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A novel gene associated with small bowel bleeding in patients taking low-dose aspirin. Dig Liver Dis 2021; 53:841-845. [PMID: 34059446 DOI: 10.1016/j.dld.2021.04.038] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 04/30/2021] [Accepted: 04/30/2021] [Indexed: 12/11/2022]
Abstract
OBJECTIVE We have previously revealed the clinical factors and genetic polymorphisms associated with gastrointestinal mucosal injury and bleeding, induced by low-dose aspirin (LDA). After performing genome-wide analysis of single nucleotide polymorphisms (SNPs) using the Drug Metabolizing Enzymes and Transporters (DMET) system among drug metabolism and transporter genes, certain SNPs were found to increase the risk for LDA-induced small bowel bleeding. The aim of this study was to identify the SNPs involved in LDA-induced small bowel bleeding. SUBJECTS AND METHODS Subjects were patients taking LDA, with small bowel bleeding diagnosed using capsule endoscopy. We investigated the clinical characteristics and the previously identified SNPs, that were examined by the DNA direct sequence method. RESULTS 56 patients with bleeding and 410 controls taking LDA were enrolled. The risk factors associated with small bowel bleeding included smoking, cerebrovascular diseases, chronic renal failure, non-steroidal anti-inflammatory drug (NSAID) or anticoagulants combination, and two SNPs (CYP4F11 20043G>A (D446N) rs1060463, GSTP1 313A>G rs1695). After propensity score matching, GSTP1 rs1695 was significantly associated with small bowel bleeding. CONCLUSION The GSTP1 SNP may be a predictive marker for small bowel bleeding among patients taking LDA.
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Increased risk of aspirin-induced gastric mucosal erosion in elderly Chinese men harboring SLCO1B1*1b/*1b while using aspirin and an ACEI or ARB concomitantly. BMC MEDICAL GENETICS 2019; 20:183. [PMID: 31727004 PMCID: PMC6857243 DOI: 10.1186/s12881-019-0918-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Accepted: 11/01/2019] [Indexed: 01/22/2023]
Abstract
Background It is well established that long-term use of aspirin can cause gastric mucosal injury. ACEIs and ARBs are inversely related to gastric ulcer development. This study aimed to evaluate the relationship between SLCO1B1 polymorphisms, which can affect ACEI and ARB transport, and gastric mucosal erosion in elderly male Chinese patients with cardiovascular disease who use aspirin. Methods Patients taking aspirin and an ACEI or ARB concomitantly who had undergone endoscopic screening for gastric erosion were analyzed for SLCO1B1 polymorphisms by a TaqMan assay. Results The frequency of the SLCO1B1*1b/*1b diplotype (42% vs. 24%; p = 0.002) was significantly higher in the gastric mucosal erosion group than in the control group. After adjustment for significant factors, SLCO1B1*1b/*1b (OR, 2.64; 95% CI, 1.59–4.17; p < 0.05) was found to be associated with gastric mucosal erosion in aspirin users. Conclusions The presence of the SLCO1B1*1b/*1b diplotype may be a risk factor for aspirin-induced gastric mucosal erosion in elderly Chinese men taking aspirin and an ACEI or ARB concomitantly.
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DMET™ (Drug Metabolism Enzymes and Transporters): a pharmacogenomic platform for precision medicine. Oncotarget 2018; 7:54028-54050. [PMID: 27304055 PMCID: PMC5288240 DOI: 10.18632/oncotarget.9927] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Accepted: 05/29/2016] [Indexed: 02/07/2023] Open
Abstract
In the era of personalized medicine, high-throughput technologies have allowed the investigation of genetic variations underlying the inter-individual variability in drug pharmacokinetics/pharmacodynamics. Several studies have recently moved from a candidate gene-based pharmacogenetic approach to genome-wide pharmacogenomic analyses to identify biomarkers for selection of patient-tailored therapies. In this aim, the identification of genetic variants affecting the individual drug metabolism is relevant for the definition of more active and less toxic treatments. This review focuses on the potentiality, reliability and limitations of the DMET™ (Drug Metabolism Enzymes and Transporters) Plus as pharmacogenomic drug metabolism multi-gene panel platform for selecting biomarkers in the final aim to optimize drugs use and characterize the individual genetic background.
