Familial inflammatory disease: differences Jews non-Jews · disease:...

Gut 1993; 34: 517-524

Familial empirical risks for inflammatory boweldisease: differences between Jews and non-Jews

H Yang, C McElree, M-P Roth, F Shanahan, S R Targan, J I Rotter

AbstractThe Jewish population has an increased fre-quency of inflammatory bowel disease com-pared with their non-Jewish neighbours.Genetic factors have been implicated in theaetiology of this disorder and may contributeto ethnic differences. This study determinedthe familial empirical risks for inflammatorybowel disease in the first degree relatives ofinflammatory bowel disease probands (forboth Jews and non-Jews) for the purpose ofaccurate genetic counselling and geneticanalysis. A total of 527 inflammatory boweldisease patients from Southern California (291Jews and 236 non-Jews) were questioned aboutinflammatory bowel disease in their firstdegree relatives (a total of 2493 individuals).Since inflammatory bowel disease has a vari-able and late age ofonset, age specific incidencedata were used to estimate the life time risksand to make valid comparisons between thedifferent groups. In the first degree relatives ofnon-Jewish probands, the life time risks forinflammatory bowel disease were 5-2% and1.6% when probands had Crohn's disease andulcerative colitis respectively. These valueswere consistently lower than the correspond-ing risks for relatives ofJewish patients - 7-8%and 4*5% for Crohn's disease and ulcerativecolitis probands respectively (p value for com-parison between Jews and non-Jews: 0*028;between ulcerative colitis and Crohn's disease:0.005). These data provide the requisite basisfor genetic counselling for these disorders inthe white American population. In addition,these different empirical risks for relatives ofJewish and non-Jewish probands allow rejec-tion of single Mendelian gene models forinflammatory bowel disease, but are consistentwith several alternative genetic models.(Gut 1993; 34: 517-524)

The aetiology and pathogenesis of the inflam-matory bowel diseases remain unknown. Avail-able epidemiological data show that the Jewishpopulation has a higher risk of developinginflammatory bowel disease than other ethnicgroups, three to four times higher than their non-Jewish neighbours.1-' Within the Jewish popula-tion, heterogeneity was found among the dif-ferent historical ethnic subgroups,'I` that isAmerican or European Ashkenazi Jews seem tohave an increased risk compared with Sephardicor Oriental Jews,' 8 and Ashkenazi Jews ofmiddle European origin have an excess riskrelative to those of Polish/Russian origin.9 '°Although the different incidence/prevalenceamong the different Jewish subgroups maysuggest environmental aetiological agents," the

repeated observations that the Jewish populationhas a consistently increased incidence/preval-ence compared with other ethnic groups in thesame location, and that this occurs across dif-ferent time periods as well as different geo-graphical areas,3 12 indicates a genetic predisposi-tion to develop this disease.Both an increased frequency of a positive

family history of inflammatory bowel diseaseamong inflammatory bowel disease patients andan increased risk of inflammatory bowel diseasein their relatives are the evidence for familialaggregation of the disease.3 13-15 This familialaggregation of inflammatory bowel disease hasbeen shown in both Jewish and non-Jewishfamilies. The ethnic differences reviewed aboveand the familial aggregation might be the resultof either genetic or environmental factors actingalone, or together. The increased monozygotictwin concordance rates,'6 the rarity of inflam-matory bowel disease concordance in spouses,4 15and the numerous instances of affectedrelatives whose disease onset is completelyseparated geographically and temporally fromother affected family members,'7 argues, how-ever, for a major genetic component to diseasesusceptibility. In addition, the co-occurrence ofulcerative colitis and Crohn's disease in the samefamilies suggests that these two disorders (ora subset of these disorders) share a commongenetic background.3' 15We have previously reported familial

empirical risk estimates of inflammatory boweldisease, as well as the more appropriate ageadjusted risks for genetic counselling andmodelling in Ashkenazi Jews in the UnitedStates.'8 As there is a different populationfrequency of inflammatory bowel disease inJews and non-Jews, these empirical risk dataare needed for each group to provide morespecific risk estimates for genetic counselling.In addition, the comparison of familial aggrega-

TABLE I Stromgren's methodfor calculation ofage correctedrisk estimatesfor inflammatory bowel disease

Age bi c(y) ai (%) (%) d

<10 1 0 70 1 79 1-79 0 008910-19 2 5-26 13-48 15-27 0.085320-29 3 7 53 19-30 34 57 0-249230-39 4 5 33 13 66 48-23 0414040-49 5 5-90 15-12 63 35 0 557950-59 6 5 34 13-68 77 03 0 701960-69 7 520 1333 9036 0-836970+ 8 3-76 9-64 100 00 0-9518Total 39-02 100-00

ai =age specific incidence rates (per 100 000) of ulcerative colitisand Crohn's disease for whites, Baltimore, 1977-1979.b =proportion of total risk by age group, bi(%)=ai x I00%/Eai.c,=cumulative proportional risk, c,(%)-=b(b%)di=correction factor for ith age group, di=(bi/2+Ci )/100.

Division of MedicalGenetics, Division ofGastroenterology, andInflammatory BowelDisease Center,Departments of Medicineand Pediatrics, Cedars-Sinai Medical Center andUCLA School ofMedicine, Los Angeles,USAH YangC McElreeM-P RothS R TarganJ I Rotter

Division ofGastroenterology,Department of Medicine,University ofCalifornia atLos Angeles, USAF Shanahan

INSERM Unite 100,Toulouse, FranceM-P RothCorrespondence to:Dr H Yang, Division ofMedical Genetics, Cedars-Sinai Medical Center, 8700Beverly Boulevard, LosAngeles, CA 90048.Accepted for publication7 September 1992

517

on Decem

ber 17, 2020 by guest. Protected by copyright.

http://gut.bmj.com

/G

ut: first published as 10.1136/gut.34.4.517 on 1 April 1993. D

ownloaded from

http://gut.bmj.com/

Yang, McElree, Roth, Shanahan, Targan, Rotter

tion of inflammatory bowel disease in these twoethnic groups may contribute to understandingof the aetiologies of the disorder.

