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Inflammatory bowel disease: germs or genes?
COMMENTARY
Inflammatory bowel disease: germs genes?
or
See page 1212 Most gastroenterologists, if asked about the cause of inflammatory bowel disease (IBD), would plump for an infectious agent. Our failure to identify the pathogen does not diminish this likelihood. In which case, why study the genetics of IBD? The evidence for a genetic component to the development of IBD is strong. Thus, in addition to racial and ethnic differences in prevalence, there is a clear familial aggregation, even when affected family members have never met and share no more environmental factors than do the rest of the population. The overall risk of developing IBD in first-degree relatives of an index case is 5-9% in siblings and offspring.’2 Genetic factors seem to be more important for susceptibility to Crohn’s disease than to ulcerative colitis: in a population-based study of unselected twins, 8 of 18 monozygotic and 1 of 26 dizygotic twin-pairs were concordant for Crohn’s disease, whereas the figures for ulcerative colitis were 1 of 16 and 0 of 20, respectively. However, most cases of IBD cannot be attributed to genetic susceptibility since segregation analysis4 tells us that a genetic predisposition to IBD is present in only about 10% of patients. Despite the observed familial aggregation, there is no consistent pattern of inheritance. Possible modes of inheritance are simple mendelian inheritance (ie, autosomal dominant or recessive; clearly not X-linked), multifactorial (ie, with more than one locus contributing), or some combination of genetic factors
(genetic heterogeneity). If Crohn’s disease and ulcerative colitis are each heterogeneous in their aetiology, and disease subgroups are unknowingly pooled (eg, in population studies where genetic associations are sought), the power of the genetic marker studies will be reduced. This problem can be addressed by studying homogeneous populations-eg, families in which more than one member has IBD-and choosing a method to increase the sensitivity of the
analysis. Linkage studies determine whether marker alleles are inherited together with the disease of interest within a family. When simple mendelian inheritance is not apparent, the most appropriate analysis is a non-parametric linkage study-eg, the "affected-sibpair" method. Information is analysed only for the affected siblings in a family, so the results are not influenced by confounding factors such as age of onset
Affected
or
penetrance.
sibpair analysis is based on the knowledge that, at any locus, an individual has a 1 in 4 chance of sharing both inherited parental alleles with any sibling, a 1 in 2 chance of sharing one or other allele with any sibling, and a 1 in 4 chance of sharing none of his or her alleles with any sibling. If several pairs of affected siblings share parental alleles more commonly than expected by chance, the implication is that the marker gene is inherited together with the disease gene-ie, they are physically linked. In the report by Satsangi et al in this issue, the figures for major histocompatibility complex (MHC) class II gene sharing between affected siblings in ulcerative colitis were 15:13:1 for 2, 1, and 0 alleles instead of the expected ratio of 1:2:1. The observed ratio for Crohn’s disease (12:22:8) was not significantly different from that expected, even 1198
patients were studied. There is strong evidence for linkage between the genes of the MHC class II and ulcerative colitis, but not Crohn’s disease. What does this mean? There are several possibilities. The
though
more
association of ulcerative colitis with genes of the MHC might suggest that the genes are responsible for the development of disease, for example by the selection or presentation of specific peptides (derived from "self" or infectious agents). But are the MHC class II genes sufficient for development of disease? The MHC class II findings might indicate the presence of other host-response genes that also reside within the MHC-eg, tumour necrosis factor or complement components. Other loci could also contribute to disease expression. Even in diseases where there is a very strong association between specific MHC alleles and disease (eg, HLA B27 and ankylosing spondylitis), we still do not understand how expression of the allele causes disease in affected individuals or why the disease does not occur in all individuals bearing the particular allele. Although there is a clear difference between Crohn’s disease and ulcerative colitis in the contribution of class II MHC genes to disease susceptibility, in some families both Crohn’s disease and ulcerative colitis are represented. We do not know whether these disorders are the end result of different disease