Relationship Between CARD15, SLC22A4/5, and DLG5 Polymorphisms and Early-Onset Inflammatory Bowel Diseases

Ferraris, Alessandro; Torres, Bárbara; Knafelz, D.; Barabino, A.; Lionetti, Paolo; Angelis, Gian Luigi De’; Iacono, Giuseppe; Papadatou, B.; D'Amato, Giovanna; Ciommo, Vincenzo Di; Dallapiccola, Bruno; Castro, M.

doi:10.1097/01.mib.0000217338.23065.58

Cited by 42 publications

(31 citation statements)

References 47 publications

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“…The L503F variant of SLC22A4 is more frequent in white persons from New Zealand who have Crohn's disease (Leung et al, 2006) (Table 18). Moreover, the L503F variant of SLC22A4 and the Ϫ207GϽC variant of SLC22A5 are found in adult Greek, British, and German patients with Crohn's disease, but not Italian or Hungarian patients (Gazouli et al, 2005;Török et al, 2005;Ferraris et al, 2006;Waller et al, 2006;Magyari et al, 2007;Taubert et al, 2009). Likewise, the genotype and haplotype frequencies of both of these variants are also increased in patients with ulcerative colitis .…”

Section: Apical Uptake Transporters In the Intestinementioning

confidence: 84%

Xenobiotic, Bile Acid, and Cholesterol Transporters: Function and Regulation

2010

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Section: Apical Uptake Transporters In the Intestinementioning

confidence: 84%

Xenobiotic, Bile Acid, and Cholesterol Transporters: Function and Regulation

2010

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“…The association of the R30Q variant with IBD has been supported in some studies [12,24,25,27], but failed to be replicated in others [28][29][30][31][32][33][34].…”

Section: Discussionmentioning

confidence: 96%

“…Friedrichs et al, found a male-specific association of the R30Q variant with CD, with no association of the R30Q variant with women, nor with the entire sample of men and women [27]. However, the association of the R30Q variant with IBD failed to be replicated by several other groups with samples from several different countries, including Germany, Scotland, Belgium, and Hungary [28][29][30][31][32][33][34][35][36]. A US based population of IBD patients has been also studied [17,37].…”

Section: Introductionmentioning

confidence: 99%

Genetic Association of DLG5 R30Q with Familial and Sporadic Inflammatory Bowel Disease in Men

et al. 2009

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Abstract. Background:The association of DLG5 R30Q with IBD has been replicated in several populations, but is not statistically significant in others. We studied the incidence of DLG5 alleles in a population of IBD patients from Pennsylvania. Methods: DLG5 R30Q (rs1248696) and G1066G (rs1248634) were analyzed with PCR-based RFLP methods in a total of 521 subjects, that included 105 individuals with IBD and 139 without IBD from a familial IBD registry, 107 with sporadic IBD, and 170 unrelated healthy controls. R30Q was further analyzed with SNPlex TM Genotyping System in 473 samples. Results: RFLP genotyping data showed that, DLG5 R30Q was significantly associated with IBD overall (p = 0.006), and separately with CD (p = 0.009) and UC (p = 0.024). The association of R30Q with IBD was entirely due to a male-associated effect (male vs female p = 0.015 vs 0.241 (IBD), p = 0.024 vs 0.190 (CD), and p = 0.019 vs 0.575 (UC)). The frequency of the A allele carriage was elevated in both affected and unaffected members in the familial IBD cohort compared to healthy controls (p = 0.037). In the family pedigrees, we observed differences in the expression of IBD in individuals carrying the A allele between families. Conclusions: In the studied population, DLG5 R30Q was associated with all forms of IBD. An elevated presence of the R30Q variant was observed in all members of a familial IBD registry. This association of the R30Q variant with IBD was male-specific.

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“…These studies included diverse populations and originated from Canada [6,13,14], the UK [15][16][17][18], Germany [19], New Zealand [20], Spain [21], Italy [22,23], Belgium [24], Greece [25], Sweden [26] and Japan [27,28]. One Japanese and another Hungarian study with a small number of subjects found no association between OCTN 1&2 transporter polymorphisms and CD [28,29]; thus there could be ethnic differences in IBD5 locus mutations and propensity for Crohn's disease [7].…”

Section: Discussionmentioning

confidence: 99%

Spontaneous development of intestinal and colonic atrophy and inflammation in the carnitine-deficient jvs (OCTN2−/−) mice

Shekhawat

Srinivas

Matern

et al. 2007

Molecular Genetics and Metabolism

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Carnitine is essential for transport of long-chain fatty acids into mitochondria for their subsequent β-oxidation, but its role in the gastrointestinal tract has not been well described. Recently several genetic epidemiologic studies have shown strong association between mutations in carnitine transporter genes OCTN1 and OCTN2 and a propensity to develop Crohn's disease. This study aims to investigate role of carnitine and β-oxidation in the GI tract. We have studied the gastrointestinal tract effects of carnitine deficiency in a mouse model with loss-of-function mutation in the OCTN2 carnitine transporter. juvenile visceral steatosis (OCTN2 -/-) mouse spontaneously develops intestinal villous atrophy, breakdown and inflammation with intense lymphocytic and macrophage infiltration, leading to ulcer formation and gut perforation. There is increased apoptosis of jvs (OCTN2 -/-) gut epithelial cells. We observed an up-regulation of heat shock factor-1 (HSF-1) and several heat shock proteins (HSPs) which are known to regulate OCTN2 gene expression. Intestinal and colonic epithelial cells in wild type mice showed high expression and activity of the enzymes of β-oxidation pathway. These studies provide evidence of an obligatory role for carnitine in the maintenance of normal intestinal and colonic structure and morphology. Fatty acid oxidation, a metabolic pathway regulated by carnitine-dependent entry of long-chain fatty acids into mitochondrial matrix, is likely essential for normal gut function. Our studies suggest that carnitine supplementation, as a means of boosting fatty acid oxidation, may be therapeutically beneficial in patients with inflammation of the intestinal tract.

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Relationship Between CARD15, SLC22A4/5, and DLG5 Polymorphisms and Early-Onset Inflammatory Bowel Diseases

Abstract: Our results demonstrate that in the Italian population, the major CARD15 polymorphisms are associated with susceptibility to early-onset CD and with ileal involvement and suggest a previously unreported association with very early-onset, severe UC.

Cited by 42 publications

References 47 publications

Xenobiotic, Bile Acid, and Cholesterol Transporters: Function and Regulation

Xenobiotic, Bile Acid, and Cholesterol Transporters: Function and Regulation

Genetic Association of DLG5 R30Q with Familial and Sporadic Inflammatory Bowel Disease in Men

Spontaneous development of intestinal and colonic atrophy and inflammation in the carnitine-deficient jvs (OCTN2−/−) mice

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