Familial aggregation of inflammatory bowel disease in northern Italy: A multicenter study

GASTROENTEROLOGY

1992:103:514-519

Familial Aggregation of Inflammatory Bowel Disease in Northern Italy: A Multicenter Study GIANMICHELE MARIATERESA

MEUCCI, MAURIZIO VECCHI, GIUSEPPE TORGANO, ARRIGONI, ALBERT0 PRADA, FRANCESCO ROCCA,

MARCELLO CURZIO, ANGELO PERA, ROBERTO DE FRANCHIS, and the GRUPPO DI STUDIO PER LE MALATTIE INFIAMMATORIE INTESTINAL1

(IBD STUDY

GROUP)

To assess the familial aggregation of inflammatory bowel disease (IBD)in Italy, the family pedigrees of 411 patients with ulcerative colitis (UC) and 241 patients with Crohn’s disease (CD) seen at 14 participating hospitals were studied. Sufficient information was obtained on 97% of 3752 first-degree relatives, 80% of 8889 second-degree relatives, and 74% of 5791 cousins. Thirty-six propositi (5.52%) had a total of 44 affected relatives (18CD, 28 UC). The prevalence of IBD was higher in first- than in second-degree relatives and cousins (791,112, and 163 in 100,000, respectively). A strong intrafamilial disease concordance was observed, with 26 cases of UC and 6 of CD among relatives of UC patients and 10 cases of CD and 2 of UC among relatives of CD patients. The prevalence of UC among first-degree relatives of UC patients and that of CD among firstdegree relatives of CD patients was 880 and 531 in 100,000, respectively. In conclusion, there is a high degree of familial aggregation for IBD in Italy, with a strong intrafamilial disease concordance. he etiopathogenesis of inflammatory bowel disease (IBD) is still poorly understood; however, some lines of evidence suggest that genetic factors play an important role.’ Although no definite association with any HLA haplotypes has ever been found, it has often been reported that some IBD patients share with their healthy relatives several typical functional or immunological abnormalities, such as increased intestinal permeability,’ complement dysfunction,3 or the presence in serum of some autoantibodies.4s5 More importantly, a strong familial aggregation of both Crohn’s disease (CD) and ulcerative colitis (UC) was recognized soon after the discovery of these diseases. Apart from reports of familial case clusterings,6*7 several older studies showed a high crude rate of positive family histories of IBD among patients with IBD.“-’ More recently, some populationas well as hospital-based surveys have shown that the prevalence of both CD and UC is unquestionably

T

increased in relatives of IBD patients, especially first-degree relatives, compared with the general population.*0-‘7 However, reliable data. concerning the degree of such familial aggregation in Southern European countries are still surprisingly sparse. Because the genetic background of IBD patients may vary widely among different populations, a better elucidation of this issue may help in understanding both genetic and pathogenetic aspects of these diseases. In the present multicenter study, we report for the first time a high degree of familial aggregation of IBD in a large series of Italian IBD patients. Materials and Methods The study population consisted of patients with a firmly established diagnosis of either CD or UC who attended the gastroenterology units of 14 hospitals in Northwestern Italy during 1989 and 1990. The participating institutions were heterogeneous regarding the number of IBD patients, ranging from one large tertiary referral center with approximately 1000 patients on regular follow-up to small-hospital gastroenterology units with no more than 20 IBD patients. The number of IBD patients was 100-200 in 3 centers (1 university clinic and 2 hospital clinics), approximately 80 in 1 and 20-40 in the other 9. In 13 of these centers, every effort was made to enroll as many patients as possible, whereas in the above-mentioned tertiary referral center a random sample, including about 10% of the total patient population, was drawn. A standard questionnaire aimed at collecting data about first-degree (parents, siblings, and offspring) and seconddegree (uncles/aunts, nephews/nieces, grandparents, and grandchildren) relatives as well as about cousins was prepared and administered to patients by means of personal interviews performed by physicians at the time of outpatients visits. According to this questionnaire, patients were requested to indicate the following data for each degree of relationship: number and sex of all relatives, alive and dead; number and sex of relatives about whom the pa0 1992 by the American

