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Familial expression of anti-Saccharomyces cerevisiaemannan antibodies in aVected and unaVectedrelatives of patients with Crohns disease

C L Sutton, H Yang, Z Li, J I Rotter, S R Targan, J Braun

Abstract

BackgroundCrohns disease is a famil-

ial disorder, and antiglycan antibodies to

the cell wall mannan of Saccharomyces

cerevisiae (ASCA) are highly correlated

with Crohns disease.

Aims To determine whether there is a

familial pattern for expression of serum

levels of anti-mannan Ig, and whether this

trait is expressed in clinically unaVected

Crohns disease family members.

Methods 349 patients with Crohns dis-

ease, 87 Crohns disease aVected relatives,

333 inflammatory bowel disease (IBD)free relatives, 58 spouses, and 190 healthy

control patients were studied. Serum IgG

and IgA binding activity to S cerevisiae

cell wall mannan was quantitated by

ELISA.Results A high percentage of patients

with Crohns disease (51.9%) and aVectedfamily members (56.3%) were seroposit-ive for anti-mannan Ig, compared with the

normal control population (3.7%). Sero-positive and seronegative phenotypes ofCrohns disease probands were correlatedamong all aVected relatives, and this

association was stronger in aVected first

degree relatives. Statistical intraclass cor-relations of quantitative anti-mannan Ig

levels revealed significantly less variationwithin, rather than between families. Asignificant familial aggregation was ob-

served for aVected relatives; this was evenstronger for unaVected relatives. While asignificant familial aggregation was ob-

served among unaVected siblings pairs,there was no significant correlationamong marital pairs.

Conclusion Results show that anti-mannan Ig in family members aVectedand unaVected with Crohns disease is a

familial trait for both aVected and unaf-fected relatives. The lack of concordance

in marital pairs indicates that familialityis due in part to a genetic factor or child-hood environmental exposure.(Gut 2000;46:5863)

Keywords: Crohns disease; inflammatory boweldisease; ulcerative colitis; anti-mannan antibodies;intraclass correlation; statistical genetics

There is a recent resurgence of interest in theinterplay between environmental and geneticfactors in the pathogenesis of Crohns disease.Environmentally, Crohns disease has been

directly and indirectly associated with variousenteric microorganisms. Intestinal inflamma-tion in Crohns disease is notable for itsfrequent responsiveness to antibiotics and sus-ceptibility to bacterial faecal flow.15 Commonintestinal colonists and novel pathogens havebeen implicated in Crohns disease by directdetection or by disease associated anti-microbial immune responses.4 612 In most ani-mal models of chronic colitis, luminal microor-ganisms are a necessary cofactor for disease.1316

Several dietary antigens have also been impli-cated in the pathogenesis of inflammatory

bowel disease (IBD).

1720

DiVerential host susceptibility to Crohnsdisease has been documented by ethnic predis-position, and familial and twin aggregation.2126

Crohns disease is an oligogenic/polygenicdisorder, and a variety of human genes andloci have been implicated in disease suscep-tibility.2736

Immune responses are an important nexusof environmental factors and host genetics, anddisease specific marker antibodies in IBD havegained attention as possible manifestations ofthe disease related immune response. Inulcerative colitis, high serum levels of antineu-trophil cytoplasmic antibodies (pANCA) arestrongly correlated with disease, and several

studies have observed elevated frequency ofpANCA seropositivity in unaVected relatives ofpatients with ulcerative colitis. These findingsare interpreted as evidence that pANCAexpression is an immunological trait related todisease susceptibility.3740 In Crohns disease,serum reactivity to the cell wall mannanpolysaccharide of Saccharomyces cerevisiae(ASCA) is a serological marker for a majorityof individuals with Crohns disease.4145 Thespecificity of the anti-mannan marker antibodyfor Crohns disease (versus ulcerative colitisand other colitides) indicates that its expressionis not a simple epiphenomenon of intestinalinsult. The question addressed by the present

study is whether levels of anti-mannan anti-bodies are not only disease associated, but alsorepresent a familial immunological trait ex-pressed in unaVected family members. Usingquantitative marker antibody determinationand intraclass correlation analysis, this studyreveals that anti-mannan levels are a familialtrait, with a possible genetic component totheir pattern of expression.

