Fucosyltransferase 2 (FUT2) non-secretor status is associated with Crohn's disease

McGovern, Dermot; Jones, Michelle R.; Taylor, Kent D.; Marciante, Kristin D.; Yan, Xiaofei; Dubinsky, Marla C.; Ippoliti, Andy; Vasiliauskas, Eric; Berel, Dror; Derkowski, Carrie; Dutridge, Deb; Fleshner, Phil; Shih, David Q.; Melmed, Gil Y.; Mengesha, Emebet; King, Lily; Pressman, Sheila; Haritunians, Talin; Guo, Xiuqing; Targan, Stephan R.; Rotter, Jerome I.

doi:10.1093/hmg/ddq248

Cited by 335 publications

(281 citation statements)

References 74 publications

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“…These promising results suggest that altered O-glycosylation causes impaired mucus barrier function in a subset of UC patients and may serve as an etiological factor for UC. Notably, only one of the genes regulating glycosylation has been identified as relevant to known IBD loci (2,41). Glycosylation pathways are, however, complex (42), such as the indirect regulation of C1galt1 activity by C1GALT1C1.…”

Section: Discussionmentioning

confidence: 99%

Loss of intestinal core 1–derived O-glycans causes spontaneous colitis in mice

Fu¹,

Wei²,

Wen³

et al. 2011

J. Clin. Invest.

297

294

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Mucin-type O-linked oligosaccharides (O-glycans) are primary components of the intestinal mucins thatform the mucus gel layer overlying the gut epithelium. Impaired expression of intestinal O-glycans has been observed in patients with ulcerative colitis (UC), but its role in the etiology of this disease is unknown. Here, we report that mice with intestinal epithelial cell-specific deficiency of core 1-derived O-glycans, the predominant form of O-glycans, developed spontaneous colitis that resembled human UC, including massive myeloid infiltrates and crypt abscesses. The colitis manifested in these mice was also characterized by TNF-producing myeloid infiltrates in colon mucosa in the absence of lymphocytes, supporting an essential role for myeloid cells in colitis initiation. Furthermore, induced deletion of intestinal core 1-derived O-glycans caused spontaneous colitis in adult mice. These data indicate a causal role for the loss of core 1-derived O-glycans in colitis. Finally, we detected a biosynthetic intermediate typically exposed in the absence of core 1 O-glycan, Tn antigen, in the colon epithelium of a subset of UC patients. Somatic mutations in the X-linked gene that encodes core 1 β1,3-galactosyltransferase-specific chaperone 1 (C1GALT1C1, also known as Cosmc), which is essential for core 1 O-glycosylation, were found in Tn-positive epithelia. These data suggest what we believe to be a new molecular mechanism for the pathogenesis of UC.

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Section: Discussionmentioning

confidence: 99%

Loss of intestinal core 1–derived O-glycans causes spontaneous colitis in mice

Fu¹,

Wei²,

Wen³

et al. 2011

J. Clin. Invest.

297

294

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“…Individuals bearing at least one functional allele are known as "secretors," whereas those homozygous for loss-of-function mutations display a "nonsecretor" phenotype. It was recently shown that nonsecretor status is associated with CD susceptibility (12), and the wealth of information on the population genetics of FUT2 and its role in numerous host-microbe interactions make it an ideal candidate for describing the possible interactions between a genetic susceptibility variant and the endogenous microbiota.…”

mentioning

confidence: 99%

Colonic mucosa-associated microbiota is influenced by an interaction of Crohn disease and FUT2 ( Secretor ) genotype

Rausch

Rehman

Künzel

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

319

277

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The FUT2 (Secretor) gene is responsible for the presence of ABO histo-blood group antigens on the gastrointestinal mucosa and in bodily secretions. Individuals lacking a functional copy of FUT2 are known as “nonsecretors” and display an array of differences in susceptibility to infection and disease, including Crohn disease. To determine whether variation in resident microbial communities with respect to FUT2 genotype is a potential factor contributing to susceptibility, we performed 454-based community profiling of the intestinal microbiota in a panel of healthy subjects and Crohn disease patients and determined their genotype for the primary nonsecretor allele in Caucasian populations, W143X (G428A). Consistent with previous studies, we observe significant deviations in the microbial communities of individuals with Crohn disease. Furthermore, the FUT2 genotype explains substantial differences in community composition, diversity, and structure, and we identified several bacterial species displaying disease-by-genotype associations. These findings indicate that alterations in resident microbial communities may in part explain the variety of host susceptibilities surrounding nonsecretor status and that FUT2 is an important genetic factor influencing host–microbial diversity

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“…The mucus layer, an important component of the innate protective barriers is also affected in CD [65]. Gene loci associated with mucus production (MUC1, MUC19) [30,66], and more specifically to CD, fucosyltransferase (FUT) 2, a gene encoding alpha 1,2 fucosyltransferase, are all implicated [65].…”

Section: Important Gene Loci In CDmentioning

confidence: 99%

“…Gene loci associated with mucus production (MUC1, MUC19) [30,66], and more specifically to CD, fucosyltransferase (FUT) 2, a gene encoding alpha 1,2 fucosyltransferase, are all implicated [65]. FUT2 regulates gastrointestinal mucosal expression of blood group A and B antigens, and 20% of Caucasians are non-secretors.…”

Section: Important Gene Loci In CDmentioning

confidence: 99%

Pathogenesis of Ulcerative Colitis and Crohn’s Disease: Similarities, Differences and a Lot of Things We Do Not Know Yet

Molnár¹

2014

J Clin Cell Immunol

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The pathogenesis of inflammatory bowel diseases (IBD), such as ulcerative colitis (UC) and Crohn's disease (CD) is complex, and our knowledge on the topic is constantly growing. The two disorders are distinct, yet overlap in their clinical manifestations and underlying causes. This review aims to provide a broad overview of the numerous pathogenetic factors that can lead to the development of IBD, focusing on novel findings and on the differences between UC and CD. Recent advances in genetics have identified new components in the pathogenesis, as an example, the importance of Th17 lymphocytes and the IL-17/IL-23 pathway have been highlighted in both diseases, apart from the previously known Th1-Th2 driven processes. Genetic background of increased permeability has been explored in UC, and the role of defective autophagy was recently described in CD. Genetic alterations can lead to an exaggerated immune response to the resident microbial flora. This microflora is altered in IBD patients, probably due to their reduced ability to stabilize its bacterial components and due to different environmental factors. An exhaustive exploration of environmental factors is particularly important, as they can be influential in many cases. The impact of smoking is the most established environmental factor, having deleterious effects in CD and protective in UC. Recent opinions on other factors, such as early appendectomy, diet, reduced vitamin D levels, the use of specific medications, breastfeeding, personal hygiene and psychological factors are also discussed. Epigenetics, a new field of research, links environmental factors to genetics. Understanding these factors is of great significance as changing lifestyles and improving life circumstances have started to increase the prevalence of IBD also in developing countries.

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Fucosyltransferase 2 (FUT2) non-secretor status is associated with Crohn's disease

Cited by 335 publications

References 74 publications

Loss of intestinal core 1–derived O-glycans causes spontaneous colitis in mice

Loss of intestinal core 1–derived O-glycans causes spontaneous colitis in mice

Colonic mucosa-associated microbiota is influenced by an interaction of Crohn disease and FUT2 ( Secretor ) genotype

Pathogenesis of Ulcerative Colitis and Crohn’s Disease: Similarities, Differences and a Lot of Things We Do Not Know Yet

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