Evolution of Crohn’s disease-associated Nod2 mutations

Gasché, Christoph; Nemeth, Manuela; Grundtner, P; Willheim-Polli, Claudia; Ferenci, Péter; Schwarzenbacher, Robert

doi:10.1007/s00251-008-0274-6

Cited by 27 publications

(19 citation statements)

References 32 publications

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“…A number of genes may have coevolved with LP. For example, HLA types, leading to immune signaling,95 and the NOD2/CARD15 system are hypothesized to have evolved in response to drinking milk and the threat of infection 96. Interestingly, genetic mutations in the NOD2 system, which are associated mainly with terminal ileal CD, are largely confined to Caucasians.…”

Section: Discussionmentioning

confidence: 99%

Latitude, sunshine, and human lactase phenotype distributions may contribute to geographic patterns of modern disease: the inflammatory bowel disease model

Szilagyi¹,

Leighton²,

Burstein³

et al. 2014

CLEP

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Countries with high lactase nonpersistence (LNP) or low lactase persistence (LP) populations have lower rates of some “western” diseases, mimicking the effects of sunshine and latitude. Inflammatory bowel disease (IBD), ie, Crohn’s disease and ulcerative colitis, is putatively also influenced by sunshine. Recent availability of worldwide IBD rates and lactase distributions allows more extensive comparisons. The aim of this study was to evaluate the extent to which modern day lactase distributions interact with latitude, sunshine exposure, and IBD rates. National IBD rates, national distributions of LP/LNP, and population-weighted average national annual ultraviolet B exposure were obtained, estimated, or calculated from the literature. Negative binomial analysis was used to assess the relationship between the three parameters and IBD rates. Analyses for 55 countries were grouped in three geographic domains, ie, global, Europe, and non-Europe. In Europe, both latitude and ultraviolet B exposure correlate well with LP/LNP and IBD. In non-Europe, latitude and ultraviolet B exposure correlate weakly with LP/LNP, but the latter retains a more robust correlation with IBD. In univariate analysis, latitude, ultraviolet B exposure, and LP/LNP all had significant relationships with IBD. Multivariate analysis showed that lactase distributions provided the best model of fit for IBD. The model of IBD reveals the evolutionary effects of the human lactase divide, and suggests that latitude, ultraviolet B exposure, and LP/LNP mimic each other because LP/LNP follows latitudinal directions toward the equator. However, on a large scale, lactase patterns also follow lateral polarity. The effects of LP/LNP in disease are likely to involve complex interactions.

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Section: Discussionmentioning

confidence: 99%

Latitude, sunshine, and human lactase phenotype distributions may contribute to geographic patterns of modern disease: the inflammatory bowel disease model

Szilagyi¹,

Leighton²,

Burstein³

et al. 2014

CLEP

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“…Gasche et al recently genotyped the three NOD2 mutations in DNA from 7 sub-Saharan African populations (including 25 Yorubans) and did not identify any NOD2 mutations, including Leu1007fsinsC. (46). In a study of 3,575 healthy whites from around the world, NOD2 allele frequency was 7.8% (45).…”

Section: Discussionmentioning

confidence: 99%

“…European-African admixture among AA population has been considered as a continual process over four centuries, and the presence of NOD2 mutations may be affected by survival advantages and disadvantages. For example, NOD2 mutations may produce a survival advantage to exposure to certain infectious pathogens (46, 47). The 1.1% allele frequency we observed among AA controls is lower but within error of that expected from the 20% overall white admixture in AAs.…”

Section: Discussionmentioning

confidence: 99%

NOD2 Mutations and Anti- Saccharomyces cerevisiae Antibodies Are Risk Factors for Crohn's Disease in African Americans