Abbreviations used in this paper: ASCA,anti-Saccharomyces cerevisiae mannan antibodies; IBD,inflammatory bowel disease; pANCA, perinuclearantineutrophil cytoplasmic antibodies.

Gut 2000;46:586358

Department of

Pathology andLaboratory Medicine,

UCLA School ofMedicine, Los AngelesC L SuttonJ Braun

Division of Medical

Genetics, Departmentsof Pediatrics andMedicine, StevenSpielberg Pediatric

Research Center,Cedars-Sinai MedicalCenterH YangZ LiJ I Rotter

IBD Research Center

and Division ofGastroenterology,Cedars-Sinai MedicalCenter, Los Angeles,

California, USAS R Targan

Correspondence to:Dr J Braun, Department ofPathology and LaboratoryMedicine, CHS 13222,UCLA School of Medicine,Los Angeles, CA900951732, USA

Accepted for publication6 July 1999

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Materials and methodsPOPULATION

Serum aliquots were obtained from the IBDserum research archive at Cedars-Sinai Medi-cal Center; the patient demography of thisarchive and method of selecting probands andrelatives from the archive has been reportedpreviously.27 38 39 Subjects included 349 pa-tients with Crohns disease, 98 Crohns diseaseaVected relatives, and 333 IBD free relatives.Relatives included first degree relatives (par-ents, siblings, and children), and other moredistant relatives (uncles, nieces, grandparents,etc). There was a total of 420 relatives from126 Crohns disease only families. Within theserelatives, only 38 were other distant relatives.

Among 382 first degree relatives, 188 wereparents, 54 were children, and 140 weresiblings of Crohns disease probands. The fam-ily size of first degree relatives ranged from twoto eight;the size was three or four in about 50%of families. There was minimal diVerence inthe family size distribution between the firstdegree relatives only group and the all relativesgroup (table 1).

A concurrent set of control subjects was alsostudied from this archive, including 249patients with ulcerative colitis, and 190 healthysubjects who had no family history of ulcerativecolitis or Crohns disease. Of these 190 healthycontrols, 58 were spouses of Crohns diseaseprobands. For this study, samples were ob-

tained from Crohns disease only familiesthat is, those lacking any family history ofulcerative colitis. The relative rarity of some ofthese samples necessitated the use of serum

that had been stored for between one monthand 11 years at 80C. All subject recruitmentand experimental studies were performedunder protocols approved by the Cedars-SinaiMedical Center and UCLA Institutional Re-view Boards.

ANTI-MANNAN ANTIBODY (ASCA)DETERMINATION

Serum anti-mannan Ig levels were quantitated

using a standard calibrated enzyme linkedimmunosorbent assay (ELISA) system (Pro-metheus, San Diego, California, USA). Anti-mannan Ig cut oVvalues defining seropositivityin this assay (40 EU/ml IgG anti-mannan, and20 EU/ml IgA anti-mannan) have been previ-ously optimised for Crohns disease diagnosticaccuracy. Both quantitative (Ig level) andqualitative (seropositivity) data were analysedto evaluate the distribution of this antibody.

ANALYSIS OF GROUP AGGREGATION

The comparisons of seropositivity prevalencein diVerent groups were conducted by 2 test.The Ig levels were transformed by logarithm

before any statistical test.

ANALYSIS OF FAMILIAL AGGREGATION

Anti-mannan antibody is significantly associ-ated with Crohns disease. To reduce theconfounding eVect of the presence of thedisease, familial aggregation was evaluated intwo separate groups: those family membersaVected with Crohns disease, and those whowere not aVected with Crohns disease. Theassociation of proband seropositivity with af-fected relative seropositivity was evaluated by 2

test. In addition, the significance of the familyeVect was determined via the F statistic. Thiscompares variability among families with withinfamily variability, and was separately deter-

mined for aVected and unaVected siblings.