In this study, we ascertained both Jewish andnon-Jewish patients with inflammatory boweldisease from the same geographical area anddetermined the prevalence of inflammatorybowel disease in their first degree relatives. Acomparison of the familial aggregation betweenthese two groups was then made, taking intoaccount the age distribution in relatives. Theresults indicate distinct empirical risks for eachethnic group.

Methods

DATA COLLECTIONWe ascertained 759 patients with inflammatorybowel disease from two large west Los Angelesgastroenterology practices and from the UCLAinflammatory bowel disease clinical programmeduring the period from 1986 to 1991. The patientcomposition of these practices is mostly, but notexclusively, white and of middle and uppersocioeconomic status. A letter explaining thestudy was mailed to all patients. Of 759 initialletters sent out, 174 potential subjects wereeliminated because they had died, moved house,or further information indicated that a diagnosisof inflammatory bowel disease was incorrect.Among the remaining 585 eligible patients, 567were interviewed via telephone or at a clinicalvisit, and completed the requisite pedigree in-formation (96 9%). Only 18 (3-1%) refused toparticipate in this study. Of 567 completedinterviews, 28 were non-white subjects and thesewere omitted from the analyses conducted here.To reduce the heterogeneity in the patientpopulation, the 12 cases whose diagnosis wasindeterminate colitis were also excluded from thecurrent report. This resulted in 527 probands,through whom we collected information regard-ing inflammatory bowel disease in their 2493 firstdegree relatives.The diagnosis of ulcerative colitis or Crohn's

disease had been made by the referring gastro-enterologists and documented by endoscopic,radiological, surgical, and pathological reports.Data collected included diagnosis, age, sex, ageat onset of disease, age at diagnosis, pedigree,and ethnicity. As this is an amnestic study, weevaluated the diagnosis of inflammatory boweldisease in relatives by asking the index casesdetailed information regarding the symptoms,treatment, and the course of the disease in theirrelatives. We have also contacted more than 70%of the affected relatives themselves to verify thediagnosis of ulcerative colitis or Crohn's disease.In many cases (43%), medical records wereobtained for further confirmation. Thus, describ-ing the relative as having 'colitis' or 'bowelproblems' was not considered sufficient to classifyhim or her as affected. A positive family historywas defined as the existence of at least one otherblood relative, who could be as distant as thirddegree (for example cousin, grandparent, etc),who had either ulcerative colitis or Crohn'sdisease. In addition, all index cases were un-related to each other. In this study, we defined as

a Jewish proband those individuals with at leastone out of four grandparents of Jewish origin. Inaddition, Jewish as specified here refers to Ash-kenazi Jewish.

STATISTICAL ANALYSISThe crude prevalence of ulcerative colitis orCrohn's disease in the relatives at the time of thestudy was calculated by dividing the number ofaffected relatives by the total number of relativesof the same category. The analyses were per-formed for each category of the probands' firstdegree relatives (siblings, parents, children).Age adjusted empirical risk estimates for sib-

lings, parents, and children were then calculatedusing Stromgren's method of age correction.'920The importance ofperforming these calculationsis that inflammatory bowel disease is not presentat birth, so a true estimate of the risk is obtainedonly when one takes into account the period oflife that an individual has lived through. Thecumulative proportional risk of developing in-flammatory bowel disease up to an age of70 yearswas calculated from the age specific incidencedata per decade in Baltimore published byCalkins et a12' for both ulcerative colitis andCrohn's disease (see Table I), as there is noavailable population incidence data specificallyfrom Los Angeles.The age specific incidence rates of inflamma-

tory bowel disease (ai) provided the basis forcalculating the correction factor for the ageadjustment by Stromgren's method (Table I).The proportion of risk by age group (bi) wascalculated by dividing the incidence rate in anage group over the total risk, which is the sum ofall age specific incidence rates; specifically,bi(%)=aix 100%/fai, (for example for the 2ndage group (age 10-19 years), b2=a2x 100%/al+a2+....+a8)=5-26X100%/39 02=13 48%). Thecumulative proportional risk was defined as thesum of the risks up to a certain age - that is,ci(%)=Xbj(%) (for example for the 3rd agegroup, c3=bl+b2+b3= 1-79+13-48+ 19-30=34 57%). The correction factor was calculatedfrom the cumulative proportional risk by assum-ing an evenly distributed risk in each age interval,di=(bi/2+ci-)/100 (for example for the 4thage group, d4=b4/2+c3= l3-66%/2+34.57%=41-4%, that is, 0-414). The number of firstdegree relatives in each age group was multipliedby the specific correction factor to give an ageadjusted number of relatives at risk. The numberof relatives with inflammatory bowel diseasedivided by the age adjusted total number ofrelatives at risk yields the theoretical risk ofdeveloping inflammatory bowel disease to 70years of age, that is, the prevalence of inflam-matory bowel disease assuming that all relativeswill reach the age of 70 years and that theserelatives have a similar distribution of pro-portional risk as that reported by Calkins et al.2'The result is thereby independent of the actualage distribution. It is, therefore, optimal to usethese age adjusted empirical risk estimates tocompare familial aggregation between Jews andnon-Jews or between other populations.

Statistical analyses included Student's t testsfor quantitative traits, for example, age at onset,

518

on Decem


http://gut.bmj.com

/G


ownloaded from

http://gut.bmj.com/

Familial empirical risksfor inflammatory bowel disease: differences betweenJews and non-Jews

and X2 tests for qualitative variables. The 95%confidence intervals of the prevalence estimateswere estimated according to the assumption thatthe number of cases followed a Poisson distribu-tion when the affected frequency was less than15.11 The adjusted empirical risk of inflam-matory bowel disease (ulcerative colitis or

Crohn's) was estimated separately for relatives ofprobands with ulcerative colitis and those ofprobands with Crohn's disease. Because of thenumber of affected relatives, we did not attemptto calculate separate age adjusted empirical riskestimates for ulcerative colitis and Crohn'sdisease individually in relatives. The com-parisons of crude or adjusted empirical risksbetween groups, for example Jewish v non-

Jewish probands and ulcerative colitis v Crohn'sdisease probands, were tested by Mantel-Haenszel statistics.23

Results

PROBAND AND FAMILY PATTERNSTable II shows the distribution of probands byethnicity, type of inflammatory bowel disease,and the (male/female) sex ratio.

