Safety of COVID-19 Vaccines among Patients with Type 2 Diabetes Mellitus: Real-World Data Analysis.

BACKGROUND: Little is known about the adverse events (AEs) associated with coronavirus disease 2019 (COVID-19) vaccination in patients with type 2 diabetes mellitus (T2DM). METHODS: This study used vaccine AE reporting system data to investigate severe AEs among vaccinated patients with T2DM. A natural language processing algorithm was applied to identify people with and without diabetes. After 1:3 matching, we collected data for 6,829 patients with T2DM and 20,487 healthy controls. Multiple logistic regression analysis was used to calculate the odds ratio for severe AEs. RESULTS: After COVID-19 vaccination, patients with T2DM were more likely to experience eight severe AEs than controls: cerebral venous sinus thrombosis, encephalitis myelitis encephalomyelitis, Bell's palsy, lymphadenopathy, ischemic stroke, deep vein thrombosis (DVT), thrombocytopenia (TP), and pulmonary embolism (PE). Moreover, patients with T2DM vaccinated with BNT162b2 and mRNA-1273 were more vulnerable to DVT and TP than those vaccinated with JNJ-78436735. Among patients with T2DM administered mRNA vaccines, mRNA-1273 was safer than BNT162b2 in terms of the risk of DVT and PE. CONCLUSION: Careful monitoring of severe AEs in patients with T2DM may be necessary, especially for those related to thrombotic events and neurological dysfunctions after COVID-19 vaccination.

Relationship between drug targets and drug-signature networks: a network-based genome-wide landscape.

Drugs produce pharmaceutical and adverse effects that arise from the complex relationship between drug targets and signatures; by considering such relationships, we can begin to understand the cellular mechanisms of drugs. In this study, we selected 463 genes from the DSigDB database corresponding to targets and signatures for 382 FDA-approved drugs with both protein binding information for a drug-target score (KDTN, i.e., the degree to which the protein encoded by the gene binds to a number of drugs) and microarray signature information for a drug-sensitive score (KDSN, i.e., the degree to which gene expression is stimulated by the drug). Accordingly, we constructed two drug-gene bipartite network models, a drug-target network and drug-signature network, which were merged into a multidimensional model. Analysis revealed that the KDTN and KDSN were in mutually exclusive and reciprocal relationships in terms of their biological network structure and gene function. A symmetric balance between the KDTN and KDSN of genes facilitates the possibility of therapeutic drug effects in whole genome. These results provide new insights into the relationship between drugs and genes, specifically drug targets and drug signatures.

Corrigendum: Computational modeling for antiarrhythmic drugs for atrial fibrillation according to genotype.

[This corrects the article DOI: 10.3389/fphys.2021.650449.].

Corrigendum: Association of ZFHX3 genetic polymorphisms and extrapulmonary vein triggers in patients with atrial fibrillation who underwent catheter ablation.

[This corrects the article DOI: 10.3389/fphys.2021.807545.].

Diagnostic Performance of Antigen Rapid Diagnostic Tests, Chest Computed Tomography, and Lung Point-of-Care-Ultrasonography for SARS-CoV-2 Compared with RT-PCR Testing: A Systematic Review and Network Meta-Analysis.

(1) Background: The comparative performance of various diagnostic methods for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection remains unclear. This study aimed to investigate the comparison of the 3 index test performances of rapid antigen diagnostic tests (RDTs), chest computed tomography (CT), and lung point-of-care-ultrasonography (US) with reverse transcription-polymerase chain reaction (RT-PCR), the reference standard, to provide more evidence-based data on the appropriate use of these index tests. (2) Methods: We retrieved data from electronic literature searches of PubMed, Cochrane Library, and EMBASE from 1 January 2020, to 1 April 2021. Diagnostic performance was examined using bivariate random-effects diagnostic test accuracy (DTA) and Bayesian network meta-analysis (NMA) models. (3) Results: Of the 3992 studies identified in our search, 118 including 69,445 participants met our selection criteria. Among these, 69 RDT, 38 CT, and 15 US studies in the pairwise meta-analysis were included for DTA with NMA. CT and US had high sensitivity of 0.852 (95% credible interval (CrI), 0.791-0.914) and 0.879 (95% CrI, 0.784-0.973), respectively. RDT had high specificity, 0.978 (95% CrI, 0.960-0.996). In accuracy assessment, RDT and CT had a relatively higher than US. However, there was no significant difference in accuracy between the 3 index tests. (4) Conclusions: This meta-analysis suggests that, compared with the reference standard RT-PCR, the 3 index tests (RDTs, chest CT, and lung US) had similar and complementary performances for diagnosis of SARS-CoV-2 infection. To manage and control COVID-19 effectively, future large-scale prospective studies could be used to obtain an optimal timely diagnostic process that identifies the condition of the patient accurately.

