Genetic Analysis of Ulcerative Colitis in Japanese Individuals Using Population-specific SNP Array

Okamoto, Daisuke; Kawai, Yosuke; Kakuta, Yoichi; Naito, Takeo; Torisu, Takehiro; Hirano, Atsushi; Umeno, Junji; Fuyuno, Yuta; Li, Dalin; Nakano, Toshihiko; Izumiyama, Yasuhiro; Ichikawa, Ryo; Hiramoto, Keiichiro; Moroi, Rintaro; Kuroha, Masatake; Kanazawa, Yoshitake; Shiga, Hisashi; Tokunaga, Katsushi; Nakamura, Minoru; Esaki, Motohiro; Matsumoto, Takayuki; McGovern, Dermot; Nagasaki, Masao; Kinouchi, Yoshitaka; Masamune, Atsushi

doi:10.1093/ibd/izaa033

Cited by 12 publications

(15 citation statements)

References 38 publications

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“…We examined the correlation between SNP rs117506082 and clinical outcomes in our cohort. Our previous study showed that SNP rs117506082 at the HLA region was significantly associated with UC in the group with the GA + AA genotype [19]. In contrast, the present study revealed that the AA group had a higher proportion of pancolitis.…”

Section: Discussioncontrasting

confidence: 66%

“…The top SNP (with the lowest p value) was rs117506082. The G allele of this SNP increases the risk of UC development, whereas the A allele is a reference allele [19]. Furthermore, although the GG genotype of SNP rs117506082 was a risk factor for the onset of UC, the need for surgery in a 30-year follow-up was significantly lower in this genotype than in the GA and AA alleles, suggesting that the GG genotype might have a better clinical outcome.…”

Section: Introductionmentioning

confidence: 94%

“…The cohort was divided into 2 groups according to the presence or absence of the genotypes GG + GA or AA of SNP rs117506082 at the HLA loci (reference allele: A, alternative allele. Data from our previous study [19] were used to identify these genotypes in our cohort. Variables including sex, age at diagnosis, disease location, systemic steroid therapy, use of thiopurine and new therapeutic agents, need for colectomy, and time from diagnosis to colectomy were compared between the groups with these 2 genotypes using the χ 2 test or Wilcoxon signed-rank test.…”

Section: Analysis Of the Association Between Genotype And Long-term Prognosismentioning

confidence: 99%

“…We performed a GWAS in Japanese UC patients using a single nucleotide polymorphism (SNP) array (Japonica array) [18] developed by Tohoku University Medical Megabank Organization in Tohoku, Japan, to determine the genetic background of Japanese IBD patients. In addition, susceptibility polymorphisms strongly associated with UC were identified at the human leukocyte antigen (HLA) region [19]. The top SNP (with the lowest p value) was rs117506082.…”

Section: Introductionmentioning

confidence: 99%

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Analysis of the Long-Term Prognosis in Japanese Patients with Ulcerative Colitis Treated with New Therapeutic Agents and the Correlation between Prognosis and Disease Susceptibility Loci

Hishinuma¹,

Moroi²,

Okamoto³

et al. 2021

Inflamm Intest Dis

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Background: New therapeutic agents, including biologics and small-molecule drugs, are widely used to treat ulcerative colitis (UC). This study evaluates long-term prognosis in Japanese patients treated with these agents and the association between prognosis and genetic susceptibility to UC. Methods: We evaluated surgery-free rates using the Kaplan-Meier method in the total cohort and in patients treated with prednisolone and new therapeutic agents. Multivariate analysis was performed to identify clinical factors affecting surgical rates using Cox’s proportional hazard model. The rate of use of new therapeutic agents was compared using the Kaplan-Meier method, and multivariate analysis was conducted to investigate the correlation between the single-nucleotide polymorphism (SNP) rs117506082 and long-term prognosis. Results: Surgery-free survival decreased over time. There was no significant difference in this parameter between patients who were administered prednisolone and those who were administered new therapeutic agents. Poor response to prednisolone and treatment without topical 5-aminosalicylic acid were poor prognostic factors. Shorter time from diagnosis to initiation of treatment with new therapeutic agents was a risk factor for colectomy. The AA genotype of SNP rs117506082 was associated with a shorter time to surgery and increased use of new therapeutic agents. Conclusions: The use of new therapeutic agents might improve long-term prognosis in patients with more severe UC. Previously identified genetic risk factors were not significantly associated with a higher rate of colectomy.

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Section: Discussioncontrasting

confidence: 66%

Section: Introductionmentioning

confidence: 94%

Section: Analysis Of the Association Between Genotype And Long-term Prognosismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Analysis of the Long-Term Prognosis in Japanese Patients with Ulcerative Colitis Treated with New Therapeutic Agents and the Correlation between Prognosis and Disease Susceptibility Loci

Hishinuma¹,

Moroi²,

Okamoto³

et al. 2021

Inflamm Intest Dis

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“…There is evidence of population strati cation, such as differences between populations in the genetic factors contributing to UC risk [27,28]. We trained the PRS model on the sample sets containing only Europeans.…”

Section: Population Strati Cationmentioning

confidence: 99%

Factors influencing the power of polygenic risk score: a survey based on a genotype array dataset of an ulcerative colitis cohort

Liu

Jing

et al. 2022

Preprint

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BackgroundPolygenic risk scores (PRSs) are personalized assessments based on the cumulative effect of a larger number of genetic variants, and the PRS has been utilized to estimate the risk of a disease or disease-related trait for an individual. However, the capability of PRS can be interfered with by multiple factors spanning from the generating genome-wide association study (GWAS) summary to the PRS calculation. In this study, based on a large cohort of 2,781 ulcerative colitis (UC) cases and 2,876 healthy controls with available genotype array data, we systematically analyzed factors that could affect the power of PRS, including GWAS summary statistics, population stratification, impact of variants and imputation reference panels.ResultsWe eventually established the best model achieving an AUC of 0.715 (95% CI 0.702-0.729) in prediction using 2,669 UC cases and 2,846 healthy controls of genetically identified Europeans. And samples in the top 5% of the PRS distribution had more than seven times higher risk of UC than samples in the lowest 95% (OR=7.014, 95% CI 4.977-9.884).ConclusionOur analyses demonstrated that including population-specific, more associated SNPs and selecting GWAS summary statistics results from similar population structure can improve the power of PRS, strictly following the principle of focusing on one population in all aspects of generating PRS, which can be a cost-effective way to apply genotype array-derived PRS to practical risk estimation.

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Real-world NUDT15 genotyping and thiopurine treatment optimization in inflammatory bowel disease: a multicenter study

Makuuchi,

Kakuta,

Umeno

et al. 2024

J Gastroenterol

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Background This study evaluated the effectiveness of NUDT15 codon 139 genotyping in optimizing thiopurine treatment for inflammatory bowel disease (IBD) in Japan, using real-world data, and aimed to establish genotype-based treatment strategies. Methods A retrospective analysis of 4628 IBD patients who underwent NUDT15 codon 139 genotyping was conducted. This study assessed the purpose of the genotyping test and subsequent prescriptions following the obtained results. Outcomes were compared between the Genotyping group (thiopurine with genotyping test) and Non-genotyping group (thiopurine without genotyping test). Risk factors for adverse events (AEs) were analyzed by genotype and prior genotyping status. Results Genotyping test for medical purposes showed no significant difference in thiopurine induction rates between Arg/Arg and Arg/Cys genotypes, but nine Arg/Cys patients opted out of thiopurine treatment. In the Genotyping group, Arg/Arg patients received higher initial doses than the Non-genotyping group, while Arg/Cys patients received lower ones (median 25 mg/day). Fewer AEs occurred in the Genotyping group because of their lower incidence in Arg/Cys cases. Starting with < 25 mg/day of AZA reduced AEs in Arg/Cys patients, while Arg/Arg patients had better retention rates when maintaining ≥ 75 mg AZA. Nausea and liver injury correlated with thiopurine formulation but not dosage. pH-dependent mesalamine reduced leukopenia risk in mesalamine users. Conclusions NUDT15 codon 139 genotyping effectively reduces thiopurine-induced AEs and improves treatment retention rates in IBD patients after genotype-based dose adjustments. This study provides data-driven treatment strategies based on genotype and identifies risk factors for specific AEs, contributing to a refined thiopurine treatment approach.

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Genetic Analysis of Ulcerative Colitis in Japanese Individuals Using Population-specific SNP Array

Cited by 12 publications

References 38 publications

Analysis of the Long-Term Prognosis in Japanese Patients with Ulcerative Colitis Treated with New Therapeutic Agents and the Correlation between Prognosis and Disease Susceptibility Loci

Analysis of the Long-Term Prognosis in Japanese Patients with Ulcerative Colitis Treated with New Therapeutic Agents and the Correlation between Prognosis and Disease Susceptibility Loci

Factors influencing the power of polygenic risk score: a survey based on a genotype array dataset of an ulcerative colitis cohort

Real-world NUDT15 genotyping and thiopurine treatment optimization in inflammatory bowel disease: a multicenter study

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