processes or whether there is some commonality in either the genetic background (say a shared locus elsewhere in the genome) or in the organism or agent that triggers these diseases. The importance of Satsangi’s report lies not just in the presence (or absence) of specific MHC associations with ulcerative colitis (and Crohn’s disease), but in the finding that genetically complex diseases are amenable to such analysis. Now that several widely spread and highly polymorphic markers are available (so-called, microsatellites), sibpair or affected-relative-pair analysis is possible for any part of the genome.s Approaches with candidate genes (such as those in the MHC) are now supplemented by techniques that permit large genome-wide searches. Recently Hugot et al described how, using microsatellites and affected-sibpair analysis, they mapped a susceptibility locus for Crohn’s disease to chromosome 16.6 Knowledge of genetic associations should help clarify the issues involved in the development of sporadic forms of IBD. At this point, if we were to hazard a guess as to the origin of IBD, we would say both germs and genes. Paul Pavli, Juleen Cavanaugh, Michael Grimm Gastroenterology Unit, Woden Valley Hospital, Canberra, ACT, and John Curtin School of Medical Research, Australian National University, Australia 1
2
3
Yang H, Shohat T, Rotter JI. The genetics of inflammatory bowel disease. In: McDermott RP, Stenson WF, eds. Current topics in gastroenterology: inflammatory bowel disease. New York: Elsevier, 1992: 1751. Roth MP, Petersen GM, McElree C, et al. Familiar empiric risk estimates of inflammatory bowel disease in Ashkenazi Jews.
Gastroenterology 1989; 96: 1016-20. Tysk C, Lindberg E, Jarnerot G, et al. Ulcerative colitis and Crohn’s disease in an unselected population of monozygotic and dizygotic twins: a study of heritability and the influence of smoking. Gut 1988; 29: 990-96.
4
5
6
Orholm M, Iselius L, Sorensen TI, et al. Investigation of inheritance of chronic inflammatory bowel diseases by complex segregation analysis. BMJ 1993; 306: 20-24. Davies JL, KawaguchiY, Bennett ST, et al. A genome-wide search for human type 1 diabetes susceptibility genes. Nature 1994; 371: 130-36. Hugot J-P, Laurent-Puig, Gower Rousseau C, et al. Mapping of a susceptibility locus for Crohn’s disease on chromosome 16. Nature 1996, 379: 821-23.
Inflammatory bowel disease: germs genes?
or
See page 1212 Most gastroenterologists, if asked about the cause of inflammatory bowel disease (IBD), would plump for an infectious agent. Our failure to identify the pathogen does not diminish this likelihood. In which case, why study the genetics of IBD? The evidence for a genetic component to the development of IBD is strong. Thus, in addition to racial and ethnic differences in prevalence, there is a clear familial aggregation, even when affected family members have never met and share no more environmental factors than do the rest of the population. The overall risk of developing IBD in first-degree relatives of an index case is 5-9% in siblings and offspring.’2 Genetic factors seem to be more important for susceptibility to Crohn’s disease than to ulcerative colitis: in a population-based study of unselected twins, 8 of 18 monozygotic and 1 of 26 dizygotic twin-pairs were concordant for Crohn’s disease, whereas the figures for ulcerative colitis were 1 of 16 and 0 of 20, respectively. However, most cases of IBD cannot be attributed to genetic susceptibility since segregation analysis4 tells us that a genetic predisposition to IBD is present in only about 10% of patients. Despite the observed familial aggregation, there is no consistent pattern of inheritance. Possible modes of inheritance are simple mendelian inheritance (ie, autosomal dominant or recessive; clearly not X-linked), multifactorial (ie, with more than one locus contributing), or some combination of genetic factors
(genetic heterogeneity). If Crohn’s disease and ulcerative colitis are each heterogeneous in their aetiology, and disease subgroups are unknowingly pooled (eg, in population studies where genetic associations are sought), the power of the genetic marker studies will be reduced. This problem can be addressed by studying homogeneous populations-eg, families in which more than one member has IBD-and choosing a method to increase the sensitivity of the
analysis. Linkage studies determine whether marker alleles are inherited together with the disease of interest within a family. When simple mendelian inheritance is not apparent, the most appropriate analysis is a non-parametric linkage study-eg, the "affected-sibpair" method. Information is analysed only for the affected siblings in a family, so the results are not influenced by confounding factors such as age of onset
Affected
or
penetrance.