Family size (number of first degree relatives)ranged from 2 to 19 with a median of 4 for bothJews and non-Jews, and a mean of 4-5 for Jewsand 5-1 for non-Jews. There were 39 Jewishfamilies and 15 non-Jewish families with at leastone additional relative affected with inflamma-tory bowel disease among the first degree relativesof the inflammatory bowel disease probands (seeTable III). Among these multiply affectedfamilies, 10 (26%) of the Jewish families and 8(53%) of the non-Jewish families include bothulcerative colitis and Crohn's disease affectedindividuals in the same family (p=0053).

AGE AT ONSET OF INFLAMMATORY BOWEL DISEASEIN PROBANDSThe probands with Crohn's disease had a younger

age of onset (23-1 (14-0), n=257) than those withulcerative colitis (27-7 (16-6), n=267). The dif-ference was highly significant (p<0-001). Theage at diagnosis was on the average 4 years laterthan the age at onset. The analysis of age atdiagnosis of disease showed the same differencebetween ulcerative colitis and Crohn's diseaseprobands as that indicated in the analysis of ageat onset. This was true for all additional analyses.When the comparisons ofage at onset between

ulcerative colitis and Crohn's disease were strati-fied by the presence or absence ofa family historyof inflammatory bowel disease, the differencebetween ulcerative colitis and Crohn's diseasedisappeared for those individuals with a positive

TABLE II Proband distribution by ethnicity, inflammatorybowel disease, and sex ratio (malelfemale)

J7ews Non-Jews Total

No Sex ratio No Sex ratio No Sex ratio

Ulcerative colitis 157 1-3 112 1-2 269 1-2Crohn's disease 134 0-9 124 0-8 258 0-8Total 291 1-1 236 1-0 527 1-0

TABLE III Distribution ofaffected individuals injewish andnon-Jewishfamilies

No offamilies with n affected individuals

Type offamily n=I n=2 n=3 n=4 Total

Jews:Ulcerative colitis only 139 17 0 0 156Crohn's disease only 113 10 1 1 125Mixed* 0 7 3 0 10

Total 252 34 4 1 291Non-Jews:

Ulcerative colitis only 108 1 1 0 110Crohn's disease only 113 3 1 1 118Mixed* 0 5 3 0 8

Total 221 9 5 1 236

*Mixed: families with both ulcerative colitis and Crohn's diseasepatients.

TABLE IV Comparison ofage at onset ofulcerative colitis andCrohn's disease probands

Ulcerative colitis Crohn's disease(mean (SD) (no))* (mean (SD) (no))* p value

Overall total 27-7 (16-6) (267) 23-1 (14-0) (257) 0 0006Positive 23-3 (15-0) (47) 23-3 (15 1) (59) 0-981

family historyNegative 28-6 (16-8) (220) 23-0 (13-7) (198) 0-0003

family historyJews, total 28-7 (16-8) (156) 24-1 (14-8) (133) 0-014Positive 24-8 (14-6) (35) 24-0 (17-6) (36) 0-836


family historyNon-Jews, total 26-3 (16-3) (111) 22-0 (13-2) (124) 0-026Positive 19-0 (16-0) (12) 22-1 (10-3) (23) 0-493


family history

*Mean (SD) (number of probands whose age at onset wasrecorded, three with missing data).

family history (Table IV). Among ulcerativecolitis patients, the age at onset of disease waslower in those with a positive family history thanin those with a negative family history - ages 23- 3and 28-6 years, respectively (p<0-05). In con-trast, there was no significant difference of age atonset among Crohn's disease patients betweenthose with or without a positive family history.The same relationships between age at onset andfamily history were observed in both Jewish andnon-Jewish patients (the lower portions of theTable IV).

Although non-Jewish patients had a youngerage of onset than Jewish patients (24-1 (14-9) v26-6 (16- 1), the difference was not of sufficientmagnitude to attain statistical significance(p=007).

POSITIVE FAMILY HISTORY OF INFLAMMATORYBOWEL DISEASEOf the 258 patients with Crohn's disease, therewere 60 (23-3%) with a positive family history,while among patients with ulcerative colitis, 47out of 269 (17-5%) had a positive family history.Table V shows the distribution of affected rela-tives by the clinical type of disease. The datashow: (1) that the greatest risk to relatives is forthe same disease occurring as in the index cases;(2) that affected relatives may develop eitherform ofinflammatory bowel disease; and (3) thatCrohn's disease probands tend to have a muchhigher frequency of relatives affected with ulcer-

519

on Decem


http://gut.bmj.com

/G


ownloaded from

http://gut.bmj.com/


ative colitis than ulcerative colitis probands haverelatives affected with Crohn's disease (109% v3 7%, p<0002). This is true even when firstdegree relatives only were considered in theanalysis (6-6% v 15%, p=0-021). This patternheld for both Jewish and non-Jewish families.

Jewish probands had an increased positivefamily history compared with non-Jewish pro-bands, 24-3% and 14-6%, respectively (p<001).This is true. for ulcerative colitis and Crohn'sdisease probands analysed separately (22-3% v10-7% for ulcerative colitis, p=0014; and 26-6%v 18-1% for Crohn's disease, p=0 097).

EMPIRICAL RISKS IN THE FIRST DEGREE RELATIVESThe crude, uncorrected empirical risks in thefirst degree relatives of Jewish and non-Jewishprobands are summarised in Table VI (A),separately by both type of relationship (siblings,parents, offspring, and all first degree relatives)and by type of proband - that is those withCrohn's disease or ulcerative colitis. Table VI (B)

TABLE V Positive family history ofinflammatory bowel disease in uclerative colitis (UC) andCrohn's disease (CD) probands*

Disease in relatives p value4No of UV v CD

Disease in proband probands UC (%) CD (%) Mixed (%)t Total (%) relatives

UC 269 37(13-8) 6(2 2) 4(1-5) 47(17-5) <0.001CD 258 19(7-4) 32(12-4) 9(3 5) 60(23 3) 0-1>p>0-05p value (UC v CD probands) 0-017 0 000 0-139 0 099Total 527 56(10-6) 38(7 2) 13(2 5) 107(20 3)First degree relatives only:UC 269 19 (7 1) 4 (1 5) 0 23 (8 6) <0 005CD 258 13 (5 0) 19 (7 4) 4 (1-6) 36 (14-0) >0 25

p value (UC v CD probands) 0-331 0-001 0-040 0 049Total 527 32 (6-1) 23 (4 4) 4 (0 8) 59 (11-2)

*Both Jews and non-Jews have the same trend.tWith several affected relatives, some affected with ulcerative colitis and some with Crohn's disease.tp values from the X2 test ofgoodness of fit with the null hypothesis that the frequency of a positivehistory of ulcerative colitis is equal to the frequency of a positive history of Crohn's disease in eitherulcerative colitis or Crohn's disease probands.

