Immunochip Analysis Identification of 6 Additional Susceptibility Loci for Crohnʼs Disease in Koreans

Yang, Suk Kyun; Hong, Myunghee; Choi, Hyunchul; Zhao, Wanting; Jung, Yoojin; Haritunians, Talin; Ye, Byong Duk; Kim, Kyung Jo; Park, Sang Hyoung; Lee, Inchul; Cheon, Jae Hee; Kim, Young Ho; Jang, Byung Ik; Kim, Hyun Soo; Choi, Jai Hyun; Koo, Ja Seol; Lee, Ji Hyun; Jung, Sung Ae; Shin, Hyoung Doo; Kang, Daehee; Youn, Hee Shang; Taylor, Kent D.; Rotter, Jerome I.; Liu, Jing; McGovern, Dermot P.; Song, Kyuyoung

doi:10.1097/mib.0000000000000268

Cited by 68 publications

(71 citation statements)

References 35 publications

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“…rs1250550 was found to be an early-onset IBD-specific SNP in the region of ZMIZ1 [29, 30]. rs1250569 which lies within ZMIZ1, was also found to be a susceptibility locus for CD in Koreans [9]. Our data support the notion that there is an association between rs1250569 and susceptibility to early-onset Crohn’s disease.…”

Section: Discussionsupporting

confidence: 79%

“…Recently, an immuno-chip analysis of a Korean population identified rs1250569 in zinc finger MIZ-type containing 1 (ZMIZ1) as a novel susceptibility locus for Crohn's disease that increased susceptibility in an Asian population [9]. rs1042522, in tumour protein p53 (TP53), has previously been observed in a variety of cancers and associated with an increased risk of IBD in Canadians [10].…”

Section: Introductionmentioning

confidence: 99%

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Identification of Two Additional Susceptibility Loci for Inflammatory Bowel Disease in a Chinese Populationy

Lan¹,

Lan

Chang³

et al. 2017

Cell Physiol Biochem

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Background/Aims: To investigate the associations between the rs1250569 (zinc finger MIZ-type containing 1, ZMIZ1), rs1042522 (tumour protein p53, TP53), and rs10114470 (tumour necrosis factor-like cytokine 1A, TL1A) polymorphisms and the development of inflammatory bowel disease (IBD) in a Chinese (Han) population. We analysed the expression of genes that predispose patients to Crohn’s disease (CD) and ulcerative colitis (UC). Methods: A total of 381 IBD patients and 517 healthy controls were recruited into our study. Polymorphisms at the three loci were genotyped using polymerase chain reaction-ligation detection reactions (PCR-LDR). Genotype-phenotype correlations were analysed. Blood and gut samples were obtained and analysed using quantitative real-time PCR (qRT-PCR), western blot analysis, and immunohistochemistry to investigate the mRNA and protein levels and in situ expression of genes found to predispose patients to IBD. Furthermore, the expression of susceptible genes was further verified using a mouse dextran sulphate sodium (DSS)-induced acute colitis model. Results: No significant association was detected between rs1250569 and rs1042522 genotypes and CD or UC susceptibility. However, the frequency of allele A of rs1250569 was much higher in CD patients than that in healthy controls (55.03% vs. 48.48%, respectively; p = 0.044). The mutation rates at rs10114470 were dramatically lower at both the genotype and allele level in patients than those in healthy controls (p = 0.002 at both the genotype and allele level). Additionally, increased ZMIZ1 and TL1A levels were detected in intestinal samples obtained from both IBD patients and DSS-treated mice. Conclusion: rs1250569 (ZMIZ1) and rs10114470 (TL1A) are two novel loci that indicate susceptibility to IBD in Han-Chinese patients. Consistent with previous studies, TL1A expression levels were higher in Chinese Han IBD patients and DSS-treated mice. Most importantly, we found that ZMIZ1 expression was markedly higher in both IBD patients and mice with experimentally induced colitis, suggesting that ZMIZ1 plays important roles in the pathogenesis of IBD.

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Section: Discussionsupporting

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Identification of Two Additional Susceptibility Loci for Inflammatory Bowel Disease in a Chinese Populationy

Lan¹,

Lan

Chang³

et al. 2017

Cell Physiol Biochem

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“…We next examined the potential associations of type I Paneth cell phenotype with 56 SNPs, selected based on known CD susceptibility associations (3,5,(21)(22)(23)(27)(28)(29) or known association with Paneth cell function (17) (Supplemental Table 3). These SNPs include coding variants for ATG16L1 (T300A) associated with Paneth cell defects in North American CD cohorts and in genetic mouse models (18,19,30).…”

