Table 1. Genetic associations in Crohn's disease with a relevance in the specialized antimicrobial producing Paneth cell
FactorFull gene nameCore functionsRelevance in Paneth cell
Factors with a direct link to Paneth cell function
NOD2/CARD15*Nucleotide‐binding oligomerization domain‐containing protein 2/caspase recruitment domain‐containing protein 15Intracellular PRR sensing bacterial muramyldipeptideNOD2 is involved in the expression of Paneth cell defensins and the activation of innate antimicrobial defense strategies (Begue et al, 2006). Carriers of a frameshift risk variant have been reported to exhibit particularly low Paneth cell α‐defensin levels (Bevins et al, 2009; Wehkamp et al, 2005b).
Atg16L1*Autophagy related 16‐like 1 (S. cerevisiae)Part of a protein complex involved in autophagy, the major degradation system of cytoplasmatic componentsATG16L1 is involved in the granule exocytosis pathway and respectively the secretion of Paneth cell AMPs. Patients carrying the associated risk variants display Paneth cell abnormalities (Cadwell et al, 2008)
XBP1X‐box binding protein 1Important transcription factor in the ER stress response as well as secretory cell development and maintenanceXBP1 deletion results in apoptotic Paneth cell loss and reduced antimicrobial activity. In addition to the association of common SNPs, the gene also exhibits rare hypomorphic non‐synonymus variants in IBD patients (Kaser et al, 2008)
LRP6*Low density lipoprotein related receptor 6Wnt Co‐receptor, R‐Spondin receptor and LGR interaction partner with an important role in β‐catenin dependent WntLRP6 expression levels are linked to those of Paneth cell HD5 in vitro. The receptor's mRNA is furthermore reduced in small intestinal CD and an early onset associated non‐synonymous risk variant precedes even further reduced levels of HDs (Koslowski et al, 2012)
TCF7L2*Transcription factor 7‐like 2 (T‐cell specific, HMG‐box), also known as TCF4Transcription factor and interaction partner of β‐catenin. Important regulator of Wnt target genesTCF7L2 is reduced in and genetically associated with small intestinal CD. It binds the promoter region of HD5/6 and regulates the α‐defensins transcriptional expression (Koslowski et al, 2009b; Wehkamp et al, 2007)
Factors with a hypothesized role in diminished Paneth cell function in CD patients
Lef1Lymphoid enhancer‐binding factor 1Transcription factor and interaction partner of β‐catenin. Important regulator of Wnt target genes and associated with CD (Dinu et al, 2012). It's role in canonical Wnt would support a potential involvement in Paneth cell function and in particular in the regulation of the α‐defensins HD5 and HD6A CDH1 CD risk haplotype precedes increased cytoplasmic E‐cadherin likely due to a truncated form of the protein. This protein version also promotes impaired β‐catenin localisation in vitro and might therefore be relevant for the canonical Wnt activity in Paneth cells (Muise et al, 2009)
CDH1Cadherin‐1 or epithelial cadherin (E‐cadherin)A calcium‐dependent cell–cell adhesion glycoprotein involved in mechanisms regulating epithelial cell adhesion, mobility and proliferation
KCNN4*Potassium intermediate/small conductance calcium‐activated channel, subfamily N, member 4Part of a voltage‐independent potassium (K(+)) channel activated by intracellular calcium (Ca(2+))The genetically associated KCNN4 encodes KCa3.1, which is found in Paneth cells. NOD2 risk variant carriers also exhibit reduced KCNN4 mRNA (Simms et al, 2010). In mice, a Ca(2+)‐activated K(+) channel modulates Paneth cell secretion (Ayabe et al, 2002) which might allow to hypothesize a similar relevance of KCa3.1 in humans
  • *Associations are known to be stronger or specific to the small intestinal Crohn's disease subphenotype.