Genetics of Inflammatory Bowel Disease

Jean-Paul Achkar, MD, Bret A. Lashner, MD, Cleveland Clinic Foundation, Cleveland, Ohio


April 19, 2002

In This Article

The Search for IBD Susceptibility Genes

The search for specific IBD susceptibility genes has been difficult due to complex genetic factors, such as the absence of simple Mendelian inheritance patterns, incomplete penetrance, genetic heterogeneity, and the involvement of more than 1 susceptibility gene.[1] An oligogenic model (limited number of genes acting together) or a genetic heterogeneity model are the most likely modes of inheritance for IBD.[1,4]

A number of genetic linkage studies have been performed to identify IBD susceptibility loci.[13,14,15,16,17,18,19,20,21,22,23] Linkage methods show chromosomal locations of susceptibility genes by studying the transmission of genetic markers of known chromosomal location within families.[1] To date, 5 confirmed linkages (meaning significant linkage found in one study and replication of the linkage with a nominal P-value < .01 in an independent study) for IBD have been identified: (1) linkage between CD and a locus on chromosome 16 (the IBD1 locus); (2) linkage between IBD (especially UC) and a locus on chromosome 12q (the IBD2 locus); (3) linkage between IBD (especially CD) and a locus on chromosome 6p (the IBD3 locus); (4) linkage between CD and a locus on chromosome 14q (the IBD4 locus); and (5) linkage between IBD (especially CD) and a locus on chromosome 3p21.[14,17,24,25,26,27,28,29,30,31,32] Other significant linkages to IBD that have not yet been confirmed in independent study populations include linkage between early age of onset CD and a locus on chromosome 5q (the IBD5 locus), linkage between IBD and a locus on chromosome 19p (the IBD6 locus), linkage between IBD and a locus on chromosome 1p (the IBD7 locus), and linkage between IBD and a locus on chromosome 3p25-26.[16,23,33,34,35]

Recently, 3 independent groups have found that the linkage between CD and the pericentromeric region of chromosome 16 (the IBD1 locus) is due to CD-associated genetic variants in the NOD2 (nucleotide-binding oligomerization domain 2) gene.[36,37,38] Three coding region variants in this gene (Leu1007insC, Gly908Arg, and Arg702Trp) are associated with CD, but not with UC.[39] Patients carrying 1 high-risk allele have a 1.5- to 3.0-fold increased risk of developing CD, whereas those carrying 2 high-risk alleles (homozygous for the same risk allele or compound heterozygous for 2 different risk alleles) have a 14- to 44-fold increased risk of developing CD.[36,37,38] However, NOD2 variants only account for 20% to 30% of all CD cases. The NOD2 protein is primarily expressed in monocytes and is involved in apoptosis and nuclear factor-kappa B activation.[39] One of the coding region variants (Leu1007insC) leads to a frameshift mutation with the resultant production of a truncated protein. Preliminary functional data demonstrate that this mutation may result in hyporesponsiveness to bacterial lipopolysaccharides, suggesting an association between the innate immune response to intestinal bacteria and the pathogenesis of CD.[37]


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