Gastroenterological 0016-5085/92/$3.00

Association

August 1992

tients had sufficient information concerning the presence or absence of IBD (it was assumed that a patient could pro-

vide “sufficient information” on a given relative when the patient claimed to be currently in touch with the relative and to be sure that if the relative were affected by IBD or by any other chronic disease, he or she would have been aware of it); and number and sex of relatives, if any, with an established diagnosis of IBD. Medical records of such relatives were requested for review, and only subjects in whom it was possible to confirm the reported diagnosis in this way were regarded as having IBD. Several demographic (age, sex, origin, address) as well as clinical (type, location, duration, age at onset of disease) data were also recorded, and mean age, mean age at onset, and mean duration of disease were calculated. Whenever two or more members of the same family were attending the same clinic, only one (i.e., the first coming to clinic during the study period) was regarded as a propositus, while the other(s) were regarded as relatives. Similarly, cross-checks were made to identify affected members of the same family attending different clinics among the 14 participating centers; however, this never happened. Frequencies of IBD were calculated by dividing the number of relatives with the disease by the number of those about whom sufficient information was obtained; 95% confidence intervals for these proportions were calculated based on the Poisson distribution. Frequencies of IBD in different groups of relatives were compared using Fisher’s Exact Test, while crude rates of positive family history between CD and UC patients were compared using the x2 test. Because only incidence data are available as epidemiological figures of IBD in Italy,“’ the observed frequencies could be compared only to an estimated prevalence in the general population as given by the formula P = It, where P is prevalence, I is incidence, and t is duration of disease (i.e., the mean time from diagnosis to death).lg This comparison was carried out by means of inference on a binomial distribution. Continuous variables were compared using Student’s t test for unpaired data.

Results A total of 652 patients were included in the study, with a minimum of 11 and a maximum of 123 patients enrolled in each center. Of these patients, 92 were the random sample from the tertiary referral center, as described in Materials and Methods; the remaining 560 subjects represented 82.5% of all IBD patients attending the other 13 participating institutions, with enrollment rates varying from 47% to 100% among centers. It should be noted that in 9 of these 13 centers, including all of the largest ones, an enrollment rate of 280% was achieved; the other 4 were small centers, with 20-40 IBD patients on regular follow-up. Of the enrolled subjects, 411 had UC and 241 had CD. The mean age of patients was 42 years (range, 15-87 years). The family pedigrees of these 652 pa-

FAMILIAL AGGREGATION

OF IBD IN ITALY

515

tients included a total of 18,412 relatives: 3752 firstdegree relatives, 8869 second-degree relatives and 5791 cousins: sufficient information on 15,047 (81.7%) of them was available. Different rates of sufficient information were obtained when patients were interviewed about their relatives; the highest rate (98.5%) was for data regarding parents, and the lowest (68.2%) was for grandparents. These percentages were not significantly different between CD and UC patients’ pedigrees (Table 1). A positive family history of IBD was reported by 36 patients: 26 (6.32%) of 411 with UC and 10 (4.15%) of 241 with CD (P = 0.319; NS); in every case, the reported diagnoses were confirmed by reviewing the relevant medical records. Therefore, the resulting overall crude rate of positive family histories was 5.52%. Thirty patients had only one affected relative, 5 had 2, and 1 had 4. This last patient was a Z&year-old woman whose mother had CD, whose sisters both had UC, and whose uncle (a mother’s brother) was affected by UC. Thus, 44 IBD cases (28 UC, 16 CD) were identified among the 15,047 relatives on whom sufficient information was available, giving an overall prevalence of 0.29%. Only 12 of these 44 patients were attending the same clinic as the corresponding propositi; the remaining 32 had never been seen in any of the 14 participating institutions and were identified merely by means of the family investigation. The highest prevalence was observed among siblings (1.2%), the lowest among grandchildren (0%) (Table 2). The overall IBD prevalence was 791 in 100,000 (491 in 100,000 for UC and 300 in 100,000 for CD) among first-degree relatives, 113 in 100,000 among second-degree relatives, and 163 in 100,000 among cousins (Table 3). The prevalence of UC and of CD was significantly higher in first-degree than in second-degree relatives or cousins (P < 0.005 to P < 0.001; x2 or Fisher’s Exact Test as appropriate). When the family pedigrees were divided according to the diagnosis of the propositi, a strong disease concordance was evident; in fact, there were 10 cases of CD and only 2 of UC among relatives of CD patients, whereas 26 cases of UC but only 6 of CD were recorded in families of UC patients. Therefore, the prevalence of CD among first-degree relatives of CD patients was 531 in 100,000, and that of UC among first-degree relatives of UC patients was 680 in 100,000. By contrast, the corresponding figures concerning CD among relatives of UC patients and vice versa were only 170 in 100,000 and 151 in 100,000, respectively (Table 4). The mean age at onset of disease was virtually identical in patients with and without a positive family history of IBD [34.1 (range, 19-67) vs. 34.6 (9-76)