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Cho JH, Choi JS, Chun SW, Lee S, Han KJ, Kim HM. The IL-1B Genetic Polymorphism Is Associated with Aspirin-Induced PepticUlcers in a Korean Ethnic Group. Gut Liver 2017; 10:362-8. [PMID: 26601827 PMCID: PMC4849688 DOI: 10.5009/gnl15129] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Background/Aims Single nucleotide polymorphisms (SNPs) are associated with aspirin-induced peptic ulcers. However, SNPs of specific genes vary among races, and data regarding SNPs in the Korean population are scarce. In this study, we aimed to investigate the relationships between SNPs of the COX-1, IL-1β, IL-1RN, and TNF genes and aspirin-induced peptic ulcers, as pilot research in a Korean population. Methods Patients who had been taking low-dose aspirin (100 mg) for at least 4 weeks were prospectively enrolled. DNA was extracted from whole blood, and DNA sequencing was subsequently performed. Results A total of 48 patients were enrolled (23 peptic ulcer patients vs 25 nonulcer controls). Three exon SNPs (IL-1β -581C/T [rs1143627], IL-1β -1061C/T [rs16944], and IL-1RN -1129 [rs4251961]) and one intron SNP (IL-1β IVS2+242C/T) were significantly different between the two groups. On the multivariate analysis after adjustments for age and sex, the CC/CT genotypes of IL-1β -581C/T, and the CT/TT genotypes of IL-1β -1061C/T were positively associated with aspirin-induced peptic ulcers (odds ratio [OR], 4.6, 95% confidence interval [CI], 1.054 to 20.303, p=0.04; OR, 4.6, 95% CI, 1.054 to 20.303, p=0.04). Conclusions The IL-1β -581C/T and IL-1β -1061C/T genotypes may be associated with low-dose aspirin-induced peptic ulcers in a Korean ethnic group.
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Affiliation(s)
- Jae Hee Cho
- Division of Gastroenterology, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea
| | - Ja Sung Choi
- Department of Internal Medicine, International St. Mary's Hospital, Catholic Kwandong University College of Medicine, Incheon, Korea
| | - Song Wook Chun
- Division of Gastroenterology, Department of Internal Medicine, Myongji Hospital, Goyang, Korea
| | - Sangheun Lee
- Department of Internal Medicine, International St. Mary's Hospital, Catholic Kwandong University College of Medicine, Incheon, Korea
| | - Ki Jun Han
- Department of Internal Medicine, International St. Mary's Hospital, Catholic Kwandong University College of Medicine, Incheon, Korea
| | - Hee Man Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
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Feng A, Chuang E, Wu SH, Wang JC, Chang SN, Lin CL, Kao CH. The effect of statins on the occurrence of peptic ulcer. Eur J Intern Med 2015; 26:731-5. [PMID: 26226858 DOI: 10.1016/j.ejim.2015.07.015] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2015] [Revised: 07/13/2015] [Accepted: 07/14/2015] [Indexed: 12/26/2022]
Abstract
BACKGROUND This study was to determine the association between the use of statins and the occurrence of peptic ulcer diseases (PUD). METHODS Using the National Health Insurance Research Database to conduct a population-based cohort study. We identified 48,562 patients who were newly diagnosed with hyperlipidemia during the period of 1998 to 2011 and who were divided into two groups based on their use of statins. The non-statin cohort (without statin treatment, 24,139 patients) were 1:1 frequency matched with sex, age, year of diagnosis of hyperlipidemia and index-year to the statin cohort (24,423 patients). The relative risk of patients with and without statins treatment on the occurrence of PUD and concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin were analyzed using the univariable and multivariable Cox proportional hazards regression model. RESULTS The incidence of PUD increased with age in both cohorts and female had a higher occurrence rate than male in both cohorts. Compared with the non-statin cohort, the statin cohort was associated with a significant lower risk of PUD for all age group. The concomitant use of aspirin and/or NSAIDs had higher incidence of PUD than those without in both cohorts. Analyzing the cumulative defined daily dose (DDD) of statins indicated that high-dose groups (≧ 575 DDD) exhibited significantly decreased risk compared with non-statin users. CONCLUSION The results of the present study indicated that statins might be associated with the protection of peptic ulcer in a dose-respondent manner.
