NOD2/CARD15, TLR4 and CD14 mutations in Scottish and Irish Crohn's disease patients: evidence for genetic heterogeneity within Europe?

Arnott, Ian; Nimmo, Elaine R.; Drummond, Hazel E.; Fennell, Janice; Smith, B; Mackinlay, Eoin; Morecroft, James A.; Anderson, Niall; Kelleher, Dermot; O’Sullivan, Maria; McManus, Ross; Satsangi, Jack

doi:10.1038/sj.gene.6364111

Cited by 183 publications

(162 citation statements)

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“…19 In case-control analysis in Scottish adults and children there was significantly higher mutant allele frequency in CD patients of both 1007-/C and 908G/R but no significant difference in 702R/W frequency between cases and controls. 10,19 This study has further confirmed that there are unlikely to be other NOD2/CARD15 SNPs apart from these two (1007-/C and 908G/R) that significantly contribute to disease susceptibility in our population.…”

Section: Regression Analysis Of CD Susceptibility Genes In Scottish Csupporting

confidence: 80%

“…This is an important finding given the relatively small contribution of the three common NOD2/CARD15 mutations in the Scottish population that has been demonstrated both in children, 19 and adults with CD. 10 Indeed, it would seem on detailed analysis of the SNPs within the candidate genes studied thus far in the Scottish early-onset population that the only significant contribution to disease susceptibility comes from the NOD2/CARD15 1007-/C mutation. In support of this finding, meta-analysis data from two separate studies demonstrate that the 1007-/C mutation made the most significant contribution to increased disease susceptibility.…”

Section: Regression Analysis Of CD Susceptibility Genes In Scottish Cmentioning

confidence: 99%

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Detailed assessment of NOD2/CARD15 exonic variation in inflammatory bowel disease in Scotland: implications for disease pathogenesis

et al. 2008

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The high incidence of Scottish Crohn's disease (CD) is not explained by the common three NOD2/CARD15 variants. We aimed to identify population-specific NOD2/CARD15 coding variants. A total of 1478 (320 inflammatory bowel disease patients o16 years, 343 adult CD patients, 542 parents and 273 controls). All NOD2/CARD15 exons were sequenced in 24 CD patients. Sequencing identified 18 single-nucleotide polymorphisms (SNPs) including 4 non-synonymous coding SNPs altering the structure of the Leucine-rich region-two were well established (1007-/C and 908G/R). Two other variants, valine955isoleucine (955V/I) and methionine863valine (863M/V), were genotyped in all subjects. 863M/V carriage was not significantly higher in CD patients vs controls (1.35 vs 0.37%, P ¼ 0.27). 955V/I carriage was no higher in CD or ulcerative colitis patients (12.8 and 15.8%, respectively) compared to controls (16.2%). Transmission disequilibrium test analysis was negative. 955V/I carriage was higher in indeterminate colitis patients (n ¼ 29) compared to controls (41.4 vs 16.2%, P ¼ 0.001, OR ¼ 3.6 (1.6-8.2)). Population-specific NOD2/CARD15 exonic variants do not account for the high-CD prevalence in Scotland.

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Section: Regression Analysis Of CD Susceptibility Genes In Scottish Csupporting

confidence: 80%

Section: Regression Analysis Of CD Susceptibility Genes In Scottish Cmentioning

confidence: 99%

Detailed assessment of NOD2/CARD15 exonic variation in inflammatory bowel disease in Scotland: implications for disease pathogenesis

et al. 2008

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“…However, regional founder effects may underlie differences even within European populations, as has been suggested for NOD2 and DLG5 (24,25). Furthermore, allele frequencies of NOD2 risk alleles have been reported to vary significantly between European populations (26).…”

Section: Discussionmentioning

confidence: 98%

Association of a CD24 gene polymorphism with susceptibility to systemic lupus erythematosus