Adverse Events and Safety Profile of the COVID-19 Vaccines in Adolescents: Safety Monitoring for Adverse Events Using Real-World Data.

A COVID-19 vaccine BNT162b2 (Pfizer-BioNTech) has recently been authorized for adolescents in the US. However, the impact of adverse events on adolescents after vaccination has not been fully investigated. To assess the safety of the COVID-19 vaccine in adolescents, the incidence of adverse events (AEs) in adolescents and adults was compared after vaccination. We included 6304 adolescents (68.14 per 100,000 people) who reported adverse events using vaccine adverse event reporting system (VAERS) data from 10 May 2021 to 30 September 2021. The mean age was 13.6 ± 1.1 years and women (52.7%) outnumbered men. We analyzed severe and common adverse events in response to the COVID-19 vaccine among 6304 adolescents (68.14 per 100,000 people; 52% female; mean age, 13.6 ± 1.1 years). The risk of myocarditis or pericarditis among adolescents was significantly higher in men than in women (OR = 6.61, 95% CI = 4.43 to 9.88; p < 0.001), with a higher frequency after the second dose of the vaccine (OR = 8.52, 95% CI = 5.79 to 12.54; p < 0.001). In addition, severe adverse events such as multisystem inflammatory syndromes, where the incidence rate per 100,000 people was 0.11 (n = 10), and the relative risk was 244.3 (95% CI = 31.27 to 1908.38; p < 0.001), were significantly higher in adolescents than in adults. The risk of the inflammatory response to the COVID-19 vaccine, including myocarditis, pericarditis, or multisystem inflammatory syndromes, was significantly higher in men than in women, with a higher frequency in adolescents than in adults. The inflammation-related AEs may require close monitoring and management in adolescents.

Effects of meteorological factors and air pollutants on the incidence of COVID-19 in South Korea.

Air pollution and meteorological factors can exacerbate susceptibility to respiratory viral infections. To establish appropriate prevention and intervention strategies, it is important to determine whether these factors affect the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Therefore, this study examined the effects of sunshine, temperature, wind, and air pollutants including sulfur dioxide (SO2), carbon monoxide (CO), ozone (O3), nitrogen dioxide (NO2), particulate matter ≤2.5 µm (PM2.5), and particulate matter ≤10 µm (PM10) on the age-standardized incidence ratio of coronavirus disease (COVID-19) in South Korea between January 2020 and April 2020. Propensity score weighting was used to randomly select observations into groups according to whether the case was cluster-related, to reduce selection bias. Multivariable logistic regression analyses were used to identify factors associated with COVID-19 incidence. Age 60 years or over (odds ratio [OR], 1.29; 95% CI, 1.24-1.35), exposure to ambient air pollutants, especially SO2 (OR, 5.19; 95% CI, 1.13-23.9) and CO (OR, 1.17; 95% CI, 1.07-1.27), and non-cluster infection (OR, 1.28; 95% CI, 1.24-1.32) were associated with SARS-CoV-2 infection. To manage and control COVID-19 effectively, further studies are warranted to confirm these findings and to develop appropriate guidelines to minimize SARS-CoV-2 transmission.

The Safety of mRNA-1273, BNT162b2 and JNJ-78436735 COVID-19 Vaccines: Safety Monitoring for Adverse Events Using Real-World Data.

