Development of a uniform, very aggressive disease phenotype in all homozygous carriers of the NOD2 mutation p.Leu1007fsX1008 with Crohn's disease and active smoking status resulting in ileal stenosis requiring surgery.
Adolescent
Adult
Cohort Studies
Crohn Disease
/ complications
Female
Gene Dosage
Gene Frequency
/ genetics
Genetic Markers
Genetic Predisposition to Disease
Heterozygote
Homozygote
Humans
Ileal Diseases
/ etiology
Intestinal Obstruction
/ etiology
Logistic Models
Male
Mutation
/ genetics
Nod2 Signaling Adaptor Protein
/ genetics
Phenotype
Risk Factors
Severity of Illness Index
Smoking
/ adverse effects
Young Adult
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2020
2020
Historique:
received:
20
02
2020
accepted:
06
07
2020
entrez:
28
7
2020
pubmed:
28
7
2020
medline:
23
9
2020
Statut:
epublish
Résumé
NOD2 variants are the strongest genetic predictors for susceptibility to Crohn's disease (CD). However, the clinical value of NOD2 on an individual patient level remains controversial. We aimed to define the predictive power of the major NOD2 mutations regarding complicated CD in a large single center cohort. 1076 CD patients were prospectively genotyped for the three common CD-associated NOD2 mutations rs2066844, rs2066845, and rs2066847, followed by detailed genotype-phenotype analyses. Overall, 434 CD patients (40.3%) carried at least one of the three main NOD2 mutations. A significantly higher minor allele frequency (15.6%) of the NOD2 frameshift mutation p.Leu1007fsX1008 (rs2066847) was seen in patients with aggressive disease compared to 8.2% in patients with mild disease (p = 2.6 x 10-5). Moreover, a total of 54 CD patients (5.0%) were homozygous for this NOD2 frameshift mutation. 100% of these patients had ileal disease compared to 82% of NOD2 wild-type carriers (p<0.0001). In homozygous carriers of the NOD2 frameshift mutation, 87% presented with ileal stenosis, 68.5% had fistulas, and 72.2% required CD-related surgery despite immunosuppressive therapy in 87% of these patients. All homozygous carriers of the 1007fs mutation who were active smokers had ileal stenosis and required CD-related surgery. Homozygosity for Leu1007fsX1008 is an excellent biomarker for predicting complicated CD on an individual patient level. Active smoking and homozygosity for this mutation is associated with a 100% risk for developing ileal stenosis requiring CD-related surgery. In these patients, smoking cessation and early initiation of immunosuppressive strategies may be beneficial.
Sections du résumé
BACKGROUND
NOD2 variants are the strongest genetic predictors for susceptibility to Crohn's disease (CD). However, the clinical value of NOD2 on an individual patient level remains controversial. We aimed to define the predictive power of the major NOD2 mutations regarding complicated CD in a large single center cohort.
METHODS
1076 CD patients were prospectively genotyped for the three common CD-associated NOD2 mutations rs2066844, rs2066845, and rs2066847, followed by detailed genotype-phenotype analyses.
RESULTS
Overall, 434 CD patients (40.3%) carried at least one of the three main NOD2 mutations. A significantly higher minor allele frequency (15.6%) of the NOD2 frameshift mutation p.Leu1007fsX1008 (rs2066847) was seen in patients with aggressive disease compared to 8.2% in patients with mild disease (p = 2.6 x 10-5). Moreover, a total of 54 CD patients (5.0%) were homozygous for this NOD2 frameshift mutation. 100% of these patients had ileal disease compared to 82% of NOD2 wild-type carriers (p<0.0001). In homozygous carriers of the NOD2 frameshift mutation, 87% presented with ileal stenosis, 68.5% had fistulas, and 72.2% required CD-related surgery despite immunosuppressive therapy in 87% of these patients. All homozygous carriers of the 1007fs mutation who were active smokers had ileal stenosis and required CD-related surgery.
CONCLUSION
Homozygosity for Leu1007fsX1008 is an excellent biomarker for predicting complicated CD on an individual patient level. Active smoking and homozygosity for this mutation is associated with a 100% risk for developing ileal stenosis requiring CD-related surgery. In these patients, smoking cessation and early initiation of immunosuppressive strategies may be beneficial.
Identifiants
pubmed: 32716958
doi: 10.1371/journal.pone.0236421
pii: PONE-D-20-02655
pmc: PMC7384669
doi:
Substances chimiques
Genetic Markers
0
NOD2 protein, human
0
Nod2 Signaling Adaptor Protein
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0236421Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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