Abstract
BackgroundInfluence of genetic variants in the NOD2 gene may play a more important role in disease activity, behaviour and treatment of pediatric- than adult-onset Crohn’s disease (CD).Methods85 pediatric- and 117 adult-onset CD patients were tested for the three main NOD2 CD-associated variants (p.R702W, p.G908R and p.10007fs) and clinical data of at least two years of follow-up were compared regarding disease behaviour and activity, response to therapy and bone mineral density (BMD).ResultsChronic active and moderate to severe course of CD is associated in patients with pediatric-onset (p=0.0001) and NOD2 variant alleles (p=0.0001). In pediatric-onset CD the average PCDAI-Score was significantly higher in patients carrying NOD2 variants (p=0.0008). In addition, underweight during course of the disease (p=0.012) was associated with NOD2 variants. Interestingly, osteoporosis was found more frequently in patients carrying NOD2 variant alleles (p=0.033), especially in pediatric-onset CD patients with homozygous NOD2 variants (p=0.037). Accordingly, low BMD in pediatric-onset CD is associated with a higher PCDAI (p=0.0092), chronic active disease (p=0.0148), underweight at diagnosis (p=0.0271) and during follow-up (p=0.0109). Furthermore, pediatric-onset CD patients with NOD2 variants are more frequently steroid-dependent or refractory (p=0.048) and need long-term immunosuppressive therapy (p=0.0213).ConclusionsThese data suggests that the presence of any of the main NOD2 variants in CD is associated with osteoporosis and an age of onset dependent influence towards underweight, higher disease activity and a more intensive immunosuppressive therapy. This observation supports the idea for an early intensive treatment strategy in children and adolescent CD patients with NOD2 gene variants.
Highlights
Influence of genetic variants in the Nucleotide oligomeric domain 2 (NOD2) gene may play a more important role in disease activity, behaviour and treatment of pediatric- than adult-onset Crohn’s disease (CD)
Pediatric-onset CD patients carrying NOD2 variant alleles display a higher disease activity and underweight There is no significant influence of the main NOD2 variants in patients with CD towards extraintestinal manifestation, need for surgery or complications (Figure 1)
We found chronic active or high active course of disease in CD patients associated with pediatric-onset of disease (p=0.0001) and any of the main NOD2 variant alleles (p=0.0001)
Summary
Influence of genetic variants in the NOD2 gene may play a more important role in disease activity, behaviour and treatment of pediatric- than adult-onset Crohn’s disease (CD). The NOD2 gene is involved in the innate immune response by recognizing muramyl dipeptide of intracellular bacterial lipopolysaccharides and activating nuclear factor κB pathways [6]. NOD2 is mainly expressed in Paneth cells in the small bowel and is involved in the innate immune response to bacterial pathogens [7]. Children have shorter environmental exposure and genetic factors such as NOD2 variants may have a greater influence in the etiology and severity of CD [9]. The few studies analyzing genotype-phenotype in pediatric-onset CD with longer observation time revealed associations of NOD2 variants with disease severity and risk for surgery [11,12]
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