Bedeutung genetischer Veränderungen im NOD2-Gen bei pädiatrischen und erwachsenen Patienten mit chronisch entzündlichen Darmerkrankungen für Krankheitsaktivität, Knochendichte und Therapie

Background: Influence of genetic variants in the NOD2/CARD15 gene may play a more important role in disease behavior of pediatric-onset than in adult-onset Crohn’s disease (CD). Chronic inflammation is associated with the presence of osteoporosis. Aim: The objective of this study was to identify genotype phenotype associations between NOD2/CARD15 single nucleotide polymorphisms (SNP) genotypes and overall disease activity, disease behavior, bone mineral density and response to therapy. Methods: NOD2/CARD15 SNPs were tested in 88 patients with pediatric-onset and 104 adult-onset Crohn’s disease and compared regarding disease behavior and activity, response to therapy and bone mineral density (BMD). Results: In the adult Crohn’s group there was no significant difference between NOD2 genotype and phenotype. In contrast, pediatric-onset Crohn patients with NOD2 variants are more affected than NOD2 wild type patients. They had underweight at onset and during course of the disease more frequently. Complications and the need for surgery were observed more often and the PCDAI-score was significantly higher with more need for hospital care in the NOD2 SNP group. Furthermore, differences were found regarding the treatment. Interestingly, also the average bone mineral density (BMD) Z-score was lower in this group and osteoporosis was found more frequently than in the NOD2 wild type group. Osteoporosis was independent of disease location, but significantly associated with a higher PCDAI. Conclusions: In contrast to adult onset, there is a strong influence of NOD2 gene variants towards a more affected phenotype in pediatric-onset of Crohn’s disease with underweight, higher disease activity, the need for intensive immunosuppressive therapy, surgery and hospital care and lower bone mineral density. Thus young age and a NOD2 SNP are risk factors frequently associated with a moderate to severe course of disease

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

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