Characteristics of Japanese inflammatory bowel disease susceptibility loci

Arimura, Yoshiaki; Isshiki, Hironari; Onodera, Kei; Nagaishi, Kanna; Yamashita, Kentaro; Sonoda, Tomoko; Matsumoto, Takayuki; Takahashi, Atsushi; Takazoe, Masakazu; Yamazaki, Keiko; Kubo, Michiaki; Fujimiya, Mineko; Imai, Kohzoh; Shinomura, Yasuhisa

doi:10.1007/s00535-013-0866-2

Cited by 38 publications

(29 citation statements)

References 70 publications

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“…11 and Supplementary Table 8). The associated alleles have been implicated in risk for ulcerative colitis in multiple ancestry groups 32,33 and in Takayasu arteritis 34 .…”

Section: Resultsmentioning

confidence: 99%

Genome-wide association analysis identifies variation in vitamin D receptor and other host factors influencing the gut microbiota

et al. 2016

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Human gut microbiota is an important determinant for health and disease, and recent studies emphasize the numerous factors shaping its diversity. Here we performed a genome-wide association study (GWAS) of the gut microbiota using two cohorts from northern Germany totaling 1,812 individuals. Comprehensively controlling for diet and non-genetic parameters, we identify genome-wide significant associations for overall microbial variation and individual taxa at multiple genetic loci, including the VDR gene (encoding vitamin D receptor). We observe significant shifts in the microbiota of Vdr−/− mice relative to control mice and correlations between the microbiota and serum measurements of selected bile and fatty acids in humans, including known ligands and downstream metabolites of VDR. Genome-wide significant (P < 5 × 10−8) associations at multiple additional loci identify other important points of host–microbe intersection, notably several disease susceptibility genes and sterol metabolism pathway components. Non-genetic and genetic factors each account for approximately 10% of the variation in gut microbiota, whereby individual effects are relatively small.

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“…11 and Supplementary Table 8). The associated alleles have been implicated in risk for ulcerative colitis in multiple ancestry groups 32,33 and in Takayasu arteritis 34 .…”

Section: Resultsmentioning

confidence: 99%

Genome-wide association analysis identifies variation in vitamin D receptor and other host factors influencing the gut microbiota

et al. 2016

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“…11,12 DRB1*0405 allele confers susceptibility to CD development, whereas DRB1* 1502 allele protects against the development. 13,14 Thus, DRB1*0405 is a shared susceptibility allele for PBC and CD in the Japanese population. In the present study, therefore, to further identify shared susceptibility genes at non-HLA loci and pathogenic pathways for PBC and CD in the Japanese population, we performed a comparative case-control association study of CD susceptibility genes with PBC and vice versa.…”

Section: Introductionmentioning

confidence: 95%

Disease susceptibility genes shared by primary biliary cirrhosis and Crohn’s disease in the Japanese population

et al. 2015

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We previously identified TNFSF15 as the most significant susceptibility gene at non-HLA loci for both primary biliary cirrhosis (PBC) and Crohn's diseases (CD) in the Japanese population. The aim of this study is to identify further disease susceptibility genes shared by PBC and CD. We selected 15 and 33 genetic variants that were significantly associated with PBC and CD, respectively, based on previously reported genome-wide association studies of the Japanese population. Next, an association study was independently performed for these genetic variants in CD (1312 CD patients and 3331 healthy controls) and PBC (1279 PBC patients and 1015 healthy controls) cohorts. Two CD susceptibility genes, ICOSLG rs2838519 and IL12B rs6556412, were also nominally associated with susceptibility to PBC (P=3.85 × 10(-2) and P=8.40 × 10(-3), respectively). Three PBC susceptibility genes, CXCR5 rs6421571, STAT4 rs7574865 and NFKB1 rs230534, were nominally associated with susceptibility to CD (P=2.82 × 10(-2), P=3.88 × 10(-2) and P=2.04 × 10(-2), respectively). The effect of ICOSLG and CXCR5 variants were concordant but the effect of STAT4, NFKB1 and IL12B variants were discordant for PBC and CD. TNFSF15 and ICOSLG-CXCR5 might constitute a shared pathogenic pathway in the development of PBC and CD in the Japanese population, whereas IL12B-STAT4-NFKB1 might constitute an opposite pathogenic pathway, reflecting the different balance between Th1 and Th17 in the two diseases.

