Chapter 3
GENETICS AND THE GUT
At first glance there appears to be little role for the epidemiological aspects of hereditary disorders, especially given that such disorders represent a minor part of the load of GI diseases in most communities. However, it will become evident, with modern techniques of genetic and molecular biology, that genetic factors play a significant role in the natural history of an increasing number of disorders. However, it must be recognised that, ultimately, all cancers have a genetic basis, with cancers representing the end product of complex interaction between environmental influences and specific genes of the subject. It is proposed to discuss a number of disorders that are important, both from their frequency, and mortality and our developing knowledge of their genetic background. For those seeking more detailed information, large genetic texts are necessary (1).
1. INFLAMMATORY BOWEL DISEASE
This consists of two similar but distinct entities, ulcerative colitis (UC) and Crohn’s disease (CD), both frequent, important in terms of morbidity and mortality and for which genetic and environmental factors are intertwined in causation. The clinical factors are considered elsewhere; here we will emphasise the genetic aspects.
1.1 Racial and Ethnic Influences
For several decades it has been recognised that these are major
influences; IBD was more frequent in Jews of Ashkenazi origin than in their
fellow Americans, there was a marked north / south gradient in Europe and
Caucasians had a higher incidence than non-Caucasians of both CD and UC
18 8 Chapter 3 and in the U.S. there were higher rates in whites than blacks and Hispanics with Asians lower still. It is also evident that there is a strong familial tendency in both diseases with a 10-30 fold increase in the rate in siblings of patients. UC is increased in relatives of UC patients and CD in relatives of CD patients but CD and UC may co-exist in families more often than dictated by chance. It is also evident that familial aspects are stronger in CD (25%) than in UC (17%). In southern Israel IBD is nine times more prevalent in Jews than in non Jews. Whilst these differences may be attributed to environmental influences, several observations indicate a genetic basis; an increased prevalence in twins, absence of spouse concordance and concurrent disease in relatives widely separated geographically. Nonetheless, a straight Mendelian inheritance is excluded on the basis of these observations. Equally, detailed analysis excludes the proposal of a polygenic model where those with 10-15 specific genes develop CD, those with fewer develop UC and those with relatively only few of these genes develop UC rather than CD. The latest data indicate that the genetic basis for IBD is in the interaction of two or more major genes with genetic heterogeneity for UC and CD. This leads to the conclusion that IBD is a heterogeneous group of diseases with each subform an oligogenic disease due primarily to the interaction to a limited number of genes with or without a minor contribution from modifying genes (2).
As indicated elsewhere there are a number of epidemiological factors that influence the development of IBD such as smoking, diet, the oral contraceptive pill and appendicectomy. So these disorders have both genetic and environmental causes. A novel explanation for the relatively high frequency of the susceptibility alleles with their major roles in morbidity and mortality has been presented (3). A simple explanation is that they are due to mutations. However, their high morbidity and mortality would necessitate a very high mutation rate to compensate for the loss of life and reproductive capacity from them, one much higher than the estimated 1/10
5to 1/10
6rate per gene locus in humans.
Another explanation, the founder effect is also excluded. This concept is
that a mutation occurs in an individual and is handed down to a high
percentage of the descendants. While applicable to isolated communities
and certain ethnic groups, it is invalid for IBD with its high frequency and
wide distribution. The remaining explanation is best, namely that carriage
of the IBD gene also carries a selective advantage. Examples of this in
gastroenterology already exist; the protection against cardiovascular disease
and hypertension in DU and the protection against iron deficiency given by
haemochromatosis. The concept is that the possession of a disease .
producing gene and a benefit ultimately leads to an equilibrium between
benefit and ill effect. In a case of IBD, the presence of the IBD genes
GENETICS AND THE GUT 19 provides immunoprotection to the young in an unsanitary world. However in a sanitary world, the protective influences remain armed to protect the individual leading to hyperstimulation on contact with an infectious agent and also to the primed state leading to dysregulation of the protective processes and an autoimmune state. For the Ashkenazi Jews of central Europe living in crowded ghettoes in unsanitary conditions for centuries, the protective genes become a liability in our sanitised world. (4) The specific gene loci are referred to in the Crohn’s disease chapter.
2. GUT NEOPLASIA
Although neoplasms of the gut are the most frequent neoplasms in any organ system in humans, the vast majority appear to be caused by environmental factors interacting with host factors and how the host factors respond to the environment. Only a minority have a major hereditary component. Of these, the principal ones are colorectal cancer; for oesophagus, stomach, pancreas, and liver, genetic influences are thought to be minimal and will not be discussed further.
Neoplasia related to genetic disorders is mainly seen in the colon in Familial Adenomatous Polyposis (FAP) or Gardner syndrome and in Hereditary Non-Polyposis Colorectal Cancer (HNPCC) or Lynch syndrome where the genetic effects swamp environmental factors (5). These two have been intensively investigated producing much information about tumourigenesis in general. It is thought that colon cancer arises by one of two main pathways – a stepwise succession of cellular events involving mutations in oncogenes and / or deletions of tumour suppressor genes leading to the familiar picture of premalignant and malignant colonic lesions.
3. ADENOMATOUS POLYPOSIS COLI (APC)
This gene on chromosome 5 functions as a tumour suppressor gene. Its
protein product is ȕ catenin which is intimately involved in cellular
proliferation. A mutation in the gene occurs in Familial Adenomatous
Polyposes (FAP) and also in sporadic cancer and in around 60% of sporadic
adenomas, so that successive mutations lead to cancer. Current thought is
that tumour development occurs initially with a mutation in the APC gene
with progression through a sequence of steps associated with mutations and
represented by a sequence of morphological changes from normal through
adenoma to a cancer.
20 0 Chapter 3 4. FAMILIAL ADENOMATOUS POLYPOSIS (FAP)
This is due to a mutation in the tumour suppressor gene APC on chromosome 5q. It is an autosomal dominant in which large numbers of adenomatous polyps occur in the colon, occasionally in the small bowel and rarely in the stomach (5). The polyps occur in the young and by age 16, have developed in 50% of subjects. Death supervenes from the transition to colon cancer with death at average of 42 years, the disease being due to the loss of both APC alleles in the adenoma. There is some evidence of environmental influences having a modifying effect on the phenotypic expression in FAP.
5. HEREDITARY NON POLYPOSIS COLORECTAL CANCER (HNPCC) OR LYNCH SYNDROME This is an autosomal dominant disease associated with cancers, both colonic and at other sites. It is due to a germline mutation in one of the Mismatch Repair (MMR) genes and is characterised by microsatellite instability in the carrier. Cancer occurs mainly in the colon and to a lesser extent in the endometrium and at an earlier age, 40-54 years, and there is an increased risk of cancer in the stomach, small bowel, ovary, kidney, brain but not breast. It is not clear that environmental influences play a significant role. The syndrome probably represents about 6% of colorectal cancers.
References
1. Rimoin DL, Conner IM, Pyeritz RE, Korf BR, eds. Emory and Rimoin’s Principles and Practice of Medical Genetics. 4thed, (Churchill Livingstone, London, 2002), Vol. 2.
2. Rotter JI, Yang H, Taylor KD. Inflammatory bowel disease. In: Rimoin DL, Conner IM, Pyeritz RE, Korf BR, eds. Emory and Rimoin’s Principles and Practice of Medical Genetics 4thed. (Churchill Livingstone, London, 2002), Vol. 2.
3. Passarge E. Gastrointestinal tract and hepatobiliary duct system. In: Rimoin DL, Conner IM, Pyeritz RE, Korf BR, eds. Emory and Rimoin’s Principles and Practice of Medical Genetics 4thed. (Churchill Livingstone, London, 2002) Vol. 2.
4. Rotter JI. Inflammatory bowel disease (letter). Lancet 343,1360 (1994).
5. Boland CR, Helzer SJ. Cancer of the colon and gastrointestinal tract. In: Rimoin DL, Conner IM, Pyeritz RE, Korf BR, eds. Emory and Rimoin’s Principles and Practice of Medical Genetics. 4thed. (Churchill Livingstone, London, 2002), Vol. 2.