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Affiliation(s)
- Anning Feng
- Division of Cardiology, Cheng Hisn General Hospital, Taipei, Taiwan; Nation Yang-Ming University, Taipei, Taiwan
| | - Eric Chuang
- UC Berkeley Mishler Lab Undergraduate Researcher, Intended B.S. Molecular and Cell Biology, University of CA, Berkeley, USA
| | - Szu-Hsien Wu
- Department of Physical Medicine and Rehabilitation, Veterans General Hospital Taipei, Taipei, Taiwan; National Yang-Ming University, Taipei, Taiwan
| | - Jia-Chi Wang
- Department of Physical Medicine and Rehabilitation, Veterans General Hospital Taipei, Taipei, Taiwan; National Yang-Ming University, Taipei, Taiwan
| | - Shih-Ni Chang
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Cheng-Li Lin
- Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan; College of Medicine, China Medical University, Taichung, Taiwan
| | - Chia-Hung Kao
- Graduate Institute of Clinical Medical Science and School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan; Department of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung, Taiwan.
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Shiotani A, Murao T, Fujita Y, Fujimura Y, Sakakibara T, Nishio K, Haruma K. Single nucleotide polymorphism markers for low-dose aspirin-associated peptic ulcer and ulcer bleeding. J Gastroenterol Hepatol 2014; 29 Suppl 4:47-52. [PMID: 25521733 DOI: 10.1111/jgh.12770] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIM In our previous study, the SLCO1B1 521TT genotype and the SLCO1B1*1b haplotype were significantly associated with the risk of peptic ulcer in patients taking low-dose aspirin (LDA). The aim of the present study was to investigate pharmacogenomic profile of LDA-induced peptic ulcer and ulcer bleeding. METHODS Patients taking 100 mg of enteric-coated aspirin for cardiovascular diseases and with a peptic ulcer or ulcer bleeding and patients who also participated in endoscopic surveillance were studied. Genome-wide analysis of single nucleotide polymorphisms (SNPs) was performed using the Affymetrix DME Plus Premier Pack. SLCO1B1*1b haplotype and candidate genotypes of genes associated with ulcer bleeding or small bowel bleeding identified by genome-wide analysis were determined using TaqMan SNP Genotyping Assay kits, polymerase chain reaction-restriction fragment length polymorphism, and direct sequencing. RESULTS Of 593 patients enrolled, 111 patients had a peptic ulcer and 45 had ulcer bleeding. The frequencies of the SLCO1B1*1b haplotype and CHST2 2082 T allele were significantly greater in patients with peptic ulcer and ulcer bleeding compared to the controls. After adjustment for significant factors, the SLCO1B1*1b haplotype was associated with peptic ulcer (OR 2.20, 95% CI 1.24-3.89) and CHST2 2082 T allele with ulcer bleeding (2.57, 1.07-6.17). CONCLUSION The CHST2 2082 T allele as well as SLCO1B1*1b haplotype may identify patients at increased risk for aspirin-induced peptic ulcer or ulcer bleeding.
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Affiliation(s)
- Akiko Shiotani
- Division of Gastroenterology, Department of Internal Medicine, Kawasaki Medical School, Matsushima Kurashiki, Okayama Prefecture, Japan
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Sostres C, Gargallo CJ, Lanas A. Interaction between Helicobacter pylori infection, nonsteroidal anti-inflammatory drugs and/or low-dose aspirin use: Old question new insights. World J Gastroenterol 2014; 20:9439-9450. [PMID: 25071338 PMCID: PMC4110575 DOI: 10.3748/wjg.v20.i28.9439] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2013] [Revised: 01/15/2014] [Accepted: 04/09/2014] [Indexed: 02/06/2023] Open
Abstract
Previous reports clearly demonstrated that Helicobacter pylori (H. pylori) infection, nonsteroidal anti-inflammatory drugs (NSAID) or low dose aspirin (ASA) use significantly and independently increased the risk for the development of peptic ulcer disease. Today, the presence of H. pylori infection associated with low dose ASA and/or NSAID use in the same patient is becoming more frequent and therefore the potential interaction between these factors and the consequences of it has important implications. Whether NSAID intake in the presence of H. pylori infection may further increase the risk of peptic ulcer carried by the presence of only one risk factor is still a matter of debate. Studies on the interaction between the two risk factors yielded conflicting data and no consensus has been reached in the last years. In addition, the interaction between H. pylori infection and low-dose ASA remains even more controversial. In real clinical practice, we can find different clinical scenarios involving these three factors associated with the presence of different gastrointestinal and cardiovascular risk factors. These huge variety of possible combinations greatly hinder the decision making process of physicians.