Section: Resultsmentioning

confidence: 99%

“…For genotype-Paneth cell defect correlation, we first adopted a hypothesis-driven approach with selected SNPs (Figure 1). These SNPs include: (a) 45 SNPs shown to have CD-specific susceptibility from an ImmunoChip study examining European ancestry CD (3); (b) an additional 38 SNPs reported in European and East Asian ancestry CD (5); (c) 14 SNPs associated with East Asian (Japanese and/or Korean) CD through GWAS analyses (21,23,28,77) and deep-resequencing analysis (22); and (d) 2 functional CD-associated variants that were either reported to be associated with Paneth cell defect in our previous studies (18,19), or whose genes involved had been implicated to be associated with Paneth cell biology in preclinical studies (17,29). By excluding duplicates, a total of 73 SNPs were compiled as candidates.…”

Section: Methodsmentioning

confidence: 99%

LRRK2 but not ATG16L1 is associated with Paneth cell defect in Japanese Crohn’s disease patients

Liu¹,

Naito²,

Liu³

et al. 2017

JCI Insight

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IntroductionCrohn's disease (CD) and ulcerative colitis are 2 main classical types of inflammatory bowel disease (IBD) (1, 2). The etiology of IBD involves genetic susceptibility and environmental triggers. Over 200 single nucleotide polymorphisms (SNPs) have been associated with susceptibility to IBD (3-7). This complex genetic network indicates that IBD likely encompasses more than the 2 classical subtypes. Therefore, novel, rationally designed biomarkers that can lead to disease stratification and personalized treatments are needed (8). One candidate method to subtype CD is to define the morphological patterns of small intestinal Paneth cells based on the intracellular distribution of granules containing antimicrobial proteins (Paneth cell phenotypes) (7). Paneth cells are specialized secretory cells located at the bases of the crypts of Lieberkühn in the small intestine (9-11). These cells produce a wide repertoire of antimicrobial BACKGROUND. Morphological patterns of Paneth cells are a prognostic biomarker in Western Crohn's disease (CD) patients, and are associated with autophagy-associated ATG16L1 and NOD2 variants. We hypothesized that genetic determinants of Paneth cell phenotype in other ethnic CD cohorts are distinct but also involved in autophagy.

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“…To replicate and fine map risk loci identified in genome-wide association studies (GWAS) of autoimmune and inflammatory disorders such as RA, the Immunochip Consortium designed the Immunochip (iChip), a custom Illumina Infinium high-density array that has been used to study RA in patients of several racial and ethnic backgrounds (4)(5)(6)(7)(8). Using the iChip and many other arrays, 100 RA risk loci of genome-wide significance (p < 5 × 10 -8 ) have been identified in individuals of European and and permanent disability (1).…”

mentioning

confidence: 99%

Dense Genotyping of Immune-Related Regions Identifies Loci for Rheumatoid Arthritis Risk and Damage in African Americans

Danila

Laufer

Reynolds

et al. 2017

Mol Med

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More than 100 risk loci for rheumatoid arthritis (RA) have been identified in individuals of European and Asian descent, but the genetic basis for RA in African Americans is less well understood. We genotyped 610 African Americans with autoantibodypositive RA and 933 African American controls on the Immunochip (iChip) array. Using multivariable regression, we evaluated the association between iChip markers and the risk of RA and radiographic severity. The single nucleotide polymorphism (SNP) rs1964995 (odds ratio = 1.97, p = 1.28 × 10 -15 ) near HLA-DRB1 was the most strongly associated risk SNP for RA susceptibility; SNPs in AFF3, TNFSF11 and TNFSF18 loci were suggestively associated (10 -4 < p < 3.1 × 10 -6). Trans-ethnic fine mapping of AFF3 identified a 90% credible set containing previously studied variants, including rs9653442, rs7608424 and rs6712515, as well as the novel candidate variant rs11681966; several of these likely influence AFF3 gene expression level. Variants in TNFRSF9, CTLA4, IL2RA, C5/TRAF1 and ETS1 -but no variants within the major histocompatibility complex -were associated with RA radiographic severity. Conditional regression and pairwise linkage disequilibrium (LD) analyses suggest that additional pathogenic variants may be found in ETS1 and IL2RA beyond those found in other ethnicities. In summary, we used the dense genotyping of the iChip array and the unique LD structure of African Americans to validate known risk loci for RA susceptibility and radiographic severity, and to better characterize the associations of AFF3, ETS1 and IL2RA.

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Immunochip Analysis Identification of 6 Additional Susceptibility Loci for Crohnʼs Disease in Koreans

Cited by 68 publications

References 35 publications

Identification of Two Additional Susceptibility Loci for Inflammatory Bowel Disease in a Chinese Populationy

Identification of Two Additional Susceptibility Loci for Inflammatory Bowel Disease in a Chinese Populationy

LRRK2 but not ATG16L1 is associated with Paneth cell defect in Japanese Crohn’s disease patients

Dense Genotyping of Immune-Related Regions Identifies Loci for Rheumatoid Arthritis Risk and Damage in African Americans

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