Genetic variation in IBD: progress, clues to pathogenesis and possible clinical utility

Ye, Byong Duk; McGovern, Dermot P.

doi:10.1080/1744666x.2016.1184972

Cited by 77 publications

(52 citation statements)

References 164 publications

(279 reference statements)

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“…31 However, as discussed above, not all variants affect NUDT15 enzymatic function to the same extent and the magnitude of the deleterious effect of individual variants may differ across ethnic groups. 37 Furthermore, it is unknown whether such a marked dose reduction would compromise the therapeutic effect of thiopurines in patients with IBD. In our study of patients of non-Finnish European ancestry, almost 50% of patients with a single variant did not tolerate a rechallenge with thiopurine at a lower dose.…”

Section: Limitationsmentioning

confidence: 99%

Association of Genetic Variants in NUDT15 With Thiopurine-Induced Myelosuppression in Patients With Inflammatory Bowel Disease

Walker¹,

Harrison²,

Heap³

et al. 2019

JAMA

140

129

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IMPORTANCEUse of thiopurines may be limited by myelosuppression. TPMT pharmacogenetic testing identifies only 25% of at-risk patients of European ancestry. Among patients of East Asian ancestry, NUDT15 variants are associated with thiopurine-induced myelosuppression (TIM).OBJECTIVE To identify genetic variants associated with TIM among patients of European ancestry with inflammatory bowel disease (IBD). DESIGN, SETTING, AND PARTICIPANTSCase-control study of 491 patients affected by TIM and 679 thiopurine-tolerant unaffected patients who were recruited from 89 international sites between March 2012 and November 2015. Genome-wide association studies (GWAS) and exome-wide association studies (EWAS) were conducted in patients of European ancestry. The replication cohort comprised 73 patients affected by TIM and 840 thiopurine-tolerant unaffected patients. EXPOSURES Genetic variants associated with TIM.MAIN OUTCOMES AND MEASURES Thiopurine-induced myelosuppression, defined as a decline in absolute white blood cell count to 2.5 × 10 9 /L or less or a decline in absolute neutrophil cell count to 1.0 × 10 9 /L or less leading to a dose reduction or drug withdrawal. RESULTS Among 1077 patients (398 affected and 679 unaffected; median age at IBD diagnosis, 31.0 years [interquartile range, 21.2 to 44.1 years]; 540 [50%] women; 602 [56%] diagnosed as having Crohn disease), 919 (311 affected and 608 unaffected) were included in the GWAS analysis and 961 (328 affected and 633 unaffected) in the EWAS analysis. The GWAS analysis confirmed association of TPMT (chromosome 6, rs11969064) with TIM (30.5% [95/311] affected vs 16.4% [100/608] unaffected patients; odds ratio [OR], 2.3 [95% CI, 1.7 to 3.1], P = 5.2 × 10 −9 ). The EWAS analysis demonstrated an association with an in-frame deletion in NUDT15 (chromosome 13, rs746071566) and TIM (5.8% [19/328] affected vs 0.2% [1/633] unaffected patients; OR, 38.2 [95% CI, 5.1 to 286.1], P = 1.3 × 10 −8 ), which was replicated in a different cohort (2.7% [2/73] affected vs 0.2% [2/840] unaffected patients; OR, 11.8 [95% CI, 1.6 to 85.0], P = .03). Carriage of any of 3 coding NUDT15 variants was associated with an increased risk (OR, 27.3 [95% CI, 9.3 to 116.7], P = 1.1 × 10 −7 ) of TIM, independent of TPMT genotype and thiopurine dose.CONCLUSIONS AND RELEVANCE Among patients of European ancestry with IBD, variants in NUDT15 were associated with increased risk of TIM. These findings suggest that NUDT15 genotyping may be considered prior to initiation of thiopurine therapy; however, further study including additional validation in independent cohorts is required.

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Section: Limitationsmentioning

confidence: 99%

Association of Genetic Variants in NUDT15 With Thiopurine-Induced Myelosuppression in Patients With Inflammatory Bowel Disease

Walker¹,

Harrison²,

Heap³

et al. 2019

JAMA

140

129

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“…Furthermore, a complete makeup of the host genetics involved in UC is still not well characterized but significant research progress in the last decade has led to the identification of specific gene loci associated with disease predisposition. Prominent findings demonstrate a role for genes involved in innate responses such as nucleotide oligomerization domain 2 (NOD2) and autophagic regulator ATG16 as well as adaptive immune components of helper-T-cell types such as interleukin (IL)-10, IL-13, IL-17 and IL-23 (Liu and Stappenbeck, 2016; Ye and McGovern, 2016). Smoking, diet, infection, antibiotics and hygiene as well as other environmental factors may also contribute to UC pathogenesis by altering the gut microbiome and subsequently intestinal homeostasis (Basson et al, 2016; Zeng et al, 2016).…”

