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Keywords:

  • inflammatory bowel disease;
  • Crohn's disease;
  • ulcerative colitis;
  • twin study;
  • concordance

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Background: Genetic predisposition as a cause of inflammatory bowel disease (IBD) has been proven by both family and twin studies and genetic variants associated with the disease have been identified. The aim of our study was to determine the concordance rates for IBD in German twin pairs and to evaluate clinical characteristics of concordant and discordant twin pairs.

Methods: Patients with IBD were asked to participate and complete a questionnaire that contained questions about zygosity, demographic data, and medical history.

Results: A total of 189 twin pairs in which at least 1 member had IBD were recruited (68 monozygotic and 121 dizygotic pairs). Within monozygotic pairs, 11 out of 31 (35%) were concordant for Crohn's disease (CD) and 6 out of 37 (16%) for ulcerative colitis (UC). Two of the 58 (3%) dizygotic pairs with CD and 1 out of 63 (2%) dizygotic pairs with UC were concordant for the disease. In 14 out of 20 (70%) discordant monozygotic CD pairs and 25 out of 31 (81%) discordant monozygotic pairs with UC, the first-born was affected by IBD. For discordant dizygotic twins, the first in birth order had IBD in 33 out of 56 (59%) pairs with CD and 40 out of 62 (64.5%) pairs with UC.

Conclusions: This study confirms a stronger genetic influence in CD than in UC. The high preponderance in being affected of the first-born twin and the fact that concordance was only 35% for CD and 16% for UC monozygotic twins highlight the important role of environmental trigger factors.

(Inflamm Bowel Dis 2008)

Although remarkable progress has been made with the recent discovery of genetic factors, the etiology of inflammatory bowel diseases (IBD) has not been resolved. In both subforms, Crohn's disease (CD) and ulcerative colitis (UC), genetic factors and nongenetic trigger events are likely to play a major role.1–9 Epidemiological studies have highlighted genetic predisposition factors for IBD. Among relatives with CD and UC the odds ratio to develop IBD is in the range of 15–42 over the normal population for CD and 7–17 for UC.10–14 While several susceptibility genes have been identified for CD only DLG5 and IL23R appear to be associated with UC. On the other hand, targeted exploration has been mainly conducted in CD.1–9, 15–17 Analyses of twin pairs provide a unique opportunity to discriminate between the influence of genetic and environmental factors to phenotypic variance. However, only a few numbers of such studies have been conducted in IBD context: 80 twin pairs have been identified by the Swedish twin registry, 103 twin pairs in the Danish twin registry, and 150 British twin pairs were recruited by a questionnaire distributed by a national self-help group.18–20

The aim of our study was to determine levels of concordance for IBD in a German twin cohort and to analyze the clinical characteristics of this group.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Volunteers' Recruitment and Questionnaires

In 2004 and 2005 the German Crohn's and Colitis Association (patient association with more than 20,000 members; DCCV e.V.), and the Competence Network Inflammatory Bowel Disease (medical expert network; Kompetenznetz Darmerkrankungen e.V.) published several calls for twin pairs using advertisements and the nationwide newsletter of the patient association. Individuals were asked to participate and complete a questionnaire if they had IBD and were born as 1 of a twin pair. Among others, questions were related to zygosity, medical history, social status, lifestyle (e.g., former and present smoking status), if they grew up together, and birth order.21 Special attention was paid to the chronic IBD subphenotype i.e., CD, UC, or other chronic inflammatory disease of the bowel.

