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. Author manuscript; available in PMC: 2024 Jul 3.
Published in final edited form as: Int J Cancer. 2023 Feb 20;152(11):2303–2313. doi: 10.1002/ijc.34470

Association of inflammatory bowel disease in first-degree relatives with risk of colorectal cancer: A nationwide case-control study in Sweden

Kai Wang 1, Ola Olén 2,3,4, Louise Emilsson 5,6,7,8, Hamed Khalili 9,10,11, Jonas Halfvarson 12, Mingyang Song 1,9,10,13, Jonas F Ludvigsson 7,14,15
PMCID: PMC11221413  NIHMSID: NIHMS1994767  PMID: 36760205

Abstract

This study aims to assess the association between inflammatory bowel disease (IBD) history in first-degree relatives (FDRs) and colorectal cancer (CRC) risk. We conducted a nationwide case-control study in Sweden among 69 659 CRC cases and 343 032 non-CRC controls matched on age, sex, birth year and residence county. Through linkage of multi-generation register and the nationwide ESPRESSO (Epidemiology Strengthened by histoPathology Reports in Sweden) cohort, we ascertained IBD diagnoses among parents, full siblings and offspring of the index individuals. Odds ratios (ORs) of CRC associated with IBD family history were calculated using conditional logistic regression. 2.2% of both CRC cases (1566/69659) and controls (7676/343027) had ≥1 FDR with IBD history. After adjusting for family history of CRC, we observed no increased risk of CRC in FDRs of IBD patients (OR, 0.96; 95%CI, 0.91–1.02). The null association was consistent according to IBD subtype (Crohn’s disease or ulcerative colitis), number of FDRs with IBD (1 or ≥ 2), age at first IBD diagnosis in FDRs (<18, 18-39, 40-59 or ≥60 years), maximum location/extent of IBD or FDR relation (parent, sibling or offspring). The null association remained for early-onset CRC (diagnosed at age <50 years). In conclusion, IBD history in FDRs was not associated with an increased risk of CRC. Our findings suggest that extra screening for CRC may not be needed in the offspring, siblings or parents of IBD patients, and strengthen the theory that it is the actual inflammation or atypia of the colon in IBD patients that confers the increased CRC risk.

Keywords: colorectal cancer, family history, first-degree relatives, inflammatory bowel disease

1 |. INTRODUCTION

Colorectal cancer (CRC) is the second leading cause of cancer deaths worldwide.1 Patients with inflammatory bowel diseases (IBDs) are at an increased risk of developing CRC.2–4 This relationship leads to an implementation of CRC surveillance programs in IBD patients.5–8 IBD-associated CRC may develop at a younger age,9,10 evolve from microscopic dysplasia with an endoscopically invisible mass lesion,11 have a shorter time interval from the presence of dysplasia to carcinoma,11 and be more lethal than the typical sporadic CRC.2,3,12 These lines of evidence suggest the significance to enhance CRC screening in the high-risk population for IBD.

Family history of IBD has been established as the strongest risk factor for IBD.13–15 For example, first-degree relatives of affected probands in a Danish population had a ~15-fold higher life-time risk of IBD compared with the general population,16 and the risk increase was stronger in first-degree relatives of patients with pediatric IBD.17 Genome-wide association studies (GWAS) using unrelated IBD cases and controls have identified more than 240 heritable IBD-risk loci.14,18 Given the genetic heritability of IBD and the relationship between IBD and CRC, it is biologically plausible that relatives of IBD probands are at a higher risk of CRC. Although several prior studies investigated the association between family history of IBD and risk of CRC,19–21 these studies are limited in study power by either a small overall sample size (n < 100) or small numbers of CRC events, particularly for early-onset CRC that are diagnosed at age < 50 years. Therefore, more studies are needed to assess whether family members of affected IBD probands are at an increased risk of CRC. IBD diagnosis in FDRs (<18, 18–39, 40–59 or ≥60 years), maximum location/extent of IBD or FDR relation (parent, sibling or offspring). The null association remained for early-onset CRC (diagnosed at age <50 years). In conclusion, IBD history in FDRs was not associated with an increased risk of CRC. Our findings suggest that extra screening for CRC may not be needed in the offspring, siblings or parents of IBD patients, and strengthen the theory that it is the actual inflammation or atypia of the colon in IBD patients that confers the increased CRC risk.

In the current study, we leveraged a nationwide matched case-control design and linkage of the multi-generation register and several other nationwide registers in Sweden to identify the diagnosis of IBD among first-degree relatives of study participants. We aimed to comprehensively assess the relationship between history of IBD in firstdegree relatives and risk of CRC, and whether this relationship varies according to