Linkage studies and other inflammatory bowel disease susceptibility loci

Linkage studies in Crohn's disease proved highly informative and have led to the identification of a number of

Box 9.5 NOD2 and genome-wide association studies

As a known disease associated locus, it was reassuring that the NOD2 region was implicated in genome-wide association studies, but the data serve to highlight some caveats in the interpretation of genome-wide scans based on the specific markers analysed. In the WTCCC study, for example, a strong signal of association was found for NOD2 but not with the NOD2 insertion polymorphism or nonsynonymous SNPs, described earlier as showing the strongest disease association, as they were not part of the panel of SNP markers present on the genotyping array used in this study (WTCCC

2007; Barrett et al. 2008). Highly significant association was instead found for rs17221417, a SNP in modest linkage with the 3020insC polymorphism rs2066847, with a P value of 9.4 X 10-12 and an odds ratio of 1.29 (1.13-1.46) for heterozygotes and 1.92 (1.58-2.34) for homozygotes for the risk allele (WTCCC 2007). When rs2066847 was specifically investigated in replication studies it was, however, very significant (P = 1.5 X 10-24) and showed the largest odds ratio in case-control analysis of any replicated Crohn's disease risk locus (Barrett et al. 2008).

Figure 9.20 NOD2 3020insC variant. (A) DNA sequencing traces for part of NOD2exon 11 showing an individual without ('wild type'), heterozygous, or homozygous for the C insertion variant (rs2066847). (B) NOD2 gene exon structure and detail for exon 11 showing the DNA sequence and amino acid sequences for wild type and 3020ins. (C) NOD2 protein domain structure illustrating the position of protein truncation. Redrawn and reprinted by permission from Macmillan Publishers Ltd: Nature (Ogura et al. 2001a), copyright 2001. Gene plots with genomic location and sequences adapted from screenshot of UCSC Genome Browser (Kent et al. 2002) (http://genome.ucsc.edu/) (Human March 2006 Assembly).

Cromossomo

Figure 9.21 Chromosomal regions showing linkage with inflammatory bowel disease from a review of whole genome linkage scans. Ideogram demonstrating regions of significant linkage (dark grey shading) and suggestive linkage (light grey). Inflammatory bowel disease (IBD) loci 1-9 are indicated. Redrawn and reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Genetics (Barrett et al. 2008), copyright 2008.

Figure 9.21 Chromosomal regions showing linkage with inflammatory bowel disease from a review of whole genome linkage scans. Ideogram demonstrating regions of significant linkage (dark grey shading) and suggestive linkage (light grey). Inflammatory bowel disease (IBD) loci 1-9 are indicated. Redrawn and reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Genetics (Barrett et al. 2008), copyright 2008.

susceptibility loci in addition to IBD1. In 2004, Brant and colleagues reviewed 11 genome-wide linkage screens involving 1200 family pedigrees affected by inflammatory bowel disease analysed using microsatellite markers, with affected sib pairs most commonly analysed (Brant and Shugart 2004). Three loci were noted as showing 'good evidence' of linkage: IBD1 at chromosome 16q, IBD3 at chromosome 6p, and IBD5 at 5q31; 'promising'

loci included IBD2 (chromosome 12q13.2-q24.1), IBD4 (14q11-q12), IBD6 (19p13), IBD7 (1p36), IBD8 (16p), and IBD9 (3p26), together with chromosomes 2q, 4q, 7, 11p, and Xp.

For IBD5 at chromosome 5q31, linkage with Crohn's disease has been reproducibly and convincingly demonstrated and a specific risk haplotype resolved (Rioux et al. 2000, 2001). However, despite intensive efforts at

Population

Cases controls

Cases controls Trios

Associations observed

Chr Genes or loci

Japanese

Yamazaki et al. (2005)

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