INTRACLASS CORRELATION ANALYSIS

An intraclass correlation coeYcient (t*) isdefined as t*=2B /(

2

B + 2

w).46 The proportion

of the total variance of an observation thatoccurs among groups in this study wasrepresented by diVerent families. When t* ishigh, most of the variation is among families,and there is little variation within families.Therefore, a large t* implies that siblings aremore similar to one another than to randomlyselected individuals. t* is calculated by (MSEB MSEW)/[MSEB + (n1)MSEW], where MSEis the mean square error, B is that among fami-

lies, W is that within families, and n is averagesibship size. The average sibship size iscalculated as n = [1/(k1)]*[N( ni

2/N)],where k is the number of families, N is the totalnumber of subjects, and ni is the number ofsiblings in each family.47 The error terms foramong and within families were derived fromthe general linear model. All statistical analyseswere performed with programs of the SASInstitute, v.6.12 (Statistical Analysis System,Cary, North Carolina, USA).

Correlations among each type of relationshipin a family were calculated by the FCOR pro-gram in the Statistical Analysis for Genetic

Table 1 Distribution of family size in the study population

Proband + first deg ree only Proband + all relatives

Size Frequency Percentage Size Frequency Percentage

2 23 18 2 22 173 31 25 3 29 234 30 24 4 26 215 18 14 5 20 166 16 13 6 14 117 4 3 7 7 68 3 2 8 6 5

9 1 111 1 1

Total 125 100 Total 126 100

Table 2 Frequency of individuals positive for anti-mannan Ig

n IgA (%) IgG (%) Both (%) Either (%)

Patients with CD 349 44.4 41.8 34.4 51.9AVected relatives 87 46.0 48.3 37.9 56.3UnaVected relatives 333 4.5 6.6 1.8 9.3UnaVected spouses 58 5.2 5.2 1.7 8.6Patients with UC 249 7.6 4.0 2.4 9.2Healthy controls 132 1.5 2.3 0 3.8

Serum antimannan Ig levels were quantitated, and positive values were tabulated as greater than40 EU/ml and 20 EU/ml for IgG and IgA respectively.CD, Crohns disease; UC, ulcerative colitis.

Table 3 Family aggregation of anti-mannan levels

Phenotype

AVected siblings UnaVected siblings

t* p value t* p value

IgA 0.29 0.02 0.30 0.006IgG 0.27 0.03 0.35 0.002

t* = intraclass correlation coeYcient.

Anti-mannan antibodies in Crohns disease family members 59


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Epidemiology (SAGE) package (RammelkampCenter for Education and Research, CaseWestern Reserve University, Cleveland, Ohio,USA).48 The calculated correlation coeYcientin each group was tested for its statisticalsignificance under the null hypothesis of nocorrelation.

ResultsANTI-MANNAN Ig SEROPOSITIVITY RATESThe levels of anti-mannan IgG and IgA activitywere determined for a large sample set ofCrohns disease probands, relatives, spouses,and ulcerative colitis and healthy non-IBDcontrols. Table 2 shows the seropositivefrequencies for all populations of the currentstudy. The frequency of patients with Crohnsdisease seropositive for IgG or IgA anti-mannan antibodies was 53% of 436 totalpatients with Crohns disease (Crohns diseaseindex patients + unaVected relatives). This fre-quency was similar to previously reported

patient groups.42 44 45

Seropositivity rates were much lower inhealthy non-IBD controls (3.8%) and patientswith ulcerative colitis (9.2%) (p

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DiscussionThe present study shows that expression of theanti-mannan marker antibody (ASCA) is afamilial trait in families of patients withCrohns disease. This conclusion is based ontwo types of phenotypic analysis: concordance

of seropositivity rates in aVected family mem-bers with seropositive and seronegativeCrohns disease probands; and intraclass corre-lation of anti-mannan Ig levels in both aVectedand unaVected family members. It alsopresents two lines of evidence supporting agenetic component for familial marker anti-body expression: seropositivity rates were moreconcordant in first degree versus all relatives;

and quantitative anti-mannan levels weresignificantly correlated in sibling but not mari-tal pairs.