Diagnosis of Crohn's Disease and Ulcerative Colitis

Diagnosis of IBD was confirmed by review of the patients' original medical records including ileocolonoscopies. Forty-three percent of the patients had at least 1 clinical visit including ileocolonoscopy performed at 1 of the investigators hospitals (A.R.), which ensured thorough diagnostics in these patients. Diagnosis of CD was confirmed when at least 2 of the criteria published by Landers et al22 were fulfilled. Diagnosis of UC was based on endoscopic appearance and continuity of inflammation, histology, and proven exclusive involvement of the colon (allowing backwash-ileitis). Patients were asked about age of onset of symptoms, age at time of diagnosis, location of disease, type of disease (e.g., stricturing, inflammatory), current treatment, and treatment since diagnosis. The nondiseased twins were evaluated for signs and symptoms of IBD and records of previous ileocolonoscopies were scrutinized.

Statistical Analysis

Concordance describes the proportion of twins that share the same phenotype. The population casewise rate (i.e., “Proband concordance rate”) and the risk that a twin is affected if the co-twin is also affected were calculated according to the formula C = (2C1 + C2)/(2C1 + C2 + D) where C1 = number of concordant twin pairs in which the 2 affected members have been ascertained independently, C2 = number of concordant twin pairs in which only 1 twin is ascertained independently, D = number of pairs in which only 1 member is affected.23 The 95% exact confidence intervals for the concordance rates were calculated assuming a binomial distribution. By comparing the relative risks for the siblings of twins with CD and UC, we calculated whether genetic influence is of greater importance for 1 of the 2 diseases. According to the prevalence rates in the background population the relative risks were calculated by dividing the observed number of diseased co-twins with the expected numbers among the co-twins.24 To calculate the 95% confidence interval of the relative risk we assumed that the number of cases among the co-twins followed a Poisson distribution.19 Two relative risks were compared using the likelihood ratio test. Differences in weight and height between affected and nonaffected twins were calculated using the Wilcoxon signed rank test for zero median. By using McNemar's test for a case-control study with continuity correction, we evaluated whether smoking, birth order, and extraintestinal manifestations (EMs) were of significance for the discordance of IBD.

The univariate survival data from the Human Life-Table Database, Germany, for the period 2000–2002 was analyzed to estimate the number of twin pairs within the German population.25 The bivariate survival function in the correlated gammafrailty model follows the formula:

  • equation image

Here σ2 is the variance of frailty (nonobserved risk of mortality) and R is the correlation of the frailty for twins. The values of R and _2 were close to estimates obtained from the Danish twin study, σ2 = 1, RMZ = 0.5, RDZ = 0.25.26

The number of twin pairs with both twins survived to the age x is equal to NS(x,x), where N is the number of twin pairs at birth. The full number of twin pairs with both twins alive is equal to NxS(x,x).

The population of Germany is now approximately 82,468,000 (inhabitants), the birth rate is 8.5%,27 each 80th birth is a birth of a twin pair, and 1/3 of twin pairs are monozygotic (MZ). That is, N &Ap; 82,468,000 × 0.0085 / 81 = 86,540 newborn twin pairs, with 28,847 MZ twin pairs and 57,693 dizygotic (DZ) twin pairs. Summing the number of twin pairs from 0 to 99 years old we were able to estimate a number of 207,891 MZ twin pairs and 413,321 DZ twin pairs in German population. Let P(D/H) = 1-P(H/H) be the conditional probability for diseased co-twin given healthy twin and P(D/D) = 1-P(H/D) the conditional probability for diseased co-twin given diseased twin. From the Bayes formula we have P(D/H) = P(H/D)*P(D)/P(H) &Ap; (1-P(D/D))P(D), where P(D) = 1-P(H) is the probability to find diseased individual in the population. In our case P(D) = 48/100,000 for CD and 80/100,000 for UC.

If we observe 207,891 MZ twin pairs, then in average we have 207,891*P(D) = 100 (166) CD (UC) diseased first MZ twins and 207,891 − 100 = 207,791 (207,891 − 166 = 207,725) CD (UC) healthy first MZ twins. Additionally, for diseased first MZ twins, we have 100*P(D/D) = 52 CD (166*P(D/D) = 46 UC) diseased co-twins and for healthy first MZ twins we have 207,791*P(D/H) = 47 CD (207,725*P(D/H) = 120 UC) diseased co-twins. Approximately we have 2*100 = 200 CD (2*166 = 332 UC) diseased individuals from MZ twins or 100*(2-P(D/D)) = 147 CD (166*(2-P(D/D)) = 286 UC) MZ twin pairs with at least 1 diseased twin.

