Several further loci generating less strong evidence for association are of interest on the basis of their biological candidacy (Table 4). For example, rs9469220 (P=8.7×10-7) mapping to the human leukocyte antigen (HLA) system class II region was detected in the ‘second tier’ of associations (Table 4). This suggests a significant contribution of HLA to CD-susceptibility, though less marked than seen in classical autoimmune conditions such as RAand T1D. Another interesting candidate flagged in Table 4 is TNFAIP3 (TNFα induced protein 3), the closest gene to rs7753394 on chromosome 6q23. The protein product inhibits TNFα-induced NFκB-dependent gene expression by interfering with RIP- or TRAF-2-mediated transactivation signals—hence interacting with the same pathway as CARD15 (NOD2). Markers with lower levels of significance include rs6478108 (P=9.0×10-5) within TNFSF15 (tumour necrosis factor super family, member 15), previously reported associated with CD70; and rs3816769 (P=3.1×10-5) which maps within STAT3 (signal transducers and activator of transcription, member 3). On the X chromosome rs2807261 (P=1.3×10-7) maps 50-kb from the gene CD40LG (CD40 ligand—previously known as TNF superfamily, member 5), implicated in the regulation of B-cell proliferation, adhesion and
