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Exome sequencing identifies DLG1 as a novel gene for potential susceptibility to Crohn's disease in a Chinese family study.

Xu S, Zhou F, Tao J, Song L, Ng SC, Wang X, Chen L, Yi F, Ran Z, Zhou R, Xia B - PLoS ONE (2014)

Bottom Line: More than 100 susceptibility loci were identified in Western IBD studies, but susceptibility gene has not been found in Chinese IBD patients till now.After genotyping among case and controls, a PLINK analysis showed the variant was of significance (P<0.05). 4 CD patients of the other Chinese family bore another non-synonymous variant c.833G>A (p.R278Q) in exon 9 of DLG1.We have discovered novel genetic variants in the coding regions of DLG1 gene, the results support that DLG1 is a novel potential susceptibility gene for CD in Chinese patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology, Zhongnan Hospital of Wuhan University School of Medicine, Wuhan, People's Republic of China.

ABSTRACT

Background: Genetic variants make some contributions to inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). More than 100 susceptibility loci were identified in Western IBD studies, but susceptibility gene has not been found in Chinese IBD patients till now. Sequencing of individuals with an IBD family history is a powerful approach toward our understanding of the genetics and pathogenesis of IBD. The aim of this study, which focuses on a Han Chinese CD family, is to identify high-risk variants and potentially novel loci using whole exome sequencing technique.

Methods: Exome sequence data from 4 individuals belonging to a same family were analyzed using bioinformatics methods to narrow down the variants associated with CD. The potential risk genes were further analyzed by genotyping and Sanger sequencing in family members, additional 401 healthy controls (HC), 278 sporadic CD patients, 123 UC cases, a pair of monozygotic CD twins and another Chinese CD family.

Results: From the CD family in which the father and daughter were affected, we identified a novel single nucleotide variant (SNV) c.374T>C (p.I125T) in exon 4 of discs large homolog 1 (DLG1), a gene has been reported to play multiple roles in cell proliferation, T cell polarity and T cell receptor signaling. After genotyping among case and controls, a PLINK analysis showed the variant was of significance (P<0.05). 4 CD patients of the other Chinese family bore another non-synonymous variant c.833G>A (p.R278Q) in exon 9 of DLG1.

Conclusions: We have discovered novel genetic variants in the coding regions of DLG1 gene, the results support that DLG1 is a novel potential susceptibility gene for CD in Chinese patients.

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Related in: MedlinePlus

Clinical characteristics of two patients in Chinese CD family A.The index patient in the family, the father (Panels A to D) had evidence of mucous membrane granulation, polypoid proliferation and hyperemia in his colonoscopy, as shown in Panels A and B. Panel C shows the patient’s pathological findings of chronic intestinal inflammation. Panel D shows the thickening of the ileum wall by small intestine computed tomography enterography (CTE). The daughter in the family is another Patient (Panels E to H). Panel E shows her anal fistula at disease onset. Endoscopy showed intestinal poly-ulcers in Panel F. A biopsy showed non-specific granulomatous inflammation, as shown in Panel G, and the higher magnification of the pathology shown in Panel H reveals negative acid-fast staining granulomas. All of the images were collected in March 2012 in Zhongnan Hospital of Wuhan University.
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pone-0099807-g001: Clinical characteristics of two patients in Chinese CD family A.The index patient in the family, the father (Panels A to D) had evidence of mucous membrane granulation, polypoid proliferation and hyperemia in his colonoscopy, as shown in Panels A and B. Panel C shows the patient’s pathological findings of chronic intestinal inflammation. Panel D shows the thickening of the ileum wall by small intestine computed tomography enterography (CTE). The daughter in the family is another Patient (Panels E to H). Panel E shows her anal fistula at disease onset. Endoscopy showed intestinal poly-ulcers in Panel F. A biopsy showed non-specific granulomatous inflammation, as shown in Panel G, and the higher magnification of the pathology shown in Panel H reveals negative acid-fast staining granulomas. All of the images were collected in March 2012 in Zhongnan Hospital of Wuhan University.

Mentions: The affected daughter developed CD at the age of 16 years in 2012, with high fever, diarrhea, oral ulcers and an anal fistula. Endoscopy showed upper digestive tract ulcers, aphthous ulcers at the ileocecal junction and colitis involving the rectum, sigmoid colon, descending colon and transverse colon. A biopsy showed non-specific granulomatous inflammation and staining was negative for acid-fast bacilli. She was finally diagnosed with CD and was treated with an intravenous injection of corticosteroids, 5-ASA, immunosuppressants and infliximab for severe refractory disease. She is now in remission with azathioprine and 5-ASA (the supporting data are provided in Fig. 1).