If we observe 413,321 DZ twin pairs, then on average we have 413,321*P(D) = 198 CD (331 UC) diseased first DZ twins and 413,321 − 198 = 413,123 CD (413,321 − 331 = 412,990 UC) healthy first DZ twins. Moreover, for diseased first MZ twins we have 198*P(D/D) = 13 CD (331*P(D/D) = 10 UC) diseased co-twins and for healthy first DZ twins we have 413,123*P(D/H) = 185 CD (412990*P(D/H) = 320 UC) diseased DZ co-twins. Approximately we have 2*198 = 396 CD (2*331 = 662 UC) diseased individuals from DZ twins or 198*(2-P(D/D)) = 383 CD (331*(2-P(D/D)) = 651 UC) DZ twin pairs with at least 1 diseased twin. For P(D/D) values we used the proband concordance rates from Table 1.

Table 1. Mono- and Dizygotic Twin Pairs Concordant and Discordant for Crohn's Disease and Ulcerative Colitis
Co-twin's Diagnosis
Index Twin's DiagnosisCDUCNo IBDPair Concordance (%)Proband Concordance (%)
  • Proband concordance rates are expressed in percentages with exact 95% confidence intervals in parentheses.

  • *

    P ≤ 0.05 compared to MZ twins with UC.

Monozygotic     
 CD1102035.5 (19.2–54.6)52.4* (36.4–68.0)
 UC063116.2 (6.2–32.0)27.9 (15.3–43.7)
Dizygotic     
 CD20563.5 (0.4–11.9)6.7 (1.9–16.2)
 UC01621.6 (0.0–8.5)3.1 (0.4–10.8)

Differences resulting in a P-value of <0.05 were considered statistically significant.

Ethics Approval

The study was approved by the ethics committee of the Medical Faculty of the Christian-Albrechts-University in Kiel and written informed consent was obtained from all patients included in this study.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Confirmation of Diagnosis

A total of 195 twin pairs replied to the announcement and 193 were qualified for further investigation by stating having a living twin and at least 1 of the twin siblings with either CD or UC. In 24 healthy twin siblings from discordant pairs (10 MZ and 8 DZ CD; 2 MZ and 4 DZ UC pairs), noteworthy gastrointestinal symptoms were identified that would be compatible with IBD but had not yet led to diagnosis of a gastrointestinal disorder. These individuals were contacted for confirmation and were hence classified as “healthy.” Diagnosis of CD or UC was further confirmed by review of medical records in 189 individuals. Four twin pairs were excluded from the study since diagnostic criteria were not fulfilled. These twins had abdominal complaints and stated suffering from CD but showed neither endoscopic, radiologic, nor histopathologic signs of the disease.

Concordance Rates

Using the zygosity questionnaire, 68 twin pairs were monozygotic and 121 were dizygotic. Eleven out of 31 (35%) MZ pairs were concordant for CD and 6 out of 37 (16%) MZ pairs were concordant for UC (Table 1, Fig. 1).

thumbnail image

Figure 1. Concordance rates in German twins with IBD.

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The concordance was much lower in DZ twin pairs and concerned 2 of the 58 pairs for CD and 1 out of 63 for UC. Most interestingly, no mixed twin pairs (i.e., CD with UC) were observed. The proband concordance rate was 52.4 among MZ twins with CD and 27.9 for MZ twins with UC. The proband concordance rate among DZ twins was 6.7 for CD and 3.1 for UC twins.