Section: Pathophysiology Of Ulcerative Colitismentioning

confidence: 99%

Sphingolipids in neutrophil function and inflammatory responses: Mechanisms and implications for intestinal immunity and inflammation in ulcerative colitis

Espaillat

Kew

Obeid

2017

Advances in Biological Regulation

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Bioactive sphingolipids are regulators of immune cell function and play critical roles in inflammatory conditions including ulcerative colitis. As one of the major forms of inflammatory bowel disease, ulcerative colitis pathophysiology is characterized by an aberrant intestinal inflammatory response that persists causing chronic inflammation and tissue injury. Innate immune cells play an integral role in normal intestinal homeostasis but their dysregulation is thought to contribute to the pathogenesis of ulcerative colitis. In particular, neutrophils are key effector cells and are first line defenders against invading pathogens. While the activity of neutrophils in the intestinal mucosa is required for homeostasis, regulatory mechanisms are equally important to prevent unnecessary activation. In ulcerative colitis, unregulated neutrophil inflammatory mechanisms promote tissue injury and loss of homeostasis. Aberrant neutrophil function represents an early checkpoint in the detrimental cycle of chronic intestinal inflammation; thus, dissecting the mechanisms by which these cells are regulated both before and during disease is essential for understanding the pathogenesis of ulcerative colitis. We present an analysis of the role of sphingolipids in the regulation of neutrophil function and the implication of this relationship in ulcerative colitis.

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“…10,20,21 Although these studies confirm that RHBDF2 plays a significant role in both autoimmune diseases and that RHBDF2 is involved in TNF-dependent septic shock, the role of RHBDF2 in IBD has only been perfunctorily explored. 22 Dysfunction of IL10 signaling is associated with early-onset IBD, 23 and polymorphisms at the IL10 locus are associated with heightened risk of the development of both ulcerative colitis and Crohn's disease. 24,25 In mice with targeted deletion of IL10, lymphocyte development and antibody production remain unaffected; however, most mice suffer from chronic enterocolitis due to mucosal hyperplasia, inflammation, and aberrant expression of major histocompatibility complex class II expressed upon epithelial cells.…”

Section: Introductionmentioning

confidence: 99%

Loss of RHBDF2 results in an early-onset spontaneous murine colitis

Geesala

Schanz

Biggs

et al. 2019

Journal of Leukocyte Biology

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Inflammatory bowel disease (IBD) is a heterogeneous group of inflammation‐mediated pathologies that include Crohn's disease and ulcerative colitis and primarily affects the colon and small intestine. Previous studies have shown that a disintegrin and metalloprotease (ADAM) 17, a membrane‐bound sheddase, capable of cleaving the proinflammatory cytokine TNF and epidermal growth factor receptor ligands, plays a critical role in maintaining gut homeostasis and modulating intestinal inflammation during IBD. Rhomboid 5 homolog 2 (RHBDF2), a catalytically inactive member of the rhomboid family of intramembrane serine proteases, was recently identified as a crucial regulator of ADAM17. Here, we assessed the role of RHBDF2 in the development of colitis in the context of IL10 deficiency. Il10−/−/Rhbdf2−/− mice developed spontaneous colitis and experienced severe weight loss starting at 8 wk of age, without the need for exogenous triggers. Severity of disease pathology in Il10−/−/Rhbdf2−/− mice correlated with a dysbiotic gut microbiota and elevated Th1‐associated immune responses with increased interferon gamma and IL2 production. In addition, Il10−/−/Rhbdf2−/− mice failed to maintain their epithelial cell homeostasis, although the intestinal epithelial barrier of Rhbdf2−/− mice is intact and loss of Rhbdf2 did not significantly exacerbate sensitivity to dextran sulfate sodium‐induced colitis, suggesting differences in the underlying disease pathway of intestinal inflammation in this model. Taken together, our results demonstrate a critical regulatory role for RHBDF2 in the maintenance of the unique homeostasis between intestinal microbiota and host immune responses in the gut that is dysregulated during the pathogenesis of IBD.

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Genetic variation in IBD: progress, clues to pathogenesis and possible clinical utility

Cited by 77 publications

References 164 publications

Association of Genetic Variants in NUDT15 With Thiopurine-Induced Myelosuppression in Patients With Inflammatory Bowel Disease

Association of Genetic Variants in NUDT15 With Thiopurine-Induced Myelosuppression in Patients With Inflammatory Bowel Disease

Sphingolipids in neutrophil function and inflammatory responses: Mechanisms and implications for intestinal immunity and inflammation in ulcerative colitis

Loss of RHBDF2 results in an early-onset spontaneous murine colitis

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