Two mRNA COVID-19 vaccines (mRNA-1273, Moderna; and BNT162b2, Pfizer-BioNTech) and one viral vector vaccine (JNJ-78436735, Janssen/Johnson and Johnson) are authorized in the US to hinder COVID-19 infections. We analyzed severe and common adverse events in response to COVID-19 vaccines using real-world, Vaccine Adverse Effect Reporting System (VAERS) data. From 14 December 2020 to 30 September 2021, 481,172 (50.7 ± 17.5 years, males 27.89%, 12.35 per 100,000 people) individuals reported adverse events (AEs). The median time to severe AEs was 2 days after injection. The risk of severe AEs following the one viral vector vaccine (OR = 1.044, 95% CI = 1.005-1.086) was significantly higher than that after the two mRNA vaccines, and the risk among males (OR = 1.374, 95% CI = 1.342-1.406) was higher than among females, except for anaphylaxis. For common AEs, however, the risk to males (OR = 0.621, 95% CI = 0.612-0.63) was lower than to females. In conclusion, we provided medical insight and clinical guidance about vaccine types by characterizing AEs using real-world data. In particular, COVID-19 mRNA vaccines are safer than viral vector vaccines with regard to coagulation disorders, whereas inflammation-related AEs are lower in the viral vaccine. The risk-benefit ratio of vaccines should be carefully considered, and close monitoring and management of severe AEs is needed.

Genome-wide association study-based prediction of atrial fibrillation using artificial intelligence.

OBJECTIVE: We previously reported early-onset atrial fibrillation (AF) associated genetic loci among a Korean population. We explored whether the AF-associated single-nucleotide polymorphisms (SNPs) selected from the Genome-Wide Association Study (GWAS) of an external large cohort has a prediction power for AF in Korean population through a convolutional neural network (CNN). METHODS: This study included 6358 subjects (872 cases, 5486 controls) from the Korean population GWAS data. We extracted the lists of SNPs at each p value threshold of the association statistics from three different previously reported ethnical-specific GWASs. The Korean GWAS data were divided into training (64%), validation (16%) and test (20%) sets, and a stratified K-fold cross-validation was performed and repeated five times after data shuffling. RESULTS: The CNN-GWAS predictive power for AF had an area under the curve (AUC) of 0.78±0.01 based on the Japanese GWAS, AUC of 0.79±0.01 based on the European GWAS, and AUC of 0.82±0.01 based on the multiethnic GWAS, respectively. Gradient-weighted class activation mapping assigned high saliency scores for AF associated SNPs, and the PITX2 obtained the highest saliency score. The CNN-GWAS did not show AF prediction power by SNPs with non-significant p value subset (AUC 0.56±0.01) despite larger numbers of SNPs. The CNN-GWAS had no prediction power for odd-even registration numbers (AUC 0.51±0.01). CONCLUSIONS: AF can be predicted by genetic information alone with moderate accuracy. The CNN-GWAS can be a robust and useful tool for detecting polygenic diseases by capturing the cumulative effects and genetic interactions of moderately associated but statistically significant SNPs. TRIAL REGISTRATION NUMBER: NCT02138695.

Computational Modeling for Antiarrhythmic Drugs for Atrial Fibrillation According to Genotype.