As illustrated in Table 2, the relative risk in MZ co-twins was significantly higher for CD than for UC. Relative risk for development of IBD in MZ twins was remarkably high in both CD (738.3; 95% confidence interval [CI]: 368.5–1320.9) and UC (202.7; 95% CI: 74.4–441.2). In DZ twins relative risks were 71.9 (95% CI: 8.7–259.9) and 19.8 (95% CI 0.5–110.5) for CD and UC, respectively.

Table 2. Relative Risk of Crohn's Disease and Ulcerative Colitis Among Co-twins of Twins with Crohn's Disease and Ulcerative Colitis
ZygosityCrohn′s DiseaseUlcerative Colitis
MZDZMZDZ
  • Numbers in parentheses = 95% confidence intervals. Prevalence in the background population: Crohn's disease 48/100,000, ulcerative colitis 80/100,000.

  • *

    P ≤ 0.05 compared to MZ twins with UC.

No. of co-twins31583763
Observed11261
Expected0.01490.02780.02960.0504
Relative risk738.3* (368.5–1320.9)71.9 (8.7–259.9)202.7 (74.4–441.2)19.8 (0.5–110.5)

Demographic Characteristics

All twins grew up together until the age of 15, 26% until the age of 30, and 13% were living together beyond the age of 30. Females represented 51%. Eighty-nine twin pairs (82 males, 96 females) had an affected index sibling with CD and 100 twin pairs (94 males, 106 females) were recruited with the index individual suffering from UC. The patients' demographic features are shown in Tables 3 and 4. The mean age was 34.4 years in pairs with CD and 33.5 years in pairs with UC. The mean age at diagnosis was 26.2 years for CD twins and 25.1 years for UC twins. No significant differences in age at diagnosis were observed between MZ and DZ or concordant and discordant twins. The diseased CD twins were significantly taller than their healthy siblings (mean height 173.0 versus 171.7 cm, P < 0.0001) whereas it was the opposite in UC (mean height healthy sibling 175.2 versus 174.0 cm for UC twin, P = 0.6149). Diseased twins were significantly lighter than their siblings: for CD, mean weight 67.8 versus 71.7 kg, P < 0.0001; for UC: 69.9 versus 73.8 kg, P < 0.0001. Interestingly, the affected sibling was the first-born (i.e., before his healthy co-twin) in 61.8% of the discordant twins with CD (70.0% of the MZ and 58.9% of the DZ twins) (P = 0.006) (Fig. 2). This finding was also observed in discordant twins with UC: 80.1% of the MZ and 64.5% of the DZ twins were the first in birth order (P < 0.0001). In our study, 40.8% of the discordant twin individuals with CD and 14.0% of the discordant twins with UC were either smokers or former smokers at the time of diagnosis compared to 36.8% and 34.4% of their healthy siblings. Frequency of smokers showed a tendency for positive association in CD but did not reach significance (P = 0.0636) and was significantly negatively associated (i.e., protective) in UC (P < 0.0001). During the time between the diagnosis and the survey, 2 (1 diseased twin in the MZ discordant twin group and 1 healthy twin in DZ discordant twin group) of the CD and 4 of the UC twins (2 diseased twins in the MZ discordant twin group and 2 nondiseased in the DZ discordant twin group) had stopped smoking. In concordant CD patients, the location of the disease according to the Vienna classification was identical in 8/11 (72.7%) MZ twins. In concordant UC twins, 5/6 (83.3%) of the MZ twins were concordant for disease location. The number of DZ concordant CD and UC pairs was too low to examine statistical significance for concordance in disease location within pairs. A trend for concordance in disease behavior (i.e., formation of fistula or strictures) was observed in CD twins: 3/11 of the MZ CD twins were concordant for occurrence of fistula and 4/11 were concordant for nonpenetrating/nonstricturing disease. No differences were observed for surgery in any of the twin pairs. Extraintestinal manifestations (eyes, skin, and joints or a combination of the latter) were noted more often in CD (74/102; 72.5%) than in UC patients (72/107; 67.3%). Remarkably, 11/76 (14.5%) of the healthy (i.e., no IBD diagnosed) CD co-twins and 16/93 (17.2%) of the healthy UC co-twins had symptoms compatible with an extraintestinal manifestation of IBD.