516

MEUCCI ET AL.

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Table 1. Relatives of Patients With IBD Overall Sufficient information obtained WJ)

Total n

Relationship Parents Offspring Siblings Uncles/aunts Nephews/nieces Grandparents Grandchildren Cousins Total

CD

Total n

98.5

482

98.5

96.1 97.8

271 592

97.8 97.3

499 1086

95.2 98.1

4134

83.6

1450

83.7

2684

83.6

1867 2608 260 5791 18,412

88.4 68.2 80.8 74.0 81.7

676 964 64 2089 6588

84.8 72.5 96.9 73.5 82.0

1191 1644 196 3702 11,824

90.5 65.6 75.5 74.2 81.6

To the best of our knowledge, this is the first study showing a high degree of familial aggregation of IBD in Southern Europe. In two previously reported series of Italian IBD patients, no relatives, or very few, were recognized as having IBD.20,21However, the number of patients included in both studies was too small for any conclusion to be drawn. Indeed, in our multicenter study of more than 600 IBD patients, about 5% of propositi had one or more relatives affected; moreover, the frequencies of IBD were nearly 800 in 100,000 among first-degree relatives and 1.2% among siblings, such figures being un-

Table 2. Prevalence of IBD Among Patients Sufficient information obtained (n) 1285 740 1641 3458 1651 1778 210 4284 15,047

Total n

Sufficient information obtained (%I

770 1678

Discussion

Parents Offspring Siblings Uncles/aunts Nephews/ nieces Grandparents Grandchildren Cousins Total

Sufficient information obtained (%I

1304

years, respectively], whereas the mean age of patients at the time of enrollment was slightly but not significantly higher in the former group [44.8 (range, 24-69) vs. 41.7 (15-87) years]. On the other hand, the mean duration of disease was significantly longer in patients with a positive family history [lo.7 (range, l-40) vs. 7.1 (l-36) years; P < O.OOl].

Relationship

UC

Relatives

Affected by CD [n (%)I 2 2 7 3

(0.15) (0.27) (0.43) (0.09)

1 (0.06) 0 (0.00)

0 (0.00) 1 (0.02) 16 (0.11)

of 652

IBD

Affected by UC [n (%)I

Total affected

4 1 13 2

(0.31) (0.13) (0.79) (0.05)

6 3 20 5

(0.47) (0.40) (1.22) (0.14)

1 1 0 6 28

(0.06) (0.06) (0.00) (0.14) (0.18)

2 1 0 7 44

(0.12) (0.06) (0.00) (0.16) (0.29)