Exome sequencing identifies DLG1 as a novel gene for potential susceptibility to Crohn's disease in a Chinese family study.

Xu S, Zhou F, Tao J, Song L, Ng SC, Wang X, Chen L, Yi F, Ran Z, Zhou R, Xia B - PLoS ONE (2014)

Clinical characteristics of two patients in Chinese CD family A.The index patient in the family, the father (Panels A to D) had evidence of mucous membrane granulation, polypoid proliferation and hyperemia in his colonoscopy, as shown in Panels A and B. Panel C shows the patient’s pathological findings of chronic intestinal inflammation. Panel D shows the thickening of the ileum wall by small intestine computed tomography enterography (CTE). The daughter in the family is another Patient (Panels E to H). Panel E shows her anal fistula at disease onset. Endoscopy showed intestinal poly-ulcers in Panel F. A biopsy showed non-specific granulomatous inflammation, as shown in Panel G, and the higher magnification of the pathology shown in Panel H reveals negative acid-fast staining granulomas. All of the images were collected in March 2012 in Zhongnan Hospital of Wuhan University.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4061034&req=5

pone-0099807-g001: Clinical characteristics of two patients in Chinese CD family A.The index patient in the family, the father (Panels A to D) had evidence of mucous membrane granulation, polypoid proliferation and hyperemia in his colonoscopy, as shown in Panels A and B. Panel C shows the patient’s pathological findings of chronic intestinal inflammation. Panel D shows the thickening of the ileum wall by small intestine computed tomography enterography (CTE). The daughter in the family is another Patient (Panels E to H). Panel E shows her anal fistula at disease onset. Endoscopy showed intestinal poly-ulcers in Panel F. A biopsy showed non-specific granulomatous inflammation, as shown in Panel G, and the higher magnification of the pathology shown in Panel H reveals negative acid-fast staining granulomas. All of the images were collected in March 2012 in Zhongnan Hospital of Wuhan University.
Mentions: The affected daughter developed CD at the age of 16 years in 2012, with high fever, diarrhea, oral ulcers and an anal fistula. Endoscopy showed upper digestive tract ulcers, aphthous ulcers at the ileocecal junction and colitis involving the rectum, sigmoid colon, descending colon and transverse colon. A biopsy showed non-specific granulomatous inflammation and staining was negative for acid-fast bacilli. She was finally diagnosed with CD and was treated with an intravenous injection of corticosteroids, 5-ASA, immunosuppressants and infliximab for severe refractory disease. She is now in remission with azathioprine and 5-ASA (the supporting data are provided in Fig. 1).

Bottom Line: More than 100 susceptibility loci were identified in Western IBD studies, but susceptibility gene has not been found in Chinese IBD patients till now.After genotyping among case and controls, a PLINK analysis showed the variant was of significance (P<0.05). 4 CD patients of the other Chinese family bore another non-synonymous variant c.833G>A (p.R278Q) in exon 9 of DLG1.We have discovered novel genetic variants in the coding regions of DLG1 gene, the results support that DLG1 is a novel potential susceptibility gene for CD in Chinese patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology, Zhongnan Hospital of Wuhan University School of Medicine, Wuhan, People's Republic of China.

ABSTRACT

Background: Genetic variants make some contributions to inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). More than 100 susceptibility loci were identified in Western IBD studies, but susceptibility gene has not been found in Chinese IBD patients till now. Sequencing of individuals with an IBD family history is a powerful approach toward our understanding of the genetics and pathogenesis of IBD. The aim of this study, which focuses on a Han Chinese CD family, is to identify high-risk variants and potentially novel loci using whole exome sequencing technique.

Methods: Exome sequence data from 4 individuals belonging to a same family were analyzed using bioinformatics methods to narrow down the variants associated with CD. The potential risk genes were further analyzed by genotyping and Sanger sequencing in family members, additional 401 healthy controls (HC), 278 sporadic CD patients, 123 UC cases, a pair of monozygotic CD twins and another Chinese CD family.

Results: From the CD family in which the father and daughter were affected, we identified a novel single nucleotide variant (SNV) c.374T>C (p.I125T) in exon 4 of discs large homolog 1 (DLG1), a gene has been reported to play multiple roles in cell proliferation, T cell polarity and T cell receptor signaling. After genotyping among case and controls, a PLINK analysis showed the variant was of significance (P<0.05). 4 CD patients of the other Chinese family bore another non-synonymous variant c.833G>A (p.R278Q) in exon 9 of DLG1.

Conclusions: We have discovered novel genetic variants in the coding regions of DLG1 gene, the results support that DLG1 is a novel potential susceptibility gene for CD in Chinese patients.

Show MeSH
Related in: MedlinePlus