Table 3. Demographic and Clinical Characteristics of 89 German Twin Pairs with Crohn's Disease
 Monozygotic Pairs (n=31)Dizygotic Pairs (n=58)
Concordant Pairs (n=11)Discordant Pairs (n=20)Concordant Pairs (n=2)Discordant Pairs (n=56)
CD (n=11)CD Co- Twin (n=11)CD (n=20)Healthy (n=20)CD (n=2)CD Co- twin (n=2)CD (n=56)Healthy (n=56)
  • aIn year 2006.

  • *

    P < 0.05 compared to co-twin.

  • **

    P < 0.01 compared to co-twin.

  • ***

    P < 0.001 compared to co-twin.

  • ****

    P < 0.0001 compared to co-twin.

Males (%)12 (54.5)18 (45.0)3 (75.0)50 (44.6)
Females (%)10 (45.5)22 (55.0)1 (25.0)62 (55.4)
Agea (range)39.4 (22–62)32.5 (9–68)38.5 (36–41)34.1 (9–65)
Age at diagnosis25.5 (14–44)28.0 (16–46)24.2 (8–42) 25.5 (23–28)27.0 (24–30)29.2 (7–53) 
Height (cm) (SD)171.7 (11.0)171.5 (10.8)174.5****(8.4)173.7 (8.4)175.0 (0)174.5 (0.7)172.4****(8.1)171.0 (7.8)
Weight (kg)61.3 (9.1)68.2 (10.6)66.4 (6.6)*69.1 (9.7)83.5 (0.7)87 (7.1)68.3(10.2)****72.6 (11.4)
First born (%)8 (72.7)3 (27.3)14 (70.0)*4 (20.0)2 (100.0)0 (0.0)33 (58.9)19 (33.9)
Undetermined birth order0 (0.0)2 (10.0)0 (0.0)4 (5.4%)    
Smoker (%) at the time of diagnosis2 (18.2)3 (27.3)12 (60.0)7 (35.0)0 (0.0)0 (0.0)16 (28.6)12 (21.4)
Former smoker (%)3 (27.3)2 (18.2)0 (00.0)4 (20.0)0 (0.0)0 (0.0)3 (5.4)5 (8.9)
Never smoked (%)6 (54.5)6 (54.5)8 (40.0)9 (45.0)2 (100.0)2 (100.0)37 (66.1)39 (69.6)
Location of disease        
Terminal ileum (%)4 (36.4)2 (18.2)5 (25.0)0 (0.0)2 (100.0)1 (50.0)13 (23.2)0 (0.0)
Colon (%)3 (27.3)3 (27.3)6 (30.0)0 (0.0)0 (0.0)1 (50.0)12 (21.4)0
Ileocolon (%)4 (36.4)6 (54.5)6 (30.0)0 (0.0)0 (0.0)0 (0.0)26 (46.4)0 (0.0)
Upper GI (%)0 (0.0)0 (0.0)3 (15.0)0 (0.0)0 (0.0)0 (0.0)5 (8.9)0 (0.0)
Ems        
Eyes, skin, joint6 (54.5)4 (36.4)9 (45.0)**3 (15.0)2 (100.0)0 (0.0)31(55.4)****4 (7.1)
Combination2 (18.2)4 (36.4)5 (25.0)0 (00.0)0 (0.0)1 (50.0)10 (17.9)4 (7.1)
None3 (27.3)3 (27.3)6 (30.0)***17 (85.0)0 (0.0)1 (50.0)15(26.8)****48 (85.7)
Nonstricturing, nonpenetrating (%)8 (72.7)4 (36.4)11 (55.0)n.a.0 (0.0)0 (0.0)8 (14.3)n.a.
Stricturing disease (%)0 (0.0)2 (18.2)8 (40.0)n.a.0 (0.0)0 (0.0)15 (26.8)n.a.
Penetrating disease (%)3 (27.3)5 (45.5)1 (5.0)n.a.2 (100.0)2 (100.0)33 (58.9)n.a.
Operation (%)4 (36.4)2 (18.2)16 (80.0)n.a.1 (50.0)0 (0.0)15 (26.8)n.a.
Remission (%)7 (63.6)9 (81.8)13 (65.0)n.a.1 (50.0)1 (50.0)40 (71.4)n.a.
Systemic steroids (%)4 (36.4)6 (54.5)5 (25.0)n.a.2 (100.0)0 (0.0)10 (17.9)n.a.
Table 4. Demographic and Clinical Characteristics of 100 German Twin Pairs with Ulcerative Colitis
 Monozygotic Pairs (n=37)Dizygotic Pairs (n=63)
Concordant Pairs (n=6)Discordant Pairs (n=31)Concordant Pair (n=1)Discordant Pairs (n=62)
UC (n=6)UC Co-Twin (n=6)UC (n=31)Healthy (n=31)UC (n=1)UC Co-twin (n=1)UC (n=62)Healthy (n=62)
  • a