Background: The efficacy of antiarrhythmic drugs (AAD) can vary in patients with atrial fibrillation (AF), and the PITX2 gene affects the responsiveness of AADs. We explored the virtual AAD (V-AAD) responses between wild-type and PITX2 +/--deficient AF conditions by realistic in silico AF modeling. Methods: We tested the V-AADs in AF modeling integrated with patients' 3D-computed tomography and 3D-electroanatomical mapping, acquired in 25 patients (68% male, 59.8 ± 9.8 years old, 32.0% paroxysmal type). The ion currents for the PITX2 +/- deficiency and each AAD (amiodarone, sotalol, dronedarone, flecainide, and propafenone) were defined based on previous publications. Results: We compared the wild-type and PITX2 +/- deficiency in terms of the action potential duration (APD90), conduction velocity (CV), maximal slope of restitution (Smax), and wave-dynamic parameters, such as the dominant frequency (DF), phase singularities (PS), and AF termination rates according to the V-AADs. The PITX2 +/--deficient model exhibited a shorter APD90 (p < 0.001), a lower Smax (p < 0.001), mean DF (p = 0.012), PS number (p < 0.001), and a longer AF cycle length (AFCL, p = 0.011). Five V-AADs changed the electrophysiology in a dose-dependent manner. AAD-induced AFCL lengthening (p < 0.001) and reductions in the CV (p = 0.033), peak DF (p < 0.001), and PS number (p < 0.001) were more significant in PITX2 +/--deficient than wild-type AF. PITX2 +/--deficient AF was easier to terminate with class IC AADs than the wild-type AF (p = 0.018). Conclusions: The computational modeling-guided AAD test was feasible for evaluating the efficacy of multiple AADs in patients with AF. AF wave-dynamic and electrophysiological characteristics are different among the PITX2-deficient and the wild-type genotype models.

Ethnic similarities in genetic polymorphisms associated with atrial fibrillation: Far East Asian vs European populations.

BACKGROUND: In European ancestry, 111 genetic loci were identified as associated with atrial fibrillation (AF). We explored the reproducibility of those single nucleotide polymorphisms (SNPs) in a genome-wide association study (GWAS) meta-analysis of Far East Asian populations. METHODS: We performed a meta-analysis of the Korean AF network and Japanese AF data sets (9118 cases and 33 467 controls) by an inverse-variance fixed-effects model. We compared the results with 111 previously reported SNPs proven in Europeans after excluding 36 missing loci and a locus with a minor allelic frequency (MAF) < 0.01 in the European population. RESULTS: Among remaining 74 loci, 29 loci were replicated at a P < .05, and 17 of those loci were newly found in the Far East Asian population: 3 loci with a P < 5×10-8 (METTL11B at 1q24, KCNN2 at 5q22 and LRMDA at 10q22), 4 loci at the threshold of the Bonferroni correction of P = 4.5 × 10-4  ~ 5×10-8 (KIF3C at 2p23, REEP3, NRBF2 at 10q21, SIRT1, MYPN at 10q21 and CFL2 at 14q13) and 10 SNPs with a P = .05 ~ 4.5 × 10-4 . Among 18 AF loci with a MAF< 0.01 in the Far East Asian populations, 2 loci (GATA4 at 8q23 and SGCG at 13q12) were replicated after a fine mapping. Twenty-seven AF loci, including a locus, which had a sufficient sample size to get a power of over 80% (with a type 1 error α = 4.5 × 10-4 ), were not replicated in the Far East Asian populations. CONCLUSIONS: We newly replicated 19 AF-associated genetic loci in the European descent among the Far East Asian populations. It highlights the extensive sharing of AF genetic risks across Far East Asian populations.

Association of ZFHX3 Genetic Polymorphisms and Extra-Pulmonary Vein Triggers in Patients With Atrial Fibrillation Who Underwent Catheter Ablation.