[n (%)I

822

98.5

doubtedly higher than any prevalence ever detected in the general population, all over the world.” Because no data are available on the prevalence of IBD in Italy, a direct comparison of these figures with those concerning the general population is currently impossible. However, it is generally accepted that the prevalence of a disease can be grossly estimated by multiplying the incidence by the duration of the disease itself-l9 In a recent Italian study, incidences of 2 in 100,000 per year for CD and 5 in 100,000 per year for UC’* have been recorded. Therefore, assuming a mean duration of 40 years for both diseases, the prevalence figures can be estimated as 80 in 100,000 for CD, 200 in 100,000 for UC, and 280 in 100,000 for the two diseases together. These resulting estimates are about 2.5 times smaller than the figures recorded in first-degree relatives. The probability of the observed frequencies in first-degree relatives occurring by chance in a sample drawn from a population with the above-mentioned prevalence figures is 0.00023 for CD, 0.00058 for UC, and 0.0000012 for the two diseases together-l9 It should also be noted that the above-mentioned figures most likely represent an overestimate of the real prevalence of IBD in Italy for three reasons. First, the mean duration of IBD is likely to be somewhat overestimated by the figure of 40 years, given the fact that the mean age at onset was 34 years in our patients. Second, the incidence of IBD in Italy appears to have increased in the last 3 decades,l’ and in our estimate the most recent figure of incidence was used. Third, in all published studies in which incidence and prevalence were assessed simultaneously, the ratio between the two figures never exceeded 20.” A strong disease concordance was also observed, with a 680 in 100,000 prevalence of UC among firstdegree relatives of UC patients, a 531 in 100,000 prevalence of CD among first-degree relatives of CD pa-

FAMILIAL AGGREGATION

August 1992

Table 3. Prevalence

of

IBD in Relatives of Patients

Sufficient information obtained (n)

Relationship First-degree relatives

3666

[Prevalence

11

Affected by UC (Cl.)]

(n)

300

[Prevalence

Total affected (C.I.)]

(n)

29

791 (530-1136) 113 (49-222) 163 (66-337) 292

7097

4

(155Y44)

4

(155i44)

8

Cousins

4284

1

(lY30)

6

7

15,047

16

140 (51-305) 186

NOTE. Prevalence C.I..95% confidence

28

Table 4. Comparison

therefore patients may more frequently seek care in tertiary referral centers to obtain more skilled assistance. Unfortunately, a population-based family study in Italy is still not feasible because of the lack of any registry of IBD patients; therefore, the only way to minimize the problem of selection bias is to include patients from a wide number of gastroenterology units in which both secondary and tertiary referral centers are represented. In our series a significantly larger percentage of positive family histories was observed among patients attending tertiary than secondary referral centers (data not shown); however, given the fact that only two participating institutions can be regarded as tertiary referral centers and that, overall, a very high percentage of the patients attending the clinics was included, it can be assumed that our sample is fairly representative of Italian IBD patients attending any gastroenterology clinic. When comparing our data with those from previous studies on this topic, it can be noted that our figures are much closer to those from either hospitalor population-based studies carried out in Northern

of Prevalence

of IBD in Relatives

of Patients

With CD and Patients

Relatives of patients with CD

First-degree relatives Second-degree relatives Cousins Total NOTE. Prevalence

44

per 100,000 interval.

tients, and much lower frequencies of UC among CD patients’ relatives and vice versa. On the other hand, the corresponding figures among second-degree relatives and cousins of our patients were 3--T-fold lower. However, in the absence of reliable data regarding the prevalence of IBD in the Italian general population it is impossible to infer by our data whether the risk of being affected by IBD is also increased in second-degree relatives and/or cousins of Italian IBD patients. Although crude rates of up to 40% of family IBD history,” as well as frequencies of IBD as high as 2% among siblings,13 have been described, it has been suggested that data from tertiary referral centers may grossly overestimate the real degree of familial aggregation of IBD and that a reliable estimate can be provided only by population-based studies.‘2~‘3 In fact, as a rule, patients attending tertiary referral centers have more severe disease than the average, and a correlation between familial aggregation and severity of disease may exist.‘sl” Furthermore, in families with more than one member affected by IBD, awareness of the problems associated with these diseases may be greater than in other families, and

Relationship

(CL)]

491 (291-776)

Second-degree relatives

106

[Prevalence

18

(150-537)

Total

517

With IBD

Affected by CD (n)

OF IBD IN ITALY

Sufficient information obtained (n)

Affected by CD [n (prevalence)]

Affected by UC [n (prevalence)]

With UC

Relatives of patients with UC Total affected In (prevalence)]

Sufficient information obtained (n)

Affected by CD Ln (prevalence)]

Affected by UC In (prevalence)]

[n (prevalence)]

Total affected

1316

7

532

2

152

9

684

2350

4

170

16

682

20

851

2548 1536 5400

3 0 10

228 0 185

0 0 2

0 0 37

3 0 12

118 0 222

4549 2748 9647

1 1 6

22 36 62

4 6 26

88 218 269

5 7 32

110 255 332

per 100,000.