TABLE VI (A) Prevalence ofinflammatory bowel disease infirst degree relatives ofpatientswith inflammatory bowel disease (%)

Allfirst degreeSiblings % (no) Parents % (no) Offspring % (no) % (no)

Jews:CDpatients 8-0(199) 3 0(265) 1-8(111) 4 5(575)UC patients 2-4 (252) 3-2 (313) 1-9 (157) 2-6 (722)

Non-Jews:CDpatients 3 0(268) 3-7(246) 0(117) 2-7(631)UC patients 0-4 (258) 0 9 (220) 2-3 (87) 0-9 (565)

(B) Statistical comparisons betweeneJews and non-JewsRates compared XMH2 p value

All first degree relatives:CD probands (8-0, 3 0, 1-8) v (3 0, 3 7, 0) 2 95 0-086UC probands (2-4, 3-2, 1-9) v (0 4, 0 9, 2 3) 4-01 0 045All probands (4-5, 2 6) v (2-7, 0-9) 6-87 0 009

Siblings only:CD probands (8-0) v (3 0) 5 99 0-014UC probands (2-4) v (0 4) 3-76 0 052All probands (8-0, 24) v (30, 04) 835 0 004

(C) Statistical comparisons between CD and UCRates compared XMH2 p value

All first degree relatives:Jewish probands (8-0, 3-0, 18)v(2-4, 3-2, 1-9) 2-79 0 095Non-Jewish probands (3 0, 3 7, 0) v (0-4, 0 9, 2 3) 4-59 0-032All probands (4-5, 2-7) v (2-6, 0-9) 7-44 0-006

Siblings only:Jewish probands (8 0) v (2 4) 7-68 0-006Non-Jewish probands (3-0) v (04) 5 30 0-021All probands (8-0, 3-0) v (2-4, 0-4) 11-48 0 001

CD=Crohn's disease; UC=ulcerative colitis.

presents the results of comparisons betweenJewish and non-Jewish probands for Crohn'sdisease probands only, ulcerative colitis only andthe combination of both. Table VI (C) shows theresults of comparisons between probands withCrohn's disease and those with ulcerative colitisfor Jewish and non-Jewish probands, and thecombination of both. The crude empirical riskswere higher among Jews than non-Jews. Thiswas consistent for probands with Crohn's disease(p=0 086) and for those with ulcerative colitis(p=0045). To evaluate the overall differencebetween the Jewish and non-Jewish families, wecalculated the Mantel-Haenszel statistics by con-sidering ulcerative colitis and Crohn's disease astwo strata and obtained a very significant dif-ference (p=0O009). In addition, the prevalenceof inflammatory bowel disease was higher in firstdegree relatives of Crohn's disease probandsthan in those of patients with ulcerative colitis,and this was true for both Jews and non-Jews(4-5% v 2-6% in Jews, p=0-095; 2-7% v 09% innon-Jews, p=0-032; and overall p=0 006). Totest further the validity of these conclusions, allcomparisons were also repeated by restrictingthe analysis to siblings of the probands only,since this is the group which has both the mostaccurate information and has also lived throughan extended period of risk. The results from theanalyses restricted to siblings only showed thesame basic outcomes, and yielded even greaterstatistical significance values than the resultsderived from all the first degree relatives com-bined (the lower portions of Tables VI (B) and(C) respectively).The age adjusted risk estimates for inflam-

matory bowel disease for siblings, parents,children, and for all first degree relatives com-bined as calculated by the Stromgren method aregiven in Table VII (A). The results of com-parisons between Jewish and non-Jewish pro-bands, and between Crohn's disease and ulcera-tive colitis probands, are given in Table VII (B)and (C) respectively. It should be noted that thecalculated number of individuals at risk afteradjustment for age decreased dramatically,especially in children, as a result of the largeproportion of younger individuals in this lattergroup. As described in the methods section, thedenominator was adjusted based on the pro-portional risk by age in the general population -that is, a younger person contributed less weightthan an older person (see Table I) to the 'life-time.' In general, as for the crude empirical riskestimations, the relatives of Jewish probandshave an increased age adjusted risk comparedwith the relatives of non-Jewish probands (forCrohn's: disease 7-8% v 5-2%, for ulcerativecolitis: 4 5% v 1-6%, overall comparisonp=0028). This is especially so for the siblings(forCrohn's disease: 16-8% v 7 0%, for ulcerativecolitis: 4-6% v 09%, overall p=O0Ol). Therelatives of Crohn's disease probands have anincreased risk compared with those of ulcerativecolitis probands (p=0-063 in Jews, p=0-028 innon-Jews, and the overall group, p<0005).Figure 1 indicates the age adjusted risk estimatesfor inflammatory bowel disease for the firstdegree relatives, both by the form of inflamma-tory bowel disease in the proband (ulcerative

520

on Decem


http://gut.bmj.com

/G


ownloaded from

http://gut.bmj.com/

Familial empirical risksfor inflammatory bowel disease: differences betweenJews and non-Jews

TABLE VII (A) Lifetime risk among thefirst degree relatives ofpatients with inflammatorybowel disease

Allfirst degreeSiblings % (no)* Parents % (no)* Offspring % (no)* % (no)*

Jews:CD patients 16-8 (95) 3 8 (211) 7-4 (27) 7 8 (333)UC patients 4-6 (131) 4-1 (247) 7-4 (41) 4.5 (418)