    In year 2006.

  • *

    P < 0.05 compared to co-twin.

  • **

    P < 0.01 compared to co-twin.

  • ***

    P < 0.001 compared to co-twin.

  • ****

    P < 0.0001 compared to co-twin.

Males (%)6 (50%)34 (54.8)0 (0.0)60 (48.4)    
Females (%)6 (50%)28 (45.2)2 (100.0)64 (51.6)    
Agea(range)33.3 (24–48)36.2 (16–73)40 (40–40)32.1 (15–67)    
Age at diagnosis27.7 (19–41)30.7 (23–46)26.2 (13–49) 12 (12)19 (19)24.5 (13–43) 
Height (cm)176.2 (7.1)175.7 (7.0)178.7 (8.0)****177.9 (8.0)168 (0)168 (0)171.7 (6.2)173.9 (7.3)
Weight (kg)70.5 (11.6)73.8 (12.4)75.1 (7.7)**78.9 (8.1)72 (0)75 (0)67.3 (8.4)****71.2 (9.7)
First born (%)3 (50.0)3 (50.0)25 (80.1)****2 (6.5)1 (100.0)0 (0.0)40 (64.5)***12 (19.4)
Undetermined birth order0 (0.0)4 (13.0)0 (0.0)10 (16.1)    
Smoker at the time of diagnosis2 (33.3)2 (33.3)2 (6.5)***14 (45.2)0 (0.0)0 (0.0)0 (0.0)***10 (16.1)
Former smoker (%)0 (0.0)1 (16.7)2 (6.5)2 (6.5)0 (0.0)0 (0.0)9 (14.5)6 (9.7)
Never smoked (%)4 (66.7)3 (50.0)27 (87.1)***15 (48.4)1 (100.0)1 (100.0)53 (85.5)46 (74.2)
Location of disease        
Proctitis (%)4 (66.7)3 (50.0)20 (64.5)0 (0.0)1 (100.0)1 (100.0)33 (53.2)0 (0.0)
Left-sided disease (%)2 (33.3)3 (50.0)8 (25.8)0 (0.0)0 (0.0)0 (0.0)19 (30.6)0 (0.0)
Pancolitis (%)0 (0.0)0 (0.0)3 (9.7)0 (0.0)0 (0.0)0 (0.0)10 (16.1)0 (0.0)
EMs        
Eyes, joints, skin5 (83.3)3 (50.0)4 (12.9)3 (9.7)1 (100.0)0 (0.0)30 (48.4)****8 (12.9)
Combination1 (16.7)2 (33.3)9 (29.0)*3 (9.7)0 (0.0)0 (0.0)17 (27.4)***2 (3.2)
None0 (0.0)1 (16.7)18 (58.1)**25 (80.6)0 (0.0)1 (100.0)15 (24.2)****52 (83.9)
Operation1 (16.7)0 (0.0)7 (22.6)0 (0.0)1 (100.0)0 (0.0)14 (22.6)0 (0.0)
Remission5 (83.3)2 (33.3)8 (25.8)n.a.0 (0.0)0 (0.0)52 (83.9)n.a.
System. steroids6 (100.0)3 (50.0)11 (35.5)0 (0.0)0 (0.0)0 (0.0)15 (24.2)0 (0.0)
thumbnail image