This study was based on quantitation ofanti-mannan Ig levels in a large patient serumarchive of aVected and unaVected family

members (1017 subjects). Mean anti-mannanIg levels and rates of seropositivity for Crohnsdisease probands and their aVected relativeswere significantly higher than in Crohnsdisease free and clinically normal populations.This confirmed the fundamental associationbetween this marker antibody and the presenceof Crohns disease.

If anti-mannan activity were familial, thenthe antibody status of the aVected relativeshould correlate with the status of the Crohnsdisease proband. Among all relatives, thiscategorical correlation was significant for IgG(correlation table analysis of p=0.018 andp=0.102 for IgG and IgA, respectively).

Among aV

ected first degree relatives, a strongcorrelation was observed for both IgG and IgA(p=0.01 and p=0.04). The low frequency ofseropositivity among unaVected relatives(4.5% for IgA, 6.6% for IgG) prevented usfrom using this analytical method for that sub-group. We note that in other recent studies, theelevation of seropositivity in unaVected rela-tives reached statistical significance.42 44 45

In order to evaluate quantitatively whetheranti-mannan levels are familially associated dis-tinct from disease, we determined the intraclasscorrelation coeYcients for both aVected andunaVected individuals. This comparison

Figure 2 Anti-mannan Ig levels in families.Anti-mannan Ig values are shown for each subject,g rouped vertically by family. Families are ranked byfamily mean anti-mannan Ig (solid line).

2.6

2.4

2.2

2.0

1.8

1.6

1.4

1.2

1.0

0.8

2.6

2.4

2.2

2.0

1.8

1.6

1.4

1.2

1.0

0.8

2.6

2.4

2.2

2.0

1.8

1.6

1.4

1.2

1.0

0.8

2.6

2.4

2.2

2.0

1.8

1.6

1.4

1.2

1.0

0.8

t* = 0.35p = 0.002

t* = 0.30p = 0.006

t* = 0.29p = 0.02

t* = 0.27p = 0.03

log(lgG)

log(lgA)

Families ranked by family mean anti-mannan Ig

Unaffected Affected

Figure 3 Correlations of anti-mannan Ig levels in maritalpairs and sibling pairs.

0.4

0.3

0.2

0.1

0

_0.1

_0.2

Correlationcoefficient

IgAp = 0.01

IgGp = 0.04

Sibling pairs (n = 57)

Marital pairs (n = 75)



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method utilises quantitative rather than cat-egorical (positive-negative) traits. For this rea-son, it is better for assessing groups with lowrates of the phenotype in question (in this case,marker antibody levels in unaVected familymembers). The intraclass correlation coefficientcompared the variation in anti-mannan levelsbetween and within groups. The correlationcoeYcient (t*) for this comparison will rangefrom 0 to 1; the low value reflects a trait without

intragroup specificity, and the latter represents atrait entirely segregated within a group. AmongaVected family members, anti-mannan levelswere correlated more within families thanbetween families (t*=0.27 and t*=0.29, p=0.03and p=0.02, for IgG and IgA, respectively).Notably, this correlation was even strongeramong unaVected family members (t*=0.35and t*=0.30, p=0.002 and p=0.006).

These findings are impressive when comparedwith a classic study utilising intraclass correla-tion of in vivo insulin action as a marker forgenetic susceptibility to type II diabetes. In thatstudy of the Pima Indian population, intraclasscorrelation also revealed an increased concord-

ance of fasting insulin and insulin action(glucose uptake on insulin infusion) withinfamilies rather than between families (t*=0.35and t*=0.42, p

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doi: 10.1136/gut.46.1.582000 46: 58-63Gut

C L Sutton, H Yang, Z Li, et al.

diseaseunaffected relatives of patients with Crohn's

mannan antibodies in affected andcerevisiaeSaccharomycesFamilial expression of anti-

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