Non-Jews:CD patients 7.0 (115) 4-8 (187) 0 (23) 5-2 (325)UCpatients 0.9(114) 1-2(168) 11 0(18) 1-6(300)

(B) Statistical comparisons betweenJews and non-J7ewsRates compared XMH2 p value

All first degree relatives:CD probands (16-8, 3-8, 7.4) v (7.0, 4.8, 0) 2-10 0-147UC probands (4-6, 4-1, 7.4) v (0.9, 1-2, 11.0) 3-12 0 078All probands (7 8, 4.5) v (5 2, 1-6) 4-83 0-028

Siblings only:CD probands (16-8) v (7 0) 5.02 0.025UC probands (4.6) v (0.9) 3-01 0 083All probands (16-8, 4.6) v (7.0, 0.9) 6-68 0 010

(C) Statistical comparisons between CD and UCRates compared XMH2 p value

All first degree relatives:Jewish probands (16-8, 3-8, 7.4) v (4-6, 4-1, 7.4) 3-47 0 063Non-Jewish probands (7.0, 4.8, 0) v (0 9, 1-2, 11 0) 4-82 0-028All probands (7-8, 5-2) v (4-5, 1-6) 7-83 0-005

Siblings only:Jewish probands (16-8) v (4.6) 9-42 0-002Non-Jewish probands (7.0) v (0.9) 5-60 0.018All probands (16-8, 7 0) v (4-6, 0 9) 13-47 0 000

*Age adjusted number of relatives.CD=Crohn's disease; UC= ulcerative colitis.

colitis v Crohn's disease) and the ethnicity of theprobands (Jews v non-Jews).

Table VII (A) also indicates that the parentshave a lower age adjusted risk than the siblingsand children of the probands, especially in Jews.Some possible explanations for the lower risk inparents ofprobands will be discussed below. Theestimates of empirical risks for children shouldalso be considered cautiously because of themoderate number in the denominator. Theassessments of age adjusted empirical risk forinflammatory bowel disease in the siblings ofprobands, therefore, are likely to be the most

2.

^0 8

.M

me ;,:

e) .1.:4,;44

WIth: with

Estimates oflifetime risks for inflammatory bowel disease in the first degree relatives ofulcerative colitis and ofCrohn's disease probands and their 95% confidence intervals, forJewvsand non-J7ews, respectively. Relatives ofCrohn's disease probands had an increased risk

compared with those ofulcerative colitis probands (p=O0 OOS). Relatives ofJ7ewish patients hada greater risk than relatives ofnon-_Jewish patients (p=0028).

useful and reliable estimates for genetic counsel-ling and genetic modelling. Thus, comparisonshave been made using all first degree relatives(Tables VI (B) and VII (B)) and again restrictingthe comparisons to siblings only (Tables VI (C)and VII (C)). This latter comparison regardingsiblings is likely to be particularly accurate sincethere are a large number of siblings and they arein the same generation as the probands, whichwould reduce any bias introduced by temporalchanges.

DiscussionAge adjusted empirical risks of inflammatorybowel disease for relatives of non-Jewish whitepatients with ulcerative colitis or Crohn's diseaseare reported here for the first time. We were alsoable to increase our series of American Ash-kenazi Jewish patients for these empirical riskestimations. This allowed a critical comparisonof the familial risks for the two ethnic groups inthe same geographical area. We found that theestimates of age adjusted empirical risks forinflammatory bowel disease in the relatives of thewhite non-Jewish patients were significantlylower than those for relatives of Jewish patients.Because the pattern of inheritance in inflam-matory bowel disease is not generally consideredto be consistent with any simple Mendelianmodel and there are, as yet, no accepted geneticmarkers available for risk assessment, accurateempirical risk estimates are needed for geneticcounselling. The data presented herein indicatethat there are significantly different familialempirical risks in the Jewish and non-Jewishinflammatory bowel disease populations. Thus,it is likely that individualised risk estimates foreach major ethnic group are needed to provideoptimal genetic counselling, as well as for formalmathematical modelling and genetic analysis.

Given the data regarding twins, spouses, anddistant family members, it seems that the prin-cipal contribution to familial aggregation isgenetic susceptibility. An examination of thedifferences in familial empirical risks betweenJews and non-Jews also contributes therefore tothe understanding of the genetic aetiologies ofinflammatory bowel disease. There are currentlyseveral models of the genetic susceptibility: thesimple Mendelian models, the polygenic/multi-factorial model, the multilocus/oligogenic model,and the genetic heterogeneity model.3 Using aformal genetic analytical technique called com-plex segregation analysis on amnestic familydata, a recessive gene with incomplete penetrancewas recently suggested for Crohn's disease,24while an additive major gene was similarly pro-posed for ulcerative colitis.25 If a single Men-delian gene is responsible for the susceptibility ofeither ulcerative colitis or Crohn's disease (orboth), we would expect to observe the sameempirical risks in the first degree relatives ofprobands in Jews and non-Jews even if there is adifferent population incidence in these twopopulations. That is because, for a simple Men-delian disease, the risks for the relatives of anaffected proband depend on the mode of inheri-tance, while the different incidences in thepopulation are the result of different gene fre-

''l9- '--Q,wm ' ..,. wr,t-'m ,-r

` T ,......

521

on Decem


http://gut.bmj.com

/G


ownloaded from

http://gut.bmj.com/


quencies. For example, Ashkenazi Jews have anincreased incidence of Tay-Sachs disease com-pared with non-Jews,26 yet the siblings of aproband with Tay-Sachs disease have the samerisk of developing the disease (25%) whetherthey are Jews or non-Jews. Therefore, the differ-ence in the population incidence rates27-30 and inthe familial empirical risks between Jews andnon-Jews who are from the same geographicalareas allow the formal rejection of the singleMendelian models (even with reduced pene-trance) for inflammatory bowel disease or itsclinical subtypes of ulcerative colitis and Crohn'sdisease. Such results could be the result of adifferent mode of inheritance in the two popula-tions - for example Jews having one mode andnon-Jews a different mode of inheritance forinflammatory bowel disease and/or because ofthe existence of the mixture of several modes ofinheritance in each population with each popula-tion consisting of different proportions of eachtype of inheritance. These latter speculations areconsistent with the genetic heterogeneity modelsupported by emerging genetic marker and sub-clinical marker data.3'34 The observation in thesedata that there was a difference in the proportionof families with both forms of inflammatorybowel disease - that is ulcerative colitis andCrohn's disease simultaneously - between Jewishand non-Jewish families are also consistent withthe heterogeneity model. However, the currentempirical risk data do not by themselves allow usto distinguish between these remaining differentmodels - that is the multifactorial, multilocus,and genetic heterogeneity models. In addition,these empirical risks in relatives may be modifiedby other factors which were not measured here,such as smoking. The interactions betweengenetic and potential environmental factors willneed to be evaluated to identify fully the appro-priate aetiological models for ulcerative colitisand Crohn's disease. To do this adequately,however, may require the ability to identifywhich of the relatives are at risk, by identifyingthe actual genetic susceptibilities."3134