sibpair analysis is based on the knowledge that, at any locus, an individual has a 1 in 4 chance of sharing both inherited parental alleles with any sibling, a 1 in 2 chance of sharing one or other allele with any sibling, and a 1 in 4 chance of sharing none of his or her alleles with any sibling. If several pairs of affected siblings share parental alleles more commonly than expected by chance, the implication is that the marker gene is inherited together with the disease gene-ie, they are physically linked. In the report by Satsangi et al in this issue, the figures for major histocompatibility complex (MHC) class II gene sharing between affected siblings in ulcerative colitis were 15:13:1 for 2, 1, and 0 alleles instead of the expected ratio of 1:2:1. The observed ratio for Crohn’s disease (12:22:8) was not significantly different from that expected, even 1198
patients were studied. There is strong evidence for linkage between the genes of the MHC class II and ulcerative colitis, but not Crohn’s disease. What does this mean? There are several possibilities. The
though
more
association of ulcerative colitis with genes of the MHC might suggest that the genes are responsible for the development of disease, for example by the selection or presentation of specific peptides (derived from "self" or infectious agents). But are the MHC class II genes sufficient for development of disease? The MHC class II findings might indicate the presence of other host-response genes that also reside within the MHC-eg, tumour necrosis factor or complement components. Other loci could also contribute to disease expression. Even in diseases where there is a very strong association between specific MHC alleles and disease (eg, HLA B27 and ankylosing spondylitis), we still do not understand how expression of the allele causes disease in affected individuals or why the disease does not occur in all individuals bearing the particular allele. Although there is a clear difference between Crohn’s disease and ulcerative colitis in the contribution of class II MHC genes to disease susceptibility, in some families both Crohn’s disease and ulcerative colitis are represented. We do not know whether these disorders are the end result of different disease processes or whether there is some commonality in either the genetic background (say a shared locus elsewhere in the genome) or in the organism or agent that triggers these diseases. The importance of Satsangi’s report lies not just in the presence (or absence) of specific MHC associations with ulcerative colitis (and Crohn’s disease), but in the finding that genetically complex diseases are amenable to such analysis. Now that several widely spread and highly polymorphic markers are available (so-called, microsatellites), sibpair or affected-relative-pair analysis is possible for any part of the genome.s Approaches with candidate genes (such as those in the MHC) are now supplemented by techniques that permit large genome-wide searches. Recently Hugot et al described how, using microsatellites and affected-sibpair analysis, they mapped a susceptibility locus for Crohn’s disease to chromosome 16.6 Knowledge of genetic associations should help clarify the issues involved in the development of sporadic forms of IBD. At this point, if we were to hazard a guess as to the origin of IBD, we would say both germs and genes. Paul Pavli, Juleen Cavanaugh, Michael Grimm Gastroenterology Unit, Woden Valley Hospital, Canberra, ACT, and John Curtin School of Medical Research, Australian National University, Australia 1
2
3
Yang H, Shohat T, Rotter JI. The genetics of inflammatory bowel disease. In: McDermott RP, Stenson WF, eds. Current topics in gastroenterology: inflammatory bowel disease. New York: Elsevier, 1992: 1751. Roth MP, Petersen GM, McElree C, et al. Familiar empiric risk estimates of inflammatory bowel disease in Ashkenazi Jews.
Gastroenterology 1989; 96: 1016-20. Tysk C, Lindberg E, Jarnerot G, et al. Ulcerative colitis and Crohn’s disease in an unselected population of monozygotic and dizygotic twins: a study of heritability and the influence of smoking. Gut 1988; 29: 990-96.
4
5
6
Orholm M, Iselius L, Sorensen TI, et al. Investigation of inheritance of chronic inflammatory bowel diseases by complex segregation analysis. BMJ 1993; 306: 20-24. Davies JL, KawaguchiY, Bennett ST, et al. A genome-wide search for human type 1 diabetes susceptibility genes. Nature 1994; 371: 130-36. Hugot J-P, Laurent-Puig, Gower Rousseau C, et al. Mapping of a susceptibility locus for Crohn’s disease on chromosome 16. Nature 1996, 379: 821-23.