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Shiotani A, Murao T, Fujita Y, Fujimura Y, Sakakibara T, Nishio K, Haruma K. Novel single nucleotide polymorphism markers for low dose aspirin-associated small bowel bleeding. PLoS One 2013; 8:e84244. [PMID: 24367646 PMCID: PMC3867469 DOI: 10.1371/journal.pone.0084244] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2013] [Accepted: 11/13/2013] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Aspirin-induced enteropathy is now increasingly being recognized although the pathogenesis of small intestinal damage induced by aspirin is not well understood and related risk factors have not been established. AIM To investigate pharmacogenomic profile of low dose aspirin (LDA)-induced small bowel bleeding. METHODS Genome-wide analysis of single nucleotide polymorphisms (SNPs) was performed using the Affymetrix DMET™ Plus Premier Pack. Genotypes of candidate genes associated with small bowel bleeding were determined using TaqMan SNP Genotyping Assay kits and direct sequencing. RESULTS In the validation study in overall 37 patients with small bowel bleeding and 400 controls, 4 of 27 identified SNPs: CYP4F11 (rs1060463) GG (p=0.003), CYP2D6 (rs28360521) GG (p=0.02), CYP24A1 (rs4809957) T allele (p=0.04), and GSTP1 (rs1695) G allele (p=0.04) were significantly more frequent in the small bowel bleeding group compared to the controls. After adjustment for significant factors, CYP2D6 (rs28360521) GG (OR 4.11, 95% CI. 1.62 -10.4) was associated with small bowel bleeding. CONCLUSIONS CYP4F11 and CYP2D6 SNPs may identify patients at increased risk for aspirin-induced small bowel bleeding.
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Affiliation(s)
- Akiko Shiotani
- Division of Gastroenterology, Department of Internal Medicine, Kawasaki Medical School, Kurashiki City, Okayama, Japan
| | - Takahisa Murao
- Division of Gastroenterology, Department of Internal Medicine, Kawasaki Medical School, Kurashiki City, Okayama, Japan
| | - Yoshihiko Fujita
- Department of Genome Biology, Kinki University Faculty of Medicine, Sayama City, Osaka, Japan
| | - Yoshinori Fujimura
- Department of Gastroenterology, Sakakibara Heart Institute of Okayama, Okayama City, Okayama, Japan
| | - Takashi Sakakibara
- Department of Gastroenterology, Sakakibara Heart Institute of Okayama, Okayama City, Okayama, Japan
| | - Kazuto Nishio
- Department of Genome Biology, Kinki University Faculty of Medicine, Sayama City, Osaka, Japan
| | - Ken Haruma
- Division of Gastroenterology, Department of Internal Medicine, Kawasaki Medical School, Kurashiki City, Okayama, Japan
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Shiotani A, Manabe N, Kamada T, Fujimura Y, Sakakibara T, Haruma K. Risk and preventive factors of low-dose aspirin-induced gastroduodenal injuries: a comprehensive review. J Gastroenterol Hepatol 2012; 27 Suppl 3:8-12. [PMID: 22486865 DOI: 10.1111/j.1440-1746.2012.07071.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The risk of peptic ulcer complications, particularly bleeding, is increased in association with the use of low-dose aspirin (LDA). Risk factors for upper gastrointestinal (GI) ulcer or bleeding among LDA users include a history of prior GI events, older age, chronic renal failure, combined antithrombotic therapy and nonsteroidal anti-inflammatory drugs (NSAIDs). Helicobacter pylori and aspirin seem to be independent risk factors for peptic ulcer and bleeding. The studies report conflicting findings about the effect of H. pylori infection on NSAID-related ulcers, and proton-pump inhibitors (PPIs) seem to be superior to eradication only to prevent recurrent ulcer bleeding with LDA. Previous studies indicate that hypoacidity related to corpus atrophy, as well as taking PPIs and co-treatment with angiotensin type 1 receptor blockers (ARBs) and statins seem to reduce peptic ulcer among LDA users. In addition, the interleukin-1β (IL-1β)-511 T allele and angiotensinogen (AGT)-20 CC, which work as the high-producer allele of IL-1β and AGT, are significantly associated with ulcer or ulcer bleeding. The SLCO1B1*1b haplotype, which has the highest transport activity, may diminish the preventive effect of statins or ARBs. The data are still lacking and further prospective studies are needed to identify the specific risk or protective factors for upper GI ulcer and its complications associated with LDA.
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Affiliation(s)
- Akiko Shiotani
- Department of Internal Medicine, Kawasaki Medical School, Kurashiki City, Okayama Prefecture, Japan.
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