A risk haplotype in the Solute Carrier Family 22A4/22A5 gene cluster influences phenotypic expression of Crohn’s disease

Newman, William G.; Gu, Xiangjun; Wintle, Richard F.; Cescon, David W.; Yazdanpanah, Mehrdad; Liu, Xiangdong; Peltekova, Vanya; Oene, Mark Van; Amos, Christopher I.; Siminovitch, Katherine A.

doi:10.1053/j.gastro.2004.11.056

Cited by 118 publications

(83 citation statements)

References 37 publications

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“…Also, in individuals who were negative for the IBD5 risk haplotype, we did not find a significantly increased frequency of the L503F-G-207C TC haplotype in CD cases versus controls. Our findings are consistent with several very recent studies of the contribution of these variants to CD susceptibility, [13][14][15] that do not support a causal role for these variants and are not consistent with the findings of Peltekova et al 12,25 Taken together, the weight of current evidence suggests that despite the effect of the L503F and G-207C variants on the function of the cation transporters OCTN1 and OCTN2, 12 they are unlikely to have a direct causal role in the pathogenesis of CD.…”

Section: Discussionsupporting

confidence: 86%

Sequence variation, linkage disequilibrium and association with Crohn's disease on chromosome 5q31

et al. 2006

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Chromosome 5q31 contains a cluster of genes involved in immune response, including a 250 kb risk haplotype associated with Crohn's disease (CD) susceptibility. Recently, two functional variants in , encoding the cation transporters OCTN1 and OCTN2, were proposed as causal variants for CD, but with conflicting genetic evidence regarding their contribution. We investigated this locus by resequencing the coding regions of 10 genes in 24 CD cases and deriving a linkage disequilibrium (LD) map of the 27 single nucleotide polymorphisms (SNPs) detected. Ten SNPs representative of the LD groups observed, were tested for CD association. L503F in SLC22A4 was the only nonsynonymous SNP significantly associated with CD (P ¼ 0.003), but was not associated with disease in the absence of other markers of the 250 kb risk haplotype. Two other SNPs, rs11242115 in IRF1 and rs17166050 in RAD50, lying outside the 250 kb risk haplotype, also showed CD association (P ¼ 0.019 and P ¼ 0.0080, respectively). The RAD50 gene contains a locus control region regulating expression of the Th2 cytokine genes at this locus. Other as yet undiscovered SNPs in this region may therefore modulate gene expression and contribute to the risk of CD, and perhaps of other inflammatory phenotypes.

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Section: Discussionsupporting

confidence: 86%

Sequence variation, linkage disequilibrium and association with Crohn's disease on chromosome 5q31

et al. 2006

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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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“…Although the aetiology of these diseases is not fully understood, there is strong support for a genetic component based on findings of familial aggregation, higher concordance in monozygotic twins and ethnic differences in disease prevalence. 1,2 To date, different genetic studies have shown several genes playing a relevant role in these diseases, including NOD2/CARD15, 3 DGL5, 4 SLC22A4 and SLC22A5, 5,6 TNFSF15, 7,8 NOD1/CARD4 7 and IL23R. 9,10 NOD2/CARD15 is likely to be the major genetic factor contributing to CD.…”

Section: Introductionmentioning

confidence: 99%

Association of ATG16L1 and IRGM genes polymorphisms with inflammatory bowel disease: a meta-analysis approach

et al. 2009

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The aim of this study was to determine the role of the ATG16L1 (rs2241880) and IRGM (rs13361189 and rs4958847) genes polymorphism in Crohn's disease (CD) and ulcerative colitis (UC). Our study included 557 CD and 425 UC patients and 672 ethnically matched Spanish controls and a meta-analysis with the data published to date. The polymorphisms were genotyped using predesigned TaqMan single nucleotide polymorphism genotyping assays. There was a statistically significant difference in the distribution of the ATG16L1 rs2241880 G allele between CD patients and controls in the Spanish population: P ¼ 6.5 Â 10 À9 , odds ratio (OR) ¼ 1.62. Although no differences were observed between UC patients and controls in the Spanish cohort, a meta-analysis demonstrated that the ATG16L1 G allele increase significantly risk for UC (P ¼ 0.0003, pooled OR ¼ 1.08). In addition, our meta-analysis data showed that IRGM rs13361189 and rs4958847 polymorphisms were associated with CD (rs13361189 C allele P ¼ 1.07 Â 10 À19 , pooled OR ¼ 1.34; rs4958847 A allele P ¼ 2.78 Â 10 À17 , pooled OR ¼ 1.31) and UC (rs13361189 P ¼ 0.0069, pooled OR ¼ 1.16; rs4958847 P ¼ 0.014, pooled OR ¼ 1.13). In conclusion, our results confirm the ATG16L1 rs2241880 and IRGM rs13361189 and rs4958847 polymorphisms as important markers for CD susceptibility and indicate that these variants are also associated with UC.

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A risk haplotype in the Solute Carrier Family 22A4/22A5 gene cluster influences phenotypic expression of Crohn’s disease

Cited by 118 publications

References 37 publications

Sequence variation, linkage disequilibrium and association with Crohn's disease on chromosome 5q31

Sequence variation, linkage disequilibrium and association with Crohn's disease on chromosome 5q31

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

Association of ATG16L1 and IRGM genes polymorphisms with inflammatory bowel disease: a meta-analysis approach

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