For genetic counselling purposes, we wouldconsider the empirical risks estimated for siblingsof probands more robust and reliable than thosefor parents and offspring. This is so because thesiblings are in the same generation as the pro-bands, which minimises any temporal bias, andbecause there are a large number of siblings (andthus a large adjusted number of individuals atrisk), which results in a relatively small standarderror of estimation. For offspring, the moremodest size ofdenominator (age adjusted numberof individuals at risk) introduced a relativelylarge confidence interval. The estimates for theparents were consistently lower than those forsiblings and offspring. The possible explanationsmay be as follows. Firstly, the diagnosis for theolder generation may not be as accurate as today,so that a number of cases in the older generationwent undiagnosed. Secondly, the increased in-cidence of Crohn's disease over the past severaldecades may have contributed to the lower risksfor parents compared with siblings and offspring,though most data supporting these trends havebeen reported from the United Kingdom andScandinavia."

These age adjusted risks are the lifetime risksfor inflammatory bowel disease based on theassumption that all individuals will live to 70years and experience the same distribution ofproportional risk as the Baltimore populationstudied by Calkins et al.2' Even if the latter is notthe case, the comparisons between differentgroups are valid as long as the same standarddistribution of proportional risk is used for allgroups. However, the usefulness of empiricalrisk estimates for genetic counselling and model-ling would depend on the accuracy ofthe assump-tion that all individuals will experience the samedistribution of proportional risks as the onereported by Calkins et al."2 Since there was nodata available from Los Angeles for us toevaluate this assumption directly, we comparedthe data of Calkins et al with two other USpopulation based data sets: (1) the incidencedata of Crohn's disease among residents ofOlmsted County, Minnesota, 1943-198236; and(2) the incidence data of ulcerative colitis amongresidents of Rochester, Minnesota, 1960-1979.37The results were virtually identical. These com-parisons suggested that there was a similardistribution ofproportional risks among all threeUS populations, even if the incidence mightdiffer. This additional information providessome assurance in the more general use of theempirical risk estimates reported herein forAmerican inflammatory bowel disease patients.The sample of inflammatory bowel disease

patients used to estimate familial empirical risksin the current study is not a population basedsample, and is thus similar to most otherreported empirical risk data for inflammatorybowel disease as well as other diseases.3839 Thestudied patient population is white (AshkenaziJews and non-Jews) and of middle or uppersocioeconomic status. The extensive reviews ofrisk factors for inflammatory bowel disease bynumerous authors have failed to identify anyconfirmed environmental factors associated withits development, including socioeconomic status,diet, bacterial and viral infection, and drugs, butall have indicated that there is a genetic com-ponent in the aetiology for both ulcerative colitisand Crohn's disease.3540 It is important to notethat inflammatory bowel disease in our patientswas ascertained through gastroenterology prac-tices and the inflammatory bowel disease clinicalprogramme in west Los Angeles, and that thepatients were included without initial knowledgeof their family history. Thus, we believe that theestimated empirical risks from this patientpopulation are a potentially valuable referencefor white populations for genetic counselling andgenetic modelling, at least for white Americanpopulations. In addition, as our AshkenaziJewish and non-Jewish patients were ascertainedfrom the same sources, the comparison betweenthese two ethnic groups is valid and not affectedby the ascertainment through clinical pro-grammes.We have examined the possibility ofartifactual

causes for the different empirical risks weobserved between Jews and non-Jews. Asregards empirical risk estimation, a longer dura-tion of disease may result in an individual beingmore aware of the disease and more likely to

522

on Decem


http://gut.bmj.com

/G


ownloaded from

http://gut.bmj.com/

Familial empirical risksfor inflammatory bowel disease: differences betweenJews and non-Jews 523

know more about his or her relatives' medicalproblems, especially those affected by the samedisease - that is inflammatory bowel disease.Thus, we have also examined the relationbetween the duration of the disease with thefrequency of a positive family history of inflam-matory bowel disease. There is no associationbetween these two variables in our data, and thisis true both for the Jews and non-Jews. There-fore, disease duration was not an explanation forthe difference in empirical risks between Jewsand non-Jews. In addition, family size and agedistributions of relatives did not account forthese differences. Since the total number ofaffected first degree relatives was 45 in Jews and22 in non-Jews, it is possible that a few unusualfamilies could bias the representativeness of thewhole sample. In other words, if, for example,some families had clearly dominant inheritancewith 50% of first degree relatives affected, theinclusion of these families with different fre-quencies in Jews and non-Jews would make alarge difference in the risk estimation for thewhole sample. Therefore, we have also examinedthe distribution of affected individuals in thefamilies (Table III). It did not show any particularlarge cluster in the Jewish group.