Dassopoulos

Nguyen

Talor

et al. 2010

American Journal of Gastroenterology

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Background NOD2 mutations and anti-Saccharomyces cerevisiae antibodies (ASCA) are associated with Crohn’s disease (CD), ileal involvement and complicated disease behavior in whites. ASCA and the three common NOD2 mutations have not been assessed in African American (AA) adults with CD. Methods AA patients with CD and controls were recruited by the Mid-Atlantic African American IBD Study (Johns Hopkins Hospital and satellite centers at Howard University, University of Florida, University of North Carolina, University of Pennsylvania, and the Washington Hospital Center, Washington, DC) as part of the NIDDK IBD Genetics Consortium. Genotyping for the three common CD associated NOD2 mutations (Leu1007fsinsC, G908R/2722g>c, and R702W/2104c>t) and ASCA ELISA assays were performed in 183 AA CD patients and 143 controls. Positive ASCA was based on either IgA or IgG above threshold. CD phenotyping was performed using the NIDDK IBD Genetics Consortium guidelines. Logistic regression was used to calculate adjusted odds ratios (OR) for the association between ASCA and disease phenotype. Results ASCA sensitivity and specificity in this AA population were 70.5% and 70.4% respectively. On univariate analysis, ASCA was associated with younger mean age at diagnosis (25.0±11.8 vs. 32.1±14.2 yrs, p<0.001), ileal involvement (73.0% vs. 48.0%, p=0.002), and complicated (stricturing/ penetrating) behavior (60.3% vs. 41.7%, p=0.03). On multivariate analysis, ASCA titer (/25U) was associated with ileal involvement (OR 1.18, 95% CI 1.04-1.34), complicated behavior (OR 1.13, 95% CI 1.01-1.28) and surgery (hazard ratio 1.11, 95% CI 1.02-1.21). Risks for surgery also included smoking (hazard ratio 1.50, 95% CI 1.14-1.99) and CD family history (hazard ratio 2.39, 95% CI 1.11-5.14). NOD2 carriers (all heterozygotes) were more common among CD cases than controls (8.2 vs. 2.1%; OR 4.17, 95% CI: 1.18 - 14.69). NOD2 mutation population attributable risk was 6.2%. Conclusions In comparison to whites, ASCA in AAs has a similar sensitivity but a lower specificity for CD. ASCA is associated with ileal involvement, complicated behavior and surgery in AAs with CD. NOD2 is a risk gene for AA CD, although mutation frequency and population attributable risk are much lower than in whites.

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“…Furthermore, there are marked differences in the allelic frequencies of the Nod2 variants among Caucasian populations and geographical regions in Europe (7). Because of these observations, it has been suggested that Nod2 variants linked to CD are under selection pressure possibly through bacterial infections (8). In this report, we show that Nod2 contributes to innate immune responses and regulates survival following infection with Enterococcus faecalis , an enteric commensal that is a common cause of systemic infection and lethality in humans (9).…”

Section: Introductionmentioning

confidence: 99%

Cutting Edge: Crohn’s Disease-Associated Nod2 Mutation Limits Production of Proinflammatory Cytokines To Protect the Host from Enterococcus faecalis-Induced Lethality

Kim

Shaw

Warner

et al. 2011

The Journal of Immunology

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Nod2 mutations including L1007fsinsC are associated with the development of Crohn’s disease (CD). These CD-associated Nod2 mutations are common in healthy Caucasian populations, suggesting that they may confer some protective function, but experimental evidence is lacking. Using a mouse strain that expresses Nod22939iCstop, the equivalent of the L1007fsinsC mutation, we found that macrophages homozygous for Nod22939iCstop are impaired in the recognition of MDP and E. faecalis, a commensal bacterium that is a common cause of sepsis-associated lethality in humans. Notably, Nod2 deficiency and homozygocity for Nod22939iCstop were associated with reduced production of TNF-α and IL-6 and lethality after systemic infection with E. faecalis despite normal bacteria loads. Consistently, inhibition of TNF-α Signaling protected wild-type mice from E. faecalis-induced lethality. These results suggest that the same Nod2 mutation can increase the susceptibility to CD, but also protect the host from systemic infection by a common enteric bacterium.

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Evolution of Crohn’s disease-associated Nod2 mutations

Cited by 27 publications

References 32 publications

Latitude, sunshine, and human lactase phenotype distributions may contribute to geographic patterns of modern disease: the inflammatory bowel disease model

Latitude, sunshine, and human lactase phenotype distributions may contribute to geographic patterns of modern disease: the inflammatory bowel disease model

NOD2 Mutations and Anti- Saccharomyces cerevisiae Antibodies Are Risk Factors for Crohn's Disease in African Americans

Cutting Edge: Crohn’s Disease-Associated Nod2 Mutation Limits Production of Proinflammatory Cytokines To Protect the Host from Enterococcus faecalis-Induced Lethality

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