Genetic Aspects of Inflammatory Bowel Disease

Inflammatory Bowel Disease

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Genetic Aspects of Inflammatory Bowel Disease

Goran Hellers, MD, PhD, * and Olle Bernell, MDt

In 1934 Crohn made the first description of genetic association of Crohn's disease in a man whose sister also suffered from the disease. 6 During the 1940s and 1950s there were several anecdotal reports on individual cases but it was not until the early 1960s that the increased family prevalence of inflammatory bowel disease became established. 2. 12 The early reports were usually based on selected hospital data. Crohn's disease and ulcerative colitis were furthermore usually lumped together, which makes it difficult to estimate relative risks of developing each of the diseases among family members. The risk in early reports is also usually given as simple frequencies rather than as the relative risk based on epidemiologic data concerning the incidence and prevalence of the disease in the population. Almy and Sherlock2 attempted to calculate the risk that Crohn's disease should appear at random in two individuals in the same family. The risk was stated to be 1 in 25 million population. This calculation, however, was not based on an epidemiologically limited patient material nor was it based on known family numbers and sizes within the same population as from which the patient material was drawn. There are several requirements for good studies. In order to compare different studies, these must be based on a defined geographic area, a defined period of time, and defined diagnostic criteria. All members in the family of an index case have to be investigated with respect to inflammatory bowel disease. Crohn's disease and ulcerative colitis should not be lumped together but analyzed as two separate entities. In the following article, the diseases will be dealt with separately. From the Department of Surgery, Huddinge University Hospital, Huddinge, Sweden

*Associate

Professor and Chairman tStaff Surgeon

Medical Clinics of North America-Vo!' 74, No. 1, January 1990

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CROHN'S DISEASE Overall Risk A genetic association may be due either to a single gene with or without reduced penetrance or to a multigene inheritance. Each of these two different types may also be dependent on external factors. In many studies, both first-degree and second-degree relatives and even more distant relations have been used and combined together. Since many factors are probably involved, only first-degree relatives should be used for estimating the risk. Furthermore, the relative risks should be used-that is the prevalence of the disease in the population and in relatives. There are only two studies fulfilling these requirements in the literature. In a study from Cardiff, Wales, 18 information about the family structure in all surviving patients with Crohn's disease was obtained. The prevalence of Crohn's disease in first-degree relatives was approximately 30 times the expected in the background population. A similar study from Leiden 27 yielded comparable data. When only first-degree relatives were used for comparison, the prevalence was about 13 times the expected. Another study from Stockholm used only the risk in first-degree relatives and found that the disease was five times more common than expected. 10 There are no studies in the literature in which Crohn's disease has been positively shown to be more common among second-degree relatives than expected. The marked overrepresentation in first-degree relatives and its absence in second-degree relatives does not suggest a simple mendelian inheritance, but rather a multigene inheritance since alteration of genetic material occurring within a few generations is greater with multigene than with single gene inheritance. Twin Studies There were early reports of anecdotal cases of twins concordant for either Crohn's disease or ulcerative colitis. Weterman and Pena reviewed the literature and reported on 20 pairs of monozygotic twins with Crohn's disease. 28 Seventeen of these were concordant for the disease and three discordant. There has, however, not been any firm estimation of the risk until recently. Tysk et aP6 performed a cross running between the Swedish twin register and the National Diagnosis Register of Hospital In-patients. 26 The Swedish twin register contains about 25,000 pairs of twins. They found 80 twin pairs suffering from inflammatory bowel disease. In the group of patients with Crohn's disease, 8 of 18 monozygotic pairs and 1 of 26 dizygotic pairs were concordant for the disease. The proband concordance rate among monozygotic twins was 58 per cent for Crohn's disease. Calculated heritability ofliability based on monozygotic pairs was 1. O. The majority of the concordant twins developed Crohn's disease within a period of 2 years, and the extent of disease at onset was very similar. The liability of 1.0 was corrected for common familial environmental factors which suggests a strong genetic influence.

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Ethnic Aspects Several earlier studies have suggested that Crohn's disease is more common among Jews. l , 20 This has been supported by later findings· in Scandinavia. 4, 10 These data are, however, not supported by data from Israe1. 24 In a study from Tel Aviv, the incidence in Ashkenazi Jews living in Israel was much lower than the incidence in a similar Jewish population living in the United States. The ethnic controversy is not yet settled and it is obvious that the genetic disposition for the disease may be modified by external factors, Age and Sex In a study on patients who had the diagnosis of inflammatory bowel disease established at the Cleveland Clinic prior to the age of 21 years, a number of families were studied and detailed pedigrees drawn. 7 In this group with young patients, the frequency of diseased immediate family members was 16.6 per cent. The study does not separate between ulcerative colitis and Crohn's disease but, in view of the very high numbers, the study still indicates that young age at onset may be an important factor. There are no other studies available on this particular problem that can support this finding. There is no consistent pattern concerning sex. Some investigators have found a higher incidence among men, whereas others have found the opposite, Cultural factors such as variations in food and drinking habits between the two sexes may explain the differences in certain areas. Environmental Factors Several environmental factors such as food intake, water supply, and smoking habits have been investigated and are covered in other articles. From a genetic viewpoint, the strongest arguments against a genetic factor would be a high prevalence of inflammatory bowel disease in husbands and their spouses, There are few reports in the literature of marital inflammatory bowel disease. In a recent survey,23 the literature was reviewed and seven cases reported. Four of these reports are on couples concordant for Crohn's disease, one couple concordant for ulcerative colitis, and two couples discordant. In three of these couples, one or more of the children have furthermore developed inflammatory bowel disease. Information about how long a period of time these couples spent together before they developed the disease is scarce, but in at least two of the cases they had spent approximately 10 years together before one developed the disease. Consequently, frequency of marital inflammatory bowel disease seems to be extremely low, This speaks in favor of a genetic factor rather than an environmental factor. An additional group of individuals at risk would be health care personnel taking care of patients with the disease. There have been no reports in the literature on cases of inflammatory bowel disease occurring in such individuals. Genetic Markers Many diseases occur with increased frequency in patients with a particular histocompatibility type (HLA); there are many examples such as

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diabetes mellitus and multiple sclerosis. There is a proliferation of studies on HLA markers and the susceptibility of inflammatory bowel disease. The search for such markers has not been successful and the results in the literature are contradictory. The only firm evidence is the now well accepted association between inflammatory bowel disease, ankylosing spondylitis, and HLA-B27.5 The most interesting recent finding is the suggestion that relatives of patients with Crohn's disease have an increased intestinal permeability that is similar to that found in the patients. II The hypothesis as to the etiology of Crohn's disease is that patients with the disease have an increased intestinal permeability allowing larger molecules to escape from the gut lumen into the lymphatic system. In this particular study, intestinal permeability was assessed by using polyethylene glycol (PEG)-400 ingested with a standard meal. Seventeen normal volunteers, 11 patients with Crohn's disease, and 32 healthy relatives to patients with Crohn's disease were investigated. In patients and in relatives of patients there was a twofold increase in permeability compared with controls. This suggests that the previously reported increase in intestinal permeability found in patients with Crohn's disease is not acquired but primary. 17 However, these data have recently been questioned. 3 The use of PEG400 for assessing intestinal permeability may have potential methodologic errors. Urine recovery of PEG-400 is variable and low after intravenous installation in humans. Data in the above cited study show that the apparently normal controls absorbed significantly less PEG-400 than control subjects studied elsewhere. Apparently more similar studies have to be carried out and additional markers of permeability such as 51CrEDTA have to be used. ULCERATIVE COLITIS Overall Risk As with Crohn's disease, it has long been clear that an increased familial occurrence of ulcerative colitis exists. The prevalence of familial ulcerative colitis generally seems to be somewhat smaller than for Crohn's disease. In a British study, 9 0.6 per cent 'of 1376 relatives to colitis patients also had ulcerative colitis. In a study from Chicago,16 the incidence was 1.1 per cent among 354 relatives. In Cleveland, the incidence was 4.7 per cent among 1075 relatives. 8 This study, however, included only patients 20 years or younger at time of diagnosis of ulcerative colitis. In Stockholm, an extensive study was done on all 1274 patients who had a definite diagnosis of ulcerative colitis established during the period 1955 to 1979. 21 It was possible to obtain information about family structure and diseases in 963 cases. In 65 of these, there was a positive family history of ulcerative colitis corresponding to a prevalence of 6.7 per cent. In 11 cases there was a positive family history for Crohn's disease. The incidence in second-degree relatives and more distant relations was too small to allow any conclusions.

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Twin Studies In the study based on the Swedish twin register,26 only 1 of 16 monozygotic pairs was concordant for ulcerative colitis. All 20 dizygotic pairs were discordant. The concordance rate was 6.3 per cent, which is much lower than for Crohn's disease. The authors also performed a survey of the literature that revealed only 16 published pairs of monozygotic twins with ulcerative colitis. These data indicate that there is probably a genetic factor in the etiology of ulcerative colitis, but that this is weaker than for Crohn's disease. Age and Sex Although the study from Cleveland8 is not conclusive it certainly indicates that age is a factor of importance. In the Stockholm study,21 the age at onset of the disease was lower among patients with a positive family history than among the remainder-25 and 33 years, respectively. A previous study from Chicago showed the same result. 25 The male/female ratio in Stockholm was 1.15 in patients with a positive family history and 0.78 among all patients. This corresponds to a 50 per cent female predominance. However, this is a striking finding that has not been verified in other series. In Chicago,25 there were no sex differences. Environmental Factors

It has been postulated that ulcerative colitis can be caused by an abnormal response to organisms that are not pathogenic to normal individuals. These organisms should be pathogenic only to individuals who have a genetically predetermined increased susceptibility. High antibody titres to a particular type of Escherichia coli have been found in ulcerative colitis. 13 These discoveries aroused much interest when they were made during the 1960s. It has, however, never been possible to put these findings into perspective in relation to the etiology of ulcerative colitis. Genetic Markers In the case of ulcerative colitis there is the same association with ankylosing spondylitis and HLA-B27 as for Crohn's disease. The titers of E. coli antibodies in asymptomatic relatives of patients with ulcerative colitis has also been investigated. 14 A slight increase only in female relatives was found. The unresolved problem is still how to separate the relative importance of genetic and environmental factors. One method of differentiation is that of complex segregation analysis. 15 The mixed model of complex segregation analysis can be used to separate monogenic from polygenic and environmental factors in causing familial disease aggregation. The method has been used for several disorders such as multiple sclerosis, leprosy, and diabetes mellitus. The model allows for a major locus with two alleles, a continuous variable representing polygenic and cultural inheritance as well as for random error. In a study from Stockholm,22 963 patients were interviewed and among these were 65 who had one or more relatives with ulcerative colitis. The

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complete pedigrees were done for all these 65 families. The pedigrees were than subdivided into 124 nuclear families (that is, parents and children) and submitted to segregation analysis. The multifactorial model gave a high estimate of heritability (0.999) that speaks in favor of a major gene. The best fitting model was an additive gene and there was no evidence for a multifactorial component. In summary, the study indicated that familial cases of ulcerative colitis are due to a rare additive major gene, the probability being 99 per cent that an affected individual with positive family history is heterozygous for this gene. Since only a minority of the cases are familial, however, all cases cannot be explained by an additive gene alone. For definite conclusions, an additional disease marker should be searched for and included in the analysis.

SUMMARY There is ample evidence in the literature that both Crohn's disease and ulcerative colitis are at least partly caused by genetic factors. For the future, it is important to locate markers that can separate patients from healthy individuals. The relative importance of these markers in the etiology can then be investigated by using statistical methods such as segregation analysis.

REFERENCES 1. Acheson ED: The distribution of ulcerative colitis and regional enteritis in United States veterans. Gut 1:291, 1960 2. Almy TP, Sherlock P: Genetic aspects of ulcerative colitis and regional enteritis. Gastroenterology 51:757, 1966 3. Bjarnason I, Peters TJ: Helping the mucosa make sense of macromolecules. Gut 28:1057, 1987 4. Brahme F, Lindstrom C, Wenckert A: Crohn's disease in a defined population. Gastroenterology 69:342, 1975 5. Brewerton DA, Hart FD, Nicholls A, et al: Ankylosing spondylitis and HLA 27. Lancet 1:904, 1973 6. Crohn BB, Yarnis H: Regional Ileitis, ed 2. New York, Grune & Stratton, 1958 7. Farmer RG, Michener WM, Mortimer EA: Studies offamily history among patients with lBD. Clin Gastroenterol 9:271, 1980 8. Farmer RG, Michener WM: Association of inflammatory bowel disease in families. In Rozen P (ed): The Genetics and Epidemiology of Inflammatory Bowel Disease. Basel, Karger, 1986 9. Hammer B, Ashurst P, Naish J: Diseases associated with ulcerative colitis and Crohn's disease. Gut 9:17, 1968 10. Hellers G: Crohn's disease in Stockholm county. Acta Chir Scand 490 (suppl):I, 1979 11. Hollander D, Wadheim CM, Brettholz E, et al: Increased intestinal permeability in patients with Crohn's disease and their relatives. Ann Intern Med 105:883, 1986 12. Kirsner JB, Spencer JA: Familial occurrences of ulcerative colitis, regional enteritis and ileocolitis. Ann Intern Med 59:133, 1963 13. Lagercrantz R, Hammarstrom S, Perlmann P, et al: Immunological studies in ulcerative colitis IV. J Exp Med 128:1339, 1968 14. Lagercrantz R, Hammarstrom S, Perlmann P: Immunological studies in ulcerative colitis V. Gastroenterology 60:381, 1971

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15. Lalouel JM, Morton NE: Pedigree analysis with pointers. Human Hered 30:320, 1981 16. Lashner BA, Evans AA, Kirsner JB, et al: Prevalence and incidence of inflammatory bowel disease in family members. Gastroenterology 91:1396, 1986 17. Magnusson KE, Sundqvist T, Sjodahl R, et al: Altered intestinal permeability to lowmolecular-weight polyethylene glycols (PEG-400) in patients with Crohn's disease. Acta Chir Scand 149:323, 1983 18. Mayberry JD, Rhodes J, Ncwcombe RG: Familial prevalence of inflammatory bowel disease in relatives of patients with Crohn's disease. Br Med J 284:235, 1982 19. McConnell RB: Ulcerative colitis-genetic features. Scand J Gastroent 18(suppl):14, 1983 20. Monk M, Mendeloll' AS, Siegel Cl, et al: An epidemiological study of ulcerative colitis and regional enteritis among adults in Baltimore. Gastroenterology 56:847, 1969 21. Monsen U, Brostrom 0, Nordenvall B, et aI: Prevalence of inflammatory bowel disease among relatives to patients with ulcerative colitis. Scand J Gastroenterol 22:214, 1987 22. Monsen U, Iselius L, Johansson C, et al: Genetic analysis of ulcerative colitis. Clin Genetics, in press 23. Murray CJW, Thomson ABR: Marital idiopathic inflammatory bowel disease. J Clin Gastroenterol 10:95, 1988 24. Rozen P, Zonis J, Yekutiel P, et al: Crohn's disease in the Jewish population of Tel-AvivYafo. Gastroenterology 76:25, 1979 25. Singer HC, Anderson JGD, Frischer H, et al: Familial aspects of inflammatory bowel disease. Gastroenterology 61:423, 1971 26. Tysk C, Lindberg E, Jarnerot G, et al: Ulcerative colitis and Crohn's disease in an un selected population of monozygotic and dizygotic twins. Gut 29:990, 1988 27. Weterman IT, Pena AS: Family occurrences in Dutch patients with Crohn's disease. Scand J GastroenteroI17:354, 1982 28. Weterman IT, Pena AS: Familial incidence of Crohn's disease in the Netherlands. Gastroenterology 86:449, 1984

Address reprint requests to Goran Hellers, MD, PhD Department of Surgery Karolinska Institute Huddinge University Hospital S-141 86 Huddinge Sweden