Background: The ZFHX3 gene (16q22) is the second most highly associated gene with atrial fibrillation (AF) and is related to inflammation and fibrosis. We hypothesized that ZFHX3 is associated with extra-pulmonary vein (PV) triggers, left atrial (LA) structural remodeling, and poor rhythm outcomes of AF catheter ablation (AFCA). Methods: We included 1,782 patients who underwent a de novo AFCA (73.5% male, 59.4 ± 10.8 years old, 65.9% paroxysmal AF) and genome-wide association study and divided them into discovery (n = 891) and replication cohorts (n = 891). All included patients underwent isoproterenol provocation tests and LA voltage mapping. We analyzed the ZFHX3, extra-PV trigger-related factors, and rhythm outcomes. Result: Among 14 single-nucleotide polymorphisms (SNPs) of ZFHX3, rs13336412, rs61208973, rs2106259, rs12927436, and rs1858801 were associated with extra-PV triggers. In the overall patient group, extra-PV triggers were independently associated with the ZFHX3 polygenic risk score (PRS) (OR 1.65 [1.22-2.22], p = 0.001, model 1) and a low LA voltage (OR 0.74 [0.56-0.97], p = 0.029, model 2). During 49.9 ± 40.3 months of follow-up, clinical recurrence of AF was significantly higher in patients with extra-PV triggers (Log-rank p < 0.001, HR 1.89 [1.49-2.39], p < 0.001, model 1), large LA dimensions (Log-rank p < 0.001, HR 1.03 [1.01-1.05], p = 0.002, model 2), and low LA voltages (Log-rank p < 0.001, HR 0.73 [0.61-0.86], p < 0.001, model 2) but not the ZFHX3 PRS (Log-rank p = 0.819). Conclusion: The extra-PV triggers had significant associations with both ZFHX3 genetic polymorphisms and acquired LA remodeling. Although extra-PV triggers were an independent predictor of AF recurrence after AFCA, the studied AF risk SNPs intronic in ZFHX3 were not associated with AF recurrence.

A mendelian randomization analysis: The causal association between serum uric acid and atrial fibrillation.

BACKGROUND: Observational studies have shown that high levels of serum uric acid (UA) were associated with atrial fibrillation (AF). However, the causal effect of urate on the risk of AF is still unknown. To clarify the potential causal association between UA and AF, we performed a Mendelian randomization (MR) analysis using genetic instrumental variables (IVs). MATERIALS AND METHODS: From the Korean GWAS dataset of 633 patients with AF (mean age 50.6 ± 7.8 years, 80.9% male, Yonsei AF Ablation cohort) who underwent radiofrequency catheter ablation and the data from 3533 controls (from the Korea Genome Epidemiology Study), we selected 9 SNPs, with a P value less than .05, associated with an increased UA serum level. Additionally, we calculated the weighted genetic risk score (wGRS) using the selected 9 SNPs, to use it as an instrumental variable. A Mendelian randomization analysis was calculated by a 2-stage estimator method. RESULTS: The conventional association between the serum UA and AF was significant (P = .001) after adjusting for potential confounding factors. The SNP rs1165196 on SLC17A1 (F-statistics = 208.34, 0.18 mg/mL per allele change, P < .001) and wGRS (F-statistics = 222.26, 0.20 mg/mL per 1SD change, P < .001) were significantly associated with an increase in the UA level. The MR analysis was causally associated with rs1165196 (estimated odds ratio (OR), 0.21, 95% confidence interval (CI), 0.06-0.75, P = .017), but not wGRS (estimated OR, 1.07, 95% CI, 0.57-2.01, P = .832). CONCLUSION: The serum UA level was independently associated with the AF risk.

Potential causal association of a prolonged PR interval and clinical recurrence of atrial fibrillation after catheter ablation: a Mendelian randomization analysis.

A prolonged PR interval predicts atrial fibrillation (AF) recurrence after catheter ablation. We investigated the causal association between the PR interval and AF clinical recurrence by a Mendelian randomization. We prospectively included 1722 patients with AF (73.2% male, 58.6 ± 10.8 years old, 71.3% paroxysmal AF) who underwent catheter ablation into a genome-wide association study (GWAS). We searched for the genetic associations between the PR interval and AF recurrence by analyzing 44 single nucleotide polymorphisms (SNPs) already known to be associated with the PR interval, and investigated the Mendelian randomization. Based on the quartile analysis, the highest quartile of the PR interval was associated with an increased risk of AF recurrence compared with the lowest quartile (Hazard ratio (HR) = 1.91, 95% CI = 1.51-2.42, P = 8.41 × 10-8) during 35.7 ± 28.5 months of follow-up. Among 44 SNPs known to be associated with the PR interval, two SNPs had significant associations with the PR interval (P < 0.001 for each SNP). CAV1 (HR = 1.15, 95% CI = 1.02-1.31, P = 0.024) was associated with clinical recurrence of AF. A Mendelian randomization analysis demonstrated a significant association with CAV1 (HR = 1.04, 95% CI = 1.01-1.07, P = 0.006). A prolonged PR interval was a risk factor for an AF recurrence, and the PR interval had a potentially causal association with an AF clinical recurrence after catheter ablation at the genetic level.

