Differential Effects of NOD2 Variants on Crohn's Disease Risk and Phenotype in Diverse Populations: A Metaanalysis

Economou, Michael; Trikalinos, Thomas A; Loizou, Konstantinos T.; Tsianos, Epameinondas V.; Ioannidis, John P. A.

doi:10.1111/j.1572-0241.2004.40304.x

Cited by 400 publications

(328 citation statements)

References 63 publications

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“…49 We can speculate that these common alleles with modest effects on gene function are tolerated in the innate immune system and can provide diversity in a population's response to the microbial flora, whereas alleles with stronger effects on function may only be able to survive as rare alleles in a population, a pattern observed with the CARD15 IBD risk alleles that are less common but have strong effects on disease risk. 50 Regardless of the genetic model that can explain these effects, it is clear that determining the functional consequences of these effects and mechanistic link to disease will remain a considerable challenge.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

confidence: 99%

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

et al. 2007

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“…However, as seen with the CTLA-4 risk haplotype in type 1 diabetes, the odds ratio for an autoimmune susceptibility locus can be as low as 1.18 (14), and relatively rare alleles of CARD-15 play an important role in susceptibility to Crohn's disease (for review, see ref. 15). Thus, while we have surveyed a large genomic segment in the vicinity of TLR-9, our study remains limited by its size.…”

Section: Discussionmentioning

confidence: 99%

Genetic variation in toll‐like receptor 9 and susceptibility to systemic lupus erythematosus

Jager¹,

Richardson²,

Vyse³

et al. 2006

Arthritis & Rheumatism

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Objective. Autoantibodies produced by differentiated B cells play an important role in the pathogenesis of systemic lupus erythematosus (SLE). The Toll-like receptor 9 (TLR-9) gene has recently emerged as an important costimulatory molecule for both B cells and dendritic cells that respond to chromatin immune complexes. Genetic variation affecting the function of TLR-9 may therefore increase or decrease the threshold of B cell or dendritic cell activation. This variability in activation threshold may, in turn, affect an individual's susceptibility to SLE. This study assessed the role of genetic variation within the TLR-9 gene in susceptibility to SLE.Methods. We genotyped 362 SLE-affected subject/ parent trios for 10 single-nucleotide polymorphisms (SNPs) covering a 68,742-bp genomic segment that contains the TLR-9 gene and ϳ60 kb of flanking sequence. We analyzed the data using the transmission disequilibrium test.Results. There was no association of susceptibility to SLE with any of the 9 SNPs that generated usable data or the 8 haplotypes found at a frequency of >0.05 in this population. When analyzing the subset of 143 subjects with lupus nephritis, there was also no evidence of association between disease susceptibility and any SNP or haplotype. Conclusion. These results indicate that there is no evidence that common (frequency higher than 5%) alleles of the TLR-9 gene contribute significantly to the genetic risk involved in susceptibility to SLE or lupus nephritis.Toll-like receptor 9 (TLR-9) has recently been implicated in the activation of autoreactive B cells in murine models of systemic lupus erythematosus (SLE) (1-3). Its recognition of CpG nucleotide sequences appears to enhance the activation of B cells via the B cell receptor (1-3). Subsequent studies in humans have shown that dendritic cells are activated by chromatin immune complexes and that this effect is mediated by a cooperation between TLR-9 and Fc␥ receptors (4,5). These observations suggest that genetic variation affecting the costimulatory function of TLR-9 could lead to differences in B cell response to autoantigens and dendritic cell response to chromatin immune complexes. Such genetic variation may have an effect on susceptibility to SLE.At the time of completion of our current experiment, another group presented their observation that 4 polymorphisms within a 4,334-bp segment of the TLR-9 gene demonstrated no significant association with susceptibility to SLE in a Korean population (6). We pursued a more comprehensive approach to assessing the role of genetic variation in the vicinity of TLR-9 by genotyping our collection of 362 SLE-affected subject/parent trios from the United Kingdom with single-nucleotide polymorphisms (SNPs) that tag all haplotypes with Ͼ0.05 frequency within a genomic segment, starting 30 kb upstream and ending 30 kb downDr. De Jager is the William C.

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“…NFkB activation, which is essential for the production of pro-IL-1b, is triggered when NOD2 detects bacterial muramyl dipeptide (Figure 1). Three NOD2 loss-of-function variants (rs2066844, R702W; rs2066845, G908R; rs5743294, L1007fs) that are consistently associated with CD 9 impair the activation of NFkB. 10 The argument for the existence of a synergistic interaction involving NOD2, NALP3 and CARD8 is supported by a recent study, which reported an association of CARD8 with CD only when the rs2043211 genotype was stratified for the presence of a putative gain-of-function SNP (rs35829419; Q705K) in NALP3 and the absence of the NOD2 variants (P ¼ 0.011, odds ratio (OR) ¼ 3.40, 95% confidence interval (CI) (1.32-8.76)).…”

Section: Introductionmentioning

confidence: 99%

Evidence of interaction of CARD8 rs2043211 with NALP3 rs35829419 in Crohn's disease

et al. 2010

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The location of CARD8 within an inflammatory bowel disease (IBD) locus and its role in the NALP3 inflammasome and as a nuclear factor (NF)kB inhibitor make it an attractive candidate risk gene for IBD. However, studies testing for the association of the CARD8 loss-of-function single-nucleotide polymorphism (SNP) rs2043211 with IBD have yielded mixed results. A recent study provided evidence that this discordance may result from an interaction of rs2043211 with loss-offunction variants in nucleotide-binding oligomerization domain protein 2 (NOD2) and a gain-of-function SNP (rs35829419) in NALP3. To confirm this interaction, we conducted a replication in an independent IBD sample set (n ¼ 1009 patients, n ¼ 517 controls). We found that the presence of the minor allele of rs2043211 with the major allele of rs35829419 conferred a protective effect against Crohn's disease (and vice versa), which intensified in the absence of NOD2 mutations (P 1,2/1,1 ¼ 0.009, odds ratio (OR) ¼ 0.66, 95% confidence interval (CI) (0.48-0.90); P 1,1/1,2 ¼ 0.015, OR ¼ 0.35, 95% CI (0.15-0.82)). We propose that these genotype combinations protect against gut inflammation by preventing the NALP3 inflammasome from producing excessive interleukin-1b.

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Differential Effects of NOD2 Variants on Crohn's Disease Risk and Phenotype in Diverse Populations: A Metaanalysis

Abstract: SNP8, SNP12, and SNP13 have differential effects on CD risk, with SNP13 having the strongest genetic effect. These NOD2 variants are also significant risk factors for CD phenotype, in particular ileal location.

Cited by 400 publications

References 63 publications

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

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

Genetic variation in toll‐like receptor 9 and susceptibility to systemic lupus erythematosus

Evidence of interaction of CARD8 rs2043211 with NALP3 rs35829419 in Crohn's disease

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