518

MELJCCI ET AL.

than to those coming from some terEurope 11-12~15-17 tiary referral centers of North America in which, as expected, a much higher degree of familial aggregation was reported.10’13 However, although our crude rate of positive family histories is similar to those reported in the above-mentioned European surveys, figures of prevalence, especially those concerning concordant disease among first-degree relatives, are generally 2-3-fold greater in those studies than in the present one. Whether this is due to a lower prevalence of IBD in Italy (the relative risk of IBD among relatives being the same as that of North European populations), to a truly lower relative risk among relatives, or to both, is still to be determined. It is possible that data arising from ongoing epidemiological studies’8,23,24 will soon allow clarification of this issue. The finding of a much higher prevalence of IBD among first-degree than among second-degree relatives or cousins, on the other hand, has been constant in all studies13,‘5-17 and is confirmed by our data. Although it has been suggested that such differences may be overestimated because patients can more easily recall diseases affecting closer relatives than those affecting more distant ones,13 it is generally believed that this bias is not sufficient to fully explain so large a difference. In addition, in the present study every effort was made to minimize this problem. In fact, patients were asked to indicate the relatives on whom they had positive information about the presence or absence of IBD, and only such subjects were considered in calculating frequencies of disease. Furthermore, the family pedigrees were investigated by means of face-to-face interviews performed by the same physicians who usually performed outpatient visits rather than by a self-administered questionnaire mailed to the patients’ houses. It is conceivable that this resulted in greater accuracy of data recalled by patients. Moreover, the pattern of familial aggregation we observed in the present study could by no means be explained by age-dependent differences in IBD prevalence. Should this be the case, in fact, we would anticipate observing the highest prevalence in grandparents, parents, and uncles or aunts and the lowest prevalence in offspring, nephews or nieces, and grandchildren. Indeed, we observed the highest prevalence in siblings, and the prevalence was nearly identical among cousins, nephews or nieces, and uncles or aunts. It has been reported several times that the familial aggregation of IBD is greater among relatives of CD This has also been found than of UC propositi. 6,8~10~13 for the prevalence of discordant disease (more UC in relatives of CD patients than vice versa).8s*3 Based on these observations, as well as on the finding of a

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higher concordance rate for CD than for UC among monozygotic twins,7 some years ago MC Connell proposed a theory according to which CD and UC are polygenic hereditary diseases sharing genes conferring subsceptibility. CD results when a higher number of such genes are present in a given individual, UC when that number is lower.‘*8 However, our data cannot support this hypothesis; in fact, the overall prevalence of IBD was slightly higher in pedigrees of UC than of CD patients, and the prevalence of discordant disease among first-degree relatives was nearly the same in the two groups. Data from a recent population-based study carried out in Sweden are instead entirely in keeping with MC Connell’s mode1,15~17whereas in the Danish population study the relative risk was similar for the two diseases although a much higher prevalence of UC among CD patients’ relatives than of CD among UC patients’ relatives was observed.16 Whether these puzzling discrepancies truly reflect geographical differences in the genetic background of IBD patients and/or different interactions between genetic and environmental factors deserves further evaluation. In conclusion, our study shows that in Italy, as well as in several North American and Northern European countries, the prevalence of IBD is higher among relatives of IBD patients than in the general population; therefore, familial aggregation can be regarded as a common feature of IBD in all Western countries. This finding supports the concept that genetic factors may play an important role in the pathogenesis of IBD. However, the relative importance of genetic and environmental factors in determining such familial aggregation cannot be assessed on the basis of studies such as the present one. Recently, by means of segregation analysis, it has been suggested that the pattern of familial aggregation of both CD and UC may be explained at least in part by some inheritance model, implicating the presence of genes conferring susceptibility to the disease.25+2”Moreover, some scanty evidence indicates that environmental factors, such as smoking, can act as modulators of a genetically determined susceptiFurther studies on these matbility to CD or UC. 27~28 ters in different geographical areas are warranted. References I. McConnell RB. Genetics of inflammatory

bowel disease. In: Allan RN, Keighley MRB, Alexander-Williams J, Hawkins C, eds. Inflammatory bowel disease. New York: Churchill Livingstone, 1983:8-16. 2. Hollander D. Crohn’s disease-a permeability disorder of the tight junction? Gut 1988;11:17-26. 3. Elmgreen J, Both H, Binder V. Familial occurrence of complement dysfunction in Crohn’s disease: correlation with intes-