Clinical relationship between anemia and atrial fibrillation recurrence after catheter ablation without genetic background.

BACKGROUND: Anemia is a known adverse prognostic factor among patients with cardiovascular diseases. We investigated whether the hemoglobin level was associated with the rhythm outcome after atrial fibrillation (AF) catheter ablation (AFCA). METHODS: We included 2627 patients who underwent AFCA and a guidelines-based rhythm follow-up (age 58 ± 10.9 years, 73% men, 30.6% with persistent AF), and evaluated the association of pre-AFCA anemia (haemoglobin <13 g/dL in men and <12 g/dL in women) and rhythm outcomes. We studied the mechanistic relationship between anemia and AF recurrence using a Mendelian randomization analysis (1775 subjects with genome-wide association study) after reviewing already proven 12 hemoglobin-associated genetic polymorphisms. RESULTS: The body mass index, paroxysmal AF, warfarin use, and baseline red cell distribution width were independently associated with anemia in patients with AF. During a 23-month follow-up (interval OR 9-48 months), the clinical AF recurrence rate was significantly higher in patients with than without anemia (log-rank p = 0.001; propensity score-matched log-rank p = 0.004). This pattern was more significant in male patients (Log-rank p < 0.001) or patients with paroxysmal AF (Log-rank p < 0.001). Anemia (hazard ratio [HR] 1.45 [1.17-1.80], p = 0.001), left atrial diameter (HR 1.03 [1.01-1.04], p < 0.001), a female sex (HR 1.17 [1.00-1.36], p = 0.047), and persistent AF (HR 1.58 [1.36-1.84], p < 0.001) were independently associated with post-AFCA clinical recurrence. In the Mendelian randomization, we could not find a significant direct causal relationship between anemia and AF recurrence at the genetic level. CONCLUSIONS: Pre-AFCA anemia is an independent predictor of post-AFCA clinical recurrence, especially in male patients, without a genetically direct causal relationship.

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.

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.

An Intergenic Variant rs9268877 Between HLA-DRA and HLA-DRB Contributes to the Clinical Course and Long-term Outcome of Ulcerative Colitis.

BACKGROUND AND AIMS: The genetic contribution to the prognosis of ulcerative colitis [UC] is poorly understood, and most currently known susceptibility loci are not associated with prognosis. To identify genetic variants influencing the prognosis of UC, we performed an Immunochip-based study using an extreme phenotype approach. METHODS: Based on the finding that the only association, Pdiscovery-meta <1 × 10-4, was located in the human leukocyte antigen [HLA], we focused our analyses on the HLA region. We performed the analysis using HLA imputation data from three independent discovery cohorts of 607 UC patients [243 poor-prognosis and 364 good-prognosis], followed by replication in 274 UC patients [145 poor-prognosis and 129 good-prognosis]. RESULTS: We found that rs9268877, located between HLA-DRA and HLA-DRB, was associated with poor-prognosis of UC at genome-wide significance (odds ratio [ORdiscovery] = 1.82; ORreplication = 1.55; ORcombined-meta = 1.72, pcombined-meta = 1.04 × 10-8), with effect size [OR] increasing incrementally according to worsening of prognosis in each of the three independent discovery cohorts and the replication cohort. However, rs9268877 showed no association with UC susceptibility [ORcombined-meta = 1.07, pcombined-meta = 0.135]; rs9268877 influenced 30-year clinical outcomes, and the presence of the rs9268877 risk allele had a sensitivity of 80.0% and specificity of 38.1% for colectomy. CONCLUSIONS: Our results provide new insights into prognosis-associated genetic variation in UC, which appears to be distinct from the genetic contribution to disease susceptibility. These findings could be useful in identifying poor-prognosis patients who might benefit from early aggressive therapy.