Sánchez¹,

Abelson²,

Sabio³

et al. 2007

Arthritis & Rheumatism

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Objective. To determine the potential role of the CD24 A57V gene polymorphism in systemic lupus erythematosus (SLE).Methods. We studied 3 cohorts of Caucasian patients and controls. The Spanish cohort included 696 SLE patients and 539 controls, the German cohort included 257 SLE patients and 317 controls, and the Swedish cohort included 310 SLE patients and 247 controls. The CD24 A57V polymorphism was genotyped by polymerase chain reaction, using a predeveloped TaqMan allele discrimination assay. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated.Results. In the Spanish cohort there was a statistically significant difference in the distribution of the CD24 V allele between SLE patients and controls (OR 3.6 [95% CI 2.13-6.16], P < 0.0001). In addition, frequency of the CD24 V/V genotype was increased in SLE patients compared with controls (OR 3.7 [95% CI 2.16-6.34], P < 0.00001). We sought to replicate this association with SLE in a German population and a Swedish population. A similar trend was found in the German group. The CD24 V/V genotype and the CD24 V allele were more frequent in SLE patients than in controls, although this difference was not statistically significant. No differences were observed in the Swedish group. A meta-analysis of the Spanish and German cohorts demonstrated that the CD24 V allele has a risk effect in SLE patients (pooled OR 1.25 [95% CI 1.08-1.46], P ‫؍‬ 0.003). In addition, homozygosity for the CD24 V risk allele significantly increased the effect (pooled OR 2.19 [95% CI 1.50-3.22], P ‫؍‬ 0.00007).Conclusion. These findings suggest that the CD24 A57V polymorphism plays a role in susceptibility to SLE in a Spanish population.Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with a complex pathogenesis involving multiple genetic and environmental factors. The disease is characterized by enhanced autoantibody production, abnormalities of immune/inflammatory system function, and inflammation in several organs. Al-

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“…24,25 In the first part of our study, we have therefore performed a replication study of these two alleles (NFKB1 94delATTG and TLR4 299Gly ) and extended the analysis to include all published data on these alleles, as individual replication studies have provided inconsistent results. [26][27][28][29][30][31][32][33][34][35] Combining the results in this fashion provides the necessary statistical power to evaluate genetic risk factors of modest effect, such as those observed for multigenic diseases. 36 In the second part of the study, we screened all 23 genes for association with susceptibility to IBD.…”

Section: Introductionmentioning

confidence: 99%

The role of the Toll receptor pathway in susceptibility to inflammatory bowel diseases

et al. 2007

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The intestinal flora has long been thought to play a role either in initiating or in exacerbating the inflammatory bowel diseases (IBD). Host defenses, such as those mediated by the Toll-like receptors (TLR), are critical to the host/pathogen interaction and have been implicated in IBD pathophysiology. To explore the association of genetic variation in TLR pathways with susceptibility to IBD, we performed a replication study and pooled analyses of the putative IBD risk alleles in NFKB1 and TLR4, and we performed a haplotype-based screen for association to IBD in the TLR genes and a selection of their adaptor and signaling molecules. Our genotyping of 1539 cases of IBD and pooled analysis of 4805 cases of IBD validates the published association of a TLR4 allele with risk of IBD (odds ratio (OR): 1.30, 95% confidence interval (CI): 1.15-1.48; P ¼ 0.00017) and Crohn's disease (OR: 1.33, 95% CI: 1.16-1.54; P ¼ 0.000035) but not ulcerative colitis. We also describe novel suggestive evidence that TIRAP (OR: 1.16, 95% CI: 1.04-1.30; P ¼ 0.007) has a modest effect on risk of IBD. Our analysis, therefore, offers additional evidence that the TLR4 pathway -in this case, TLR4 and its signaling molecule TIRAP -plays a role in susceptibility to IBD.

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NOD2/CARD15, TLR4 and CD14 mutations in Scottish and Irish Crohn's disease patients: evidence for genetic heterogeneity within Europe?

Cited by 183 publications

References 50 publications

Detailed assessment of NOD2/CARD15 exonic variation in inflammatory bowel disease in Scotland: implications for disease pathogenesis

Detailed assessment of NOD2/CARD15 exonic variation in inflammatory bowel disease in Scotland: implications for disease pathogenesis

Association of a CD24 gene polymorphism with susceptibility to systemic lupus erythematosus

The role of the Toll receptor pathway in susceptibility to inflammatory bowel diseases

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