Figure 2. Distribution of first- and second-born siblings in discordant twins with IBD.

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At the time of survey, 29/42 (69.0%) of the CD-affected MZ twin individuals and 42/60 (70%) of the CD patients from DZ pairs were in remission. In UC 15/43 (34.9%) of the MZ twin individuals and 52/64 (81.3) of the patients from DZ pairs were in remission. Steroids were administered to 27/102 (26.5%) of the CD and 35/107 (32.7%) of the UC patients.

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

CD and UC are multifactorial disorders with a significant genetic influence. The epidemiologic examination of monozygotic and dizygotic twins, who grew up together, allows the evaluation of heritable factors. We conducted the first German IBD twin study, 1 of the few studies published so far.18–20, 28 In comparison to the Danish and Swedish studies, our analysis was not based on a national twin register (not available in Germany) but on questionnaires sent out to twins who responded to an announcement published in different newsletters. This might lead to bias, as some twins may not have been reached. Assuming a similar prevalence of CD and UC in the twin population (only counting index patients) and using the known data for twin birth in Germany, one would expect 147 (383) living MZ (DZ) twin pairs with CD and 286 (651) living MZ (DZ) twin pairs with UC. We recruited 21.09% of the theoretically existing MZ CD twin pairs and 15.14% of the DZ CD pairs. The corresponding recruitment rates for UC are 12.94% of the MZ UC pairs and 9.83% of the DZ UC pairs. The response rate to our questionnaire that was sent out to the identified patients was 86.3%, with a male/female distribution among the CD and UC twins in the index patients as expected in the German population.29

In comparison, the Danish twin study included only twins born between 1953 and 1982 and the coverage from 1953 to 1967 reached 74.4%. In the Swedish studies the Swedish twin register has been run against the central diagnosis register of hospital inpatients, which excludes outpatients and should lead—among other biases—to an overrepresentation of UC twins. Our observations confirm that the genetic influence is higher for CD than for UC.18, 30, 31 Interestingly, no mixed concordance was observed in our twin population, as was noticed in the non-twin families.12 This may be due to the small sample of DZ twin pairs in comparison with the large non-twin family population studied.32 The proband concordance rates observed in our study were 52.4% for MZ and 6.7% for DZ CD twins. In UC twins, concordance rates were 27.9% in MZ and 3.1% in DZ pairs. These rates differ from the Danish/Swedish results (58.3–62.5% in MZ and 0.0–3.8% in DZ CD twins, 6.3–18.8% in MZ and 0.0–4.5% in DZ UC twins). The concordance rates reported by the British study are similar compared to those of the present study but cannot be used for comparison since calculation methodology differs.33 The differences in the concordance rates observed could result from different criteria that were used to establish the diagnosis. In contrast to the previous studies, clinical symptoms were not used to establish the diagnosis and all Landers criteria needed to be fulfilled. The discrepancy in concordance rates might also be explained by the different genetic background of the Danish/Swedish population, which is evidenced by differing occurrences of mutations in susceptibility genes (e.g., CARD15/NOD2 mutations).34

Generally, it can be argued that some of the healthy twins could still manifest IBD in the future and a long-time follow-up survey will be performed to evaluate this issue. It should also be pointed out that this study may reflect a certain recruitment bias which may be not present in a twin registry based on healthcare data.