It has previously been reported that familialcases tend to have a younger age of onset.41 Itseems that this finding is principally in ulcerativecolitis patients. We observed that there was asignificant difference in age at onset betweenulcerative colitis and Crohn's disease, and thatthis difference was dependent on those with apositive family history of inflammatory boweldisease. Our patients with Crohn's disease hadan earlier age of onset than those with ulcerativecolitis, and our ulcerative colitis patients withpositive family history of inflammatory boweldisease had an earlier onset than those without afamily history of inflammatory bowel disease.These data indicate that, at least in ulcerativecolitis, familial cases tended to have an earlier ageof onset than non-familial cases. A similar find-ing has been reported in other studies.42 If thisalso applies to Crohn's disease, it may be thatmost cases of Crohn's disease were geneticallydetermined, leading to their average youngerage of onset than that of the ulcerative colitispatients, even if the individual Crohn's diseasepatient does not have a positive family history.These data and this suggestion are consistentwith the data from twin and family studies whichshow that Crohn's disease co-twins have a greaterconcordance rates than ulcerative colitis co-twins, and that relatives of Crohn's diseasepatients have a higher risk for inflammatorybowel disease than those of ulcerative colitispatients.16 17 41414 In this study, we have alsoshown that relatives of Crohn's disease probandshave a significantly increased life time riskcompared with relatives of ulcerative colitisprobands, and this was true in both Jews andnon-Jews.

It has also been observed by others thatulcerative colitis and Crohn's disease occur withhigher than expected frequency in the samefamily, and that Crohn's disease probands tendedto have a higher frequency of relatives affectedwith ulcerative colitis than ulcerative colitis

probands have relatives affected with Crohn'sdisease.'5 17 18 43 44 Both our Jewish and non-Jewish data are consistent with these previousobservations. All these observations are com-patible with the suggestion that ulcerative colitisand Crohn's disease (or a subgroup) share agenetic background and that the genetic com-ponent plays a more important or more deter-minative role in Crohn's disease than in ulcer-ative colitis.

In summary, we have estimated the familialempirical risks for inflammatory bowel disease inthe first degree relatives of Jewish and non-Jewish probands with ulcerative colitis orCrohn'sdisease ascertained from the same geographicarea, taking into account the age distribution inrelatives. These estimates are important forgenetic counselling and genetic modelling. Thedegree of familiality indicated by the ageadjusted empirical risks for inflammatory boweldisease in the first degree relatives is greater inJews than that in non-Jews. An increased in-cidence rate ofinflammatory bowel disease in theJewish population and an increased risk forinflammatory bowel disease in the relatives ofJewish probands indicate formally that a singleMendelian gene model for the susceptibility toulcerative colitis or Crohn's disease is unlikely.Although the genetic heterogeneity model seemsmost likely given the data from genetic markerand subclinical marker studies, the multifac-torial model and the multilocus models cannot beexcluded with these empirical risk data alone.These results indicate the importance ofcarefullydefining the familial empirical risks in a varietyof populations and ethnic groups.

This work has been supported by NIH grant DK36200, andgrants from the Crohn's and Colitis Foundation of America, theStuart Foundations, and Cedars-Sinai Board of Governors' Chairin Medical Genetics (JIR).

1 Gilat T, Grossman A, Fireman Z, Rozen P. Inflammatorybowel disease in Jews. In: McConnell R, Rozen P, LangmanM, Gilat T, eds. The genetics and epidemiology ofinflammatorybowzel disease. New York: Karger, 1986: 135-40.

2 Rotter JI, Yang H, Shohat T. Genetic complexities of inflam-matory bowel disease and its distribution among the Jewishpeople. In: B Bonne-Tamir, A Adam, eds. Genetic diversityamonge ews: disease and markers at the DNA level. Oxford:Oxford University Press, 1992: 395-411.

3 Yang H, Shohat T, Rotter JI. The genetics of inflammatorybowel disease. In: R MacDermott, W Stenson, eds. Inflam-matory bozwel disease. New York: Elsevier, 1992: 17-51.

4 Gilat T, Ribak J, Benaroya Y, Zemishlany Z, Weissman I.Ulcerative colitis in the Jewish population of Tel-Aviv-Jafo.I. Epidemiology. Gastroenterology 1974; 66: 335-42.

5 Rozen P, Zonis J, Yekutiel P, Gilat T. Crohn's disease in theJewish population of Tel-Aviv-Jafo. Epidemiologic andclinical aspects. Gastroenterology 1979; 76: 25-30.

6 Krawiec J, Odes HS, Lasry Y, Krugliak P, Weitzman S.Aspects of the epidemiology of Crohn's disease in the Jewishpopulation in Beer Sheva, Israel. Isr J Med Sci 1984; 20:16-21.

7 Odes HS, Fraser D, Krawiec J. Incidence of idiopathiculcerative colitis in Jewish population subgroups in theBeer Sheva region of Israel. Am J Gastroenterol 1987; 82:854-8.

8 Odes HS, Fraser D, Krawiec J. Ulcerative colitis in the Jewishpopulation of southern Israel 1961-1985: epidemiologicaland clinical study. Gut 1987; 28: 1630-6.

9 Roth M-P, Petersen GM, McElree C, Feldman E, Rotter JI.Geographic origins of Jewish patients with inflammatorybowel disease. Castroenterology 1989; 97: 900-4.

10 Zlotogora J, Zimmerman J, Rachmilewitz D. Crohn's diseascin Ashkenazi Jews. Castroenterology 1990; 99: 286-7.

11 Odes HA, Fraser D, Krawiec J. Inflammatory bowel disease inmigrant and native Jewish populations of southern Israel.ScandJ3 Gastroenterol 1989; 24 (suppl 170): 36-8.

12 Odes HA, Fraser D, Krugliak P, Fenyves D, Fraser GM,Sperber AD. Inflammatory bowel disease in the BedouinArabs of southern Israel: rarity of diagnosis and clinicalfeatures. Gut 1991; 32: 1024-6.

on Decem


http://gut.bmj.com

/G


ownloaded from

http://gut.bmj.com/

524 Yang, McElree, Roth, Shanahan, Targan, Rotter

13 Orholm M, Munkholm P, Langholz E, Nielsen OH, SrensenIA, Binder V. Familial occurrence of inflammatorv boweldisease. NEnglJMed 1991; 324: 84-8.

14 Weterman IT, Pena AS. Familial incidence of Crohn's diseasein the Netherlands and a review of the literature. Gastro-enterology 1984; 86: 449-52.

15 McConnell RB. Genetics of inflammatory bowel disease. In.Allan RN, Keighley MRB, Alexander-Williams J, HawkinsCF, eds. Inflammatory bowel disease. New York: ChurchillLivingstone, 1990: 11-23.

