Age-of-onset-dependent influence of NOD2 gene variants on disease behaviour and treatment in Crohn's disease

Abstract

Background: 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).

Methods: 85 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).

Results: Chronic 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).

Conclusions: These 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.

Figure 1

Effect of NOD2 gene variants in CD patients on disease behaviour. CD patients with pediatric-onset (A) or adult-onset (B) of disease with NOD2 variant (grey bars) or NOD2 wild-type alleles (white bars) are compared regarding family history (FA) of IBD, extraintestinal manifestation (EIM), surgery or complication because of CD, and osteoporosis. BMD was available from 169 out of 202 patients. Differences were compared using chi-square or Fishers exact test, respectively. A p-value below ≤0.05 was considered to be significant.

Figure 2

Effect of NOD2 variants on PCDAI and CDAI Score in pediatric- and adult-onset CD patients. CD patients with pediatric-onset (A) and adult-onset (B) are compared regarding NOD2 variant (grey bars) or NOD2 wild-type alleles (white bars) and their average PCDAI or CDAI Score. The median (lines within the boxes), the interquartile range (boxes) and the whole range are given. Differences were compared using unpaired, two sided Mann–Whitney test. A p-value below ≤0.05 was considered to be significant.

Figure 3

Effect of NOD2 variants on underweight, growth failure, short stature and hospitalization in pediatric-onset CD patients. Pediatric-onset CD patients with NOD2 variant (grey bars) or NOD2 wild-type alleles (white bars) were compared regarding underweight at diagnosis and during follow up, growth failure, short stature and hospitalization for more than two weeks per year. BMI at diagnosis and growth delay at one-year follow-up was available from 51 out of 85 patients (39% NOD2 variant allele carriers). Differences were compared using chi-square or Fishers exact test, respectively. A p-value below ≤0.05 was considered to be significant.

Figure 4

Effect of PCDAI on BMD. CD patients with pediatric-onset are compared regarding their PCDAI and BMD z-value. The median (lines within the boxes), the interquartile range (boxes) and the whole range are given. Differences were compared using Kruskal-Wallis test. The medians varies significant (*), p-value is 0.0253 using Gaussian approximation.

Figure 5

Effect of NOD2 variant alleles on treatment in pediatric- and adult-onset CD. CD patients with pediatric-onset (A) or adult-onset (B) of disease with NOD2 variant (grey bars) or NOD2 wild-type alleles (white bars) are compared regarding steroid-dependent or refractory course of disease, need for long-term immunosuppressive therapy with azathioprine (AZA) and methotrexate (MTX) or anti-TNFα antibody. Differences were compared using chi-square or Fishers exact test, respectively. A p-value below ≤0.05 was considered to be significant.