The relative risk for the sibling of CD patients was around 738. This would lead to an assumption that substantial genetic risk factors (that would be multiplicative) may be present in the twin population.

The mean age at diagnosis of the twins was 26.4 years. This is much younger than the mean age for IBD diagnosis in the population, which ranges from 33.4–45 years for CD and is 5–10 years later for UC.35–37 The earlier age of diagnosis could represent a change over the last decade caused by a further increase in adult and pediatric prevalences that were described recently.38–42 Interestingly, age at the time of diagnosis was not different between concordant and discordant twins. This stands in contrast to the findings of a long-term follow-up Swedish twin study that observed a high degree of concordance regarding the age at diagnosis in concordant monozygotic twin pairs with CD.28 However, our results are in accordance with the Danish study, which showed no differences between MZ and DZ twins for age at diagnosis.

It is well known that the first-born baby of a twin pair has a higher body weight than the second-born and that twins who were heavier at birth are taller and slightly heavier as adults than the lighter twins.43, 44 Interestingly, the first-born twins were significantly overrepresented among the affected individuals. The lower body weight that is observed may directly relate to the disease. We noticed in a previous work that the first-born in large families is more likely to develop IBD and the present study confirmed this feature in a twin cohort in which the birth of the siblings is only different by minutes.45 This illustrates the strong influence of environmental trigger factors that might intervene early after birth (e.g., bacterial colonization) or via the placenta and not during childhood, as suggested in our previous analysis.45 Also, it has been suggested that the first-born sibling is more likely to suffer from stress caused by higher expectations of the parents compared to the second-born individual.46 As known from previous studies, stress can lead to onset of IBD in susceptible individuals.47–50

Smoking has been described as a protective factor for UC and a risk factor for CD in previous studies.51–53 Both smokers and former smokers were more frequent among the healthy UC-discordant twins than subjects who had never smoked but the smoking pattern alone could not explain the discordance in UC pairs. The role of smoking in CD has been discussed controversially: Some authors proposed smoking as a risk factor for CD, while others found no effect of smoking.54–57 A meta-analysis suggests that smokers are more than twice as likely to develop CD but the association between smoking and CD may differ depending on ethnic groups or geographic regions.56, 57 The previous twin studies identified smoking as a risk factor for CD and as protective for UC but could not prove its contribution to concordance. In our work, CD index twin individuals were more frequently smokers and former smokers but differences between affected and nonaffected co-twins were not significant. Failure to demonstrate the role of smoking as a risk factor contributing to discordance might be due to the relatively low number of probands but could also indicate that other environmental trigger factors need to be present to induce the disease.58

Several studies have shown a greater-than-expected concordance for site of manifestation and clinical type of IBD in members of multiply affected families, but this correlation was noticed in only a few IBD twin studies.28, 59, 60 In contrast to the Swedish long-term follow-up study, we do not confirm with this work the elevated concordance rates for site of manifestation and clinical type of IBD. In a follow-up study we will analyze whether these characteristics will change from the time of diagnosis to a later point in time. No correlation between extraintestinal manifestations and concordance was observed but symptoms that could be suggestive of extraintestinal affects in eyes, skin, joints, or a combination of the latter was present in a small proportion of the healthy twins, suggesting that these symptoms might precede the onset of IBD or be independently determined by genetic factors.

In our study we confirm increased concordance in CD and UC MZ twins in comparison to DZ twins. Concordance rates were higher in CD than in UC twin pairs. A relative risk of 738.3 in CD MZ twin pairs illustrates the effect size of genetic factors. In a long-term follow-up of the German twin cohort, the stability of the proband concordance rates will be examined and the genetic background of individuals will be analyzed.

Acknowledgements

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

We thank the DCCV e.V. (German Crohn's and Colitis Association), the Kompetenznetz Darmerkrankungen e.V., Frank Hinrichs, Birgit Kaltz and Karin Konrad for assistance in recruitment of twins.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
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