It's been a long time coming, but now two papers report a clear cut identification by linkage mapping of a gene involved in a common human disorder — Crohn's disease (CD). Importantly, they also indicate how the innate immune system might be involved in the aetiology of CD, because the identified gene — NOD2 — encodes an intracellular receptor for bacterial lipopolysaccharides (LPS) that activates NFB, a target of the innate immune signalling pathway and a transcriptional regulator of inflammatory genes.
     CD is a chronic inflammatory gut disorder, thought to be caused by an abnormal inflammatory response to enteric microbes. In 1996, a CD susceptibility locus, IBD1, was identified on chromosome 16. Little progress has been made since, but it is this locus that the two research teams — one European, the other US-based — tackled in their studies, using positional-cloning and candidate-gene strategies, respectively.
     Hugot et al. took a decisive step when they identified association of CD to an allele of a chromosome-16 microsatellite marker. Despite the borderline significance of this association, the authors went on to identify putative transcripts in the region of this marker, and identified over 30 single nucleotide polymorphisms (SNPs) by sequencing the region from affected and unaffected individuals. Several turned out to be non-synonymous variants in a chromosome-16 gene, NOD2. Three of these SNPs — each independently associated with disease susceptibility — altered the leucine-rich repeat (LRR) region of NOD2, which is required for LPS recognition.
     Having previously identified NOD2, Ogura et al. considered it a candidate for CD because of its chromosome-16 location. On sequencing the gene from CD individuals, they identified an insertion that caused two frameshift mutations in the LRR region and the premature truncation of NOD2. In in vitro assays, this mutant NOD2 produced considerably diminished levels of NFB activation in response to bacterial LPS compared to wild-type NOD2.
     So how could NOD2 contribute to susceptibility to CD? The innate immune system regulates the immediate immune response to bacterial pathogens, components of which are recognized in host immune cells by specific receptors, such as NOD2. A defect in this recognition might lead to an exaggerated inflammatory reaction being mediated by the adaptive immune system. Alternatively, NOD2 might act to trigger cytokines that dampen inflammatory responses. Although NOD2 does not account for all susceptibility to CD, it does provide a first glimpse into the aetiology of the disease and should speed the discovery of other CD loci and future therapies, and improve its diagnosis. These papers are hopefully the first of many such successes in grappling with the genetic basis of multifactorial, common disease.