16 Tysk C, Lindberg E, Jarnerot G, Floderus-Myrhed B. Ulcera-tive colitis and Crohn's disease in an unselected populationof monozygotic and dizygotic twins. A study of heritabilityand the influence of smoking. Gut 1988; 29: 990-6.

17 Kirsner JB. Genetic aspects of inflammatory bowel disease.Clin Gastroenterol 1973; 2: 557-76.

18 Roth M-P, Petersen GM, McElree C, Vadheim CM, PanishJF, Rotter JI. Familial recurrence risk estimates of inflam-matory bowel disease in Ashkenazi Jews. Gastroenterologv1989; 96: 1016-20.

19 Kobberling J, Untersuchungen zur Genetik des Diabetesmellitus. Eine geeignete Methode zur Durchfuhrung vonAlterskorrekturen. Diabetologia 1969; 5: 392-6.

20 Tillil H, Kobberling J. Age-corrected empirical genetic riskestimates for first-degree relatives of IDDM patients.Diabetes 1987; 36: 93-9.

21 Calkins BM, Lilienfeld AM, Garland CF, Mendeloff AI.Trends in incidence rates of ulcerative colitis and Crohn'sdisease. Dig Dis Sci 1984; 29: 913-20.

22 Snedecor GW, Cochran WG. Statistical methods. Iowa: TheIowa State University Press, 1980.

23 Rothman KJ. Modern epidemiology. Boston: Little, Brown andCompany, 1986: 177-236.

24 Kuster W, Pascoe L, Purrmann J, Funk S, Majewski F. Thegenetics of Crohn disease: complex segregation analysis of afamily study with 265 patients with Crohn disease and 5387relatives. AmJ Med Genet 1989; 32: 105-8.

25 Monsen U, Iselius L, Johansson C, Hellers G. Evidence for amajor additive gene in ulcerative colitis. Clin Genet 1989; 36:411-4.

26 Kolodny EH. Tay-Sachs disease. In: Goodman RM, MotulskyAG, eds. Genetic disease among Ashkenazi Jews. New York:Raven Press, 1979: 217-29.

27 Monk M, Mendeloff AI, Siegel CI, Lilienfeld A. An epidemio-logical study of ulcerative colitis and regional enteritisamong adults in Baltimore. I. Hospital incidence andprevalence, 1960-1963. Gastroenterology 1967; 53: 198-210.

28 Brahme F, Lindstrom C, Wenckert A. Crohn's disease in adefined population. An epidemiological study of incidence,prevalence, mortality and secular trends in the city ofMalmo, Sweden. Gastroenterology 1975; 69: 342-51.

29 Hellers G. Crohn's disease in Stockholm county, 1955-1974: a

study of epidemiology, results of surgical treatment and longterm prognosis. Acta ChirScand 1979; 490 (Suppl): 1-84.

30 Novis BH, Marks IN, Bank S, Louw JH. Incidence of Crohn'sdisease at Groote Schuur Hospital during 1970-1974.S AfrMedJ7 1975; 49: 693-7.

31 Rotter JI, Wang S-J, Yang H, McElree CK, Pressman S, et al.Genetic heterogeneity between ulcerative colitis (UC) andCrohn's disease (CD) identified by molecular HLA class IIassociation. Gastroentrology 1992; 102: A688.

32 Shanahan F, Duerr R, Rotter JI, Yang H, Sutherland L, et al.Neutrophil autoantibodies in ulcerative colitis: familialaggregation and genetic heterogeneity. Gastroenterology 1992;103: 456-61.

33 Rotter JI, Shohat T, Vadheim CM. Is IBD a genetic disease?In: D Rachmilewitz and J Zimmerman, eds. Inflammatorybowel diseases 1990. Dordrecht, The Netherlands: KluwerAcademic Publishers, 1990: 5-18.

34 Rotter JI. Immunogenetic susceptibilities in IBD. Canad7 Gastroenterol 1990; 4: 261-6.

35 Langman MJS. Epidemiology of inflammatory bowel disease.In. Allan RN, Keighley MRB, Alexander-Williams J,Hawkins CF, eds. Inflammatory bowel disease New York:Churchill Livingstone, 1990: 24-33.

36 Gollop JH, Philips SF, Melton LJ, Zinsmeister AR. Epi-demiologic aspects of Crohn's disease: a population basedstudy in Olmsted County, Minnesota, 1943-1982. Gut 1988;29: 49-56.

37 Stonnington CM, Philips SF, Melton LJ, Zinsmeister AR.Chronic ulcerative colitis: incidence and prevalence in acommunity. Gut 1987; 28: 402-9.

38 Sadovnick AD, Irwin ME, Baird PA, Beattie BL. Geneticstudies on an Alzheimer clinic population. Genetic Epidemio-logy 1989; 6: 633-43.

39 Sadovnick AD, Baird PA. The familial nature of multiplesclerosis: age-corrected empiric recurrence risks for childrenand siblings of patients. Neurology 1988; 38: 990-1.

40 Ekbom A, Adami H-O. The epidemiology of inflammatorybowel disease. In MacDermott R, Stenson WF, eds.Inflammatory bowel disease. New York: Elsevier, 1992: 1-15.

41 Farmer RG, Michener WM, Mortimer EA. Studies of familyhistory among patients with inflammatory bowel disease.Clin Gastroenterol 1980; 9: 271-7.

42 Monsen U, Brostrom 0, Nordenvall B, Sojrstad J, Hellers G.Prevalence of inflammatory bowel disease among relatives ofpatients with ulcerative colitis. Scand3 Gastroenterol 1987;22: 214-8.

43 Kirsner JB, Spencer JA: Family occurrences of ulcerativecolitis, regional enteritis and ileocolitis. Ann Int Med 1963;59: 133-44.

44 Lashner BA, Evans AA, Kirsner JB, Hanauer SB. Prevalenceand incidence of inflammatory bowel disease in familymembers. Gastroenterology 1986; 91: 1396-400.

on Decem


http://gut.bmj.com

/G


ownloaded from

http://gut.bmj.com/

Familial inflammatory disease: differences Jews non-Jews · disease:...

Documents

Transcript of Familial inflammatory disease: differences Jews non-Jews · disease:...