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tinal symptoms and hypercatabolism of complement. Gut 1985;27:151-157. Fiocchi C, Roche JK, Michener WM. High prevalence of antibodies to intestinal epithelial antigens in patients with inflammatory bowel disease and their relatives. Ann Intern Med t989;iio:786-794. Shanahan F, Duerr R, Rotter J, Yang H, Sutherland L, McElree C, Landers C, Targan S. Neutrophil autoantibodies in ulcerative colitis: familial aggregation and genetic heterogeneity (abstr). Gastroenterology 1991;100:A614. Kirsner JB, Spencer JA. Family occurrences of ulcerative colitis, regional enteritis, and ileocolitis. Ann Intern Med 1963;59:133-144. Kirsner JB. Genetic aspects of inflammatory bowel disease. Clin Gastroenterol 1973;2:557-575. Lewkonia RM, McConnell RB. Familial inflammatory bowel disease-heredity or environment? Gut 1976;17:235-243. Korelitz BI. Epidemiological evidence for a hereditary component in Crohn’s disease. In: Pena AS, Weterman IT, Booth CC, Strober W, eds. Recent advances in Crohn’s disease. Volume 1. The Hague: Martinus Nijhoff, 1981:208-212. Farmer RG, Michener WM, Mortimer EA. Studies of family history among patients with inflammatory bowel disease. Clin Gastroenterol 1980;9:271-278. Mayberry JF, Rhodes J, Newcombe RG. Familial prevalence of inflammatory bowel disease in relatives of patients with Crohn’s disease. Br Med J 1980;1:84. Weterman IT, Pena AS. Familial incidence of Crohn’s disease in the Netherlands and a review of the literature. Gastroenterology 1984;86:449-452, Lashner BA, Evans AA, Kirsner JB, Hanauer SB. Prevalence and incidence of inflammatory bowel disease in family members. Gastroenterology 1986;91:1396-1400. Fielding JF. The relative risk of inflammatory bowel disease among parents and siblings of Crohn’s disease patients. J Clin Gastroenterol 1986;8:655-657. Monsen U, Brostrom 0, Nordenwall B, Sorstad J, Hellers G. Prevalence of inflammatory bowel disease among relatives of patients with ulcerative colitis. Stand J Gastroenterol 1987;22:214-218.

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Orholm M, Munkholm P, Langholz E, Nielsen OH, Sorensen TIA, Binder V. Familial occurrence of inflammatory bowel disease. N Engl J Med 1991;324:84-88. 17. Monsen U, Bernell 0, Johansson C, Hellers G. Prevalence of inflammatory bowel disease among relatives of patients with Crohn’s disease. Stand J Gastroenterol 1991;26:302-306. ia. Amanta E, Barbara L, Biasco G, Boari C, Cacciari E, Cavalli GC, Cola B, Conti A, Corazza GG, Dal Monte PR, Di Febo G, Gandolfi L, Gasbarrini G, Gozzetti G, Lanfranchi GA, Lazzari R, Leo P, Lucisano E, Malaguti P, Marrano D, Mattei N, Miglioli M, Minni F, Muscari A, Paolucci P, Pisi E, Poggioli G, Puddu P, Re G, Roda E, Sarti F, Stefanini F, Tassinari D, Tragnone A, Volta U. Incidence and prevalence of inflammatory bowel disease in Bologna-risk factors (abstr). Stand J Gastroenterol 1989;24(suppl 58):63. 19. Armitage P, Berry G. Statistical methods in medical research. 2nd ed. Oxford: Blackwell Scientific, 1987. 20. Cardellicchio A, Lonardo A, Scuotto A, Viscardi A, Mazzacca C. Familial history in IBD (letter). Dig Dis Sci 1985;30:410.

