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

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.

Repeated exclusive enteral nutrition in the treatment of paediatric Crohn's disease: predictors of efficacy and outcome

“…In our cohort 52% of patients carried at least one NOD2 risk allele, which is slightly higher compared to frequencies of 41-46% reported from other European cohorts. [25][26][27][28] Regional or ethnical differences, spectrum of CD patients at our centre or the relatively small Aliment Pharmacol Ther 2014; 39: 1398-1407number of patients may contribute to the difference. We found that children carrying at least one of the common two missense mutations in the NOD2 gene, R702W and G908R, have a detrimental 1 year outcome.…”

Prognostic biomarkers to identify patients likely to develop severe Crohn’s disease: a systematic review

“…28,58,79 Concern regarding 'Overall applicability' was rated as 'low' or 'unclear', except for five studies. 30,46,60,67,73 ROB and applicability for individual studies are presented in Box 1 and Figures 3-5.…”

“…The studies that were rated as having a high concern were four studies with composite outcomes defined in a slightly non-standard way and one study that enrolled Indian patients who had received antituberculous therapy only. 33 Aldhous 2007 34 Annese 2005 36 Beaugerie 2006 18 Brant 2003 37 Charpentier 2014 39 Chatzicostas 2006 40 Chen 2015 41 Choung 2016 42 Cleynen 2013 43 Goel 2013 46 Gupta 2006 47 Henckaerts 2009 48 Israeli 2014 25 Jauregui-Amezaga 2015 49 Laghi 2005 54 Lakatos 2009 56 Law 2013 57 Loly 2008 20 Louis 2003 26 Lovasz 2013 27 Lunney 2015 58 Malmborg 2015 59 Mazor 2011 60 Moon 2014 61 Nasir 2013 62 Nasir 2013 63 Nunes 2013 64 Odes 2001 65 Oriuchi 2003 67 Pandey 2015 68 Papi 2005 69 Park 2013 70 Pigneur 2010 71 Pittet 2013 28 Polito 1996 72 Posovszky 2013 73 Renda 2008 75 Romberg-Camps 2009 77 Ryan 2013 78 Sabate 2008 79 Sands 2003 80 Savoye 2012 81 Schaefer 2010 …”

“…B2 and B3 Montreal disease behaviours were the strongest predictors of subsequent severe disease in our review (B2: OR 4.09, 95% CI 2.59 to 6.48; B3: OR 6.25, 95% CI 3.68 to 10.63). 73 Nasir 2013 63 Louis 2003 26 Lakatos 2005 55 Smith 2004 29 Shaoul 2009 83 Renda 2008 75 Protic 2008 74 Laghi 2005 54 Lacher 2010 53 Kugathasan 2004 51 Henckaerts 2009 48 Cleynen 2013 43 Büning 2014 38 Brant 2003 37 a Hierarchy of estimates reported: OR, adj OR, HR and adj HR. For location, prediction groupings were restricted to colon only (disease located in colon only vs. disease not located in colon only) and colon any (disease present in colon as well as potentially in other locations vs. disease not present in colon).…”

“…Similarly, any colonic disease (23 studies, 7373 participants, 3086 events) predicted lower surgical or B2/B3 risk than no colonic disease (see Table 6 and Figure 11). 31 Polito 1996 72 Posovszky 2013 73 Sands 2003 80 Mazor 2011 60 Pittet 2013 28 Lovasz 2013 27 Pandey 2015 68 Israeli 2014 25 Thia 2010 89 Song 2011 87 Chen 2015 41 Law 2013 57 Jauregui-Amezega 2015 49 Subtotal (I 2 = 68.8%, p = 0.000)…”