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“…Several HLA‐DQB1 genotypes have been strongly implicated in the Japanese population (especially DQB1*04) and some smaller studies (<500 patients) in those with European ancestry . The DQB1*04 allele group is in strong linkage disequilibrium with a number of HLA‐DRB1 alleles (including DRB1*08:01, DQB1 04:02, DRB1*04:05, DRB1*04:10 and DRB1*08:02), presenting difficulty in distinguishing DQB1 as an independent risk genotype .…”

Section: Specific Associations: Hla and Ibdmentioning

confidence: 99%

“…The serotype HLA-DQ2.5 is specifically protective for ulcerative colitis (seen in 16.43% with ulcerative colitis compared to 23.74% of controls and 26% of Crohn's disease) and this effect is more pronounced in women (>50% less frequent).48 Work by Goyette et al and De La Concha et al replicated this for all patients, with the risk for ulcerative colitis being reduced in patients with genotypes associated with the coeliac disease HLA serotypes, namely HLA-DQA1*03:01 (OR 0.68), DQA1*02:01 (OR 0.73), DQB1*03:02 (OR 0.67), DQB1*02:01 (OR 0.86) and DQB1*02:02 (OR 0.76) 25,49. Several HLA-DQB1 genotypes have been strongly implicated in the Japanese population (especially DQB1*04) and some smaller studies (<500 patients) in those with European ancestry 40,50,51. The DQB1*04 allele group is in strong linkage disequilibrium with a number of HLA-DRB1 alleles (including DRB1*08:01, DQB1 04:02, DRB1*04:05, DRB1*04:10 and DRB1*08:02), presenting difficulty in distinguishing DQB1 as an independent risk genotype 52.…”

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confidence: 99%

Review article: the genetics of the human leucocyte antigen region in inflammatory bowel disease

Ashton

Latham

Beattie

et al. 2019

Aliment Pharmacol Ther

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Summary Background The human leucocyte antigen (HLA) complex, located at chromosome 6p21.3 is a highly polymorphic region containing the classical class I and II HLA genes. The region is highly associated with inflammatory bowel disease (IBD), largely through genome‐wide association studies (GWAS). Aims To review the role of HLA in immune function, summarise data on risk/protective HLA genotypes for IBD, discuss the role of HLA in IBD pathogenesis, treatment and examine limitations that might be addressed by future research. Methods An organised search strategy was used to collate articles describing HLA genes in IBD, including Crohn's disease and ulcerative colitis. Results All classical HLA genes with variation (including HLA‐A, B, C, DRB1, DQA1, DQB1, DPA1 and DPB1) harbour IBD‐associated genotypes. The most implicated gene is HLA‐DRB1, with HLA‐DRB1*03:01 the most associated risk allele in both Crohn's disease and ulcerative colitis. Elucidating precise disease associations is challenging due to high linkage disequilibrium between HLA genotypes. The mechanisms by which risk alleles cause disease are multifactorial, with the best evidence indicating structural and electrostatic alteration impacting antigen binding and downstream signalling. Adverse medication events have been associated with HLA genotypes including with thiopurines (pancreatitis) and anti‐TNF agents (antibody formation). Conclusions The HLA complex is associated with multiple risk/protective alleles for IBD. Future research utilising long‐read technology, ascertainment of zygosity and integration in disease modelling will improve the functional understanding and clinical translation of genetic findings.

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Characteristics of Japanese inflammatory bowel disease susceptibility loci

Abstract: Results indicate that Japanese IBD susceptibility loci identified by the meta-analysis are closely associated with the HLA regions.

Cited by 38 publications

References 70 publications

Genome-wide association analysis identifies variation in vitamin D receptor and other host factors influencing the gut microbiota

Genome-wide association analysis identifies variation in vitamin D receptor and other host factors influencing the gut microbiota

Disease susceptibility genes shared by primary biliary cirrhosis and Crohn’s disease in the Japanese population

Review article: the genetics of the human leucocyte antigen region in inflammatory bowel disease

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