted OR (aOR) for the homozygous risk allele genotype was significantly higher than that for the homozygous genotype for the opposite allele: rs3810936, aOR, 5.36 (95%CI: 2.61-10.98, P = 4.6×10(-6)); rs6478108, aOR, 6.62 (95%CI: 3.03-14.46, P = 2.2×10(-6)); rs6478109, aOR, 6.24 (95%CI: 2.85-13.66, P = 4.6×10(-6)); rs7848647, aOR, 6.32 (95%CI: 2.89-13.81, P = 3.8×10(-6)). The risk allele of rs3810936 was associated with later symptom onset, later diagnosis, and the presence of perianal lesion (P = 0.013, P = 0.016 and P = 0.029). CONCLUSION: There was a significant association of TNFSF15 with pediatric CD in Korean patients.