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21. Di Simone A, Riegler G. Familial histories in ulcerative colitis (letter). Dig Dis Sci 1987;32:334. 22. Mendeloff AI, Calkins BM. Epidemiology of idiopathic inflammatory bowel disease. In: Kirsner JB, Shorter RG, eds. Inflammatory bowel disease. 3rd ed. Philadelphia: Lea & Febiger, 1988:3-34. 23. Cottone M, Orlando A, Cipolla C, Oliva L, Pagliaro L. Hospital incidence of Crohn’s disease in the province of Palermo: a two year study (abstr). Stand J Gastroenterol1989;24(suppl58):64. 24. Campanini MC, Ranzi T, Bianchi PA, Vignotti D, Lisciandrano D, Bodini P, Politi P, Zambelli A, Lupinacci G, and IBD Study Group of USSL Nos 51 and 53 (Lombardy). Incidence of inflammatory bowel disease (IBD) in a defined area of North Italy: a four-year prospective study (1990-1993) (abstr). Gastroenterology 1991;100:A3. 25. Kuster W, Pascoe L, Purrmann J, Funk S, Majewski F. The genetics of Crohn’s disease: complex segregation analysis of a family study with 265 patients with Crohn’s disease and 5,387 relatives. Am J Med Genet 1989;32:105-108, epidemiological 26. Monsen U. Inflammatory bowel disease-an and genetic study. Acta Chir Stand 199O;S559:7-42. 27. Smith MB, Lashner BA, Hanauer SB. Smoking and inflammatory bowel disease in families. Am J Gastroenterol 1988;83: 407-408.

28. Tysk C, Lindberg E, Jarnerot G, Floderus-Myrhed B. 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;29:990-996.

Received August 5, 1991. Accepted February 18, 1992. Address requests for reprints to: Roberto de Franchis, M.D., Istituto di Medicina Interna, Via Pace 9, 20122 Milan, Italy. The following Institutions, members of the G.S.M.I.I., have taken part in the study: Istituto di Medicina Interna, Universita’ di Milano, Milan: Servizio di Gastroenterologia, Ospedale di Rho: Divisione di Medicina Prima, Ospedale di Busto Arsizio; Divisione di Gastroenterologia, Ospedale di Circolo, Varese; Divisione di Gastroenterologia, Ospedale Molinette, Turin; Sezione Aggregata di Gastroenterologia, Ospedale S. Orsola, Brescia; Centro di Endoscopia Digestiva, Ospedale Civile, Brescia; Sevizio di Gastroenterologia, Ospedale Valduce, Como; Divisione di Chirurgia, Ospedale San Carlo, Milan; Servizio di Gastroenterologia, Ospedale Civile, Legnano; Servizio di Gastroenterologia. Ospedale Maggiore, Novara; Servizio di Endoscopia, Ospedale di Crema; Divisione di Medicina Prima, Ospedale di Sale; and Divisione di Medicina Prima, Ospedale di Garbagnate, Italy. Other participants: Renzo Gullotta, Luigi Gianfrate (Varese), Alessandro Paterlini, Pietro Cesari, Federico Buffoli (Brescia-Santorsola), Renzo Cestari, Paolo Ravelli, Carmen Terraroli (Brescia, Ospedale Civile), Giorgio Minoli, Gianni Imperiali, Vittorio Terruzzi (Como), Marco Astegiano, Alessandro Musso, Silvana Barbaro, Riccardo Vanni (Turin), Eugenio Limido, Enrico Lesinigo (Busto Arsizio), Aurora Bortoli, Alfred0 Porro (Rho), Giorgio Mortara, Maria Grazia Vantadori (Milan-San Carlo), Aldo Ferrara, Stefania Baroni, Stefano Caruso (Legnano), Mario de1 Piano, Pietro Occhipinti, Franc0 Montino (Novara), Alessandro Zambelli, Guido Lupinacci (Crema), Walter Piubello, Gian Piero Aimo (Sale), Enrico Colombo, Davide Redaelli (Garbagnate), Matte0 Levati, Paolo Omodei (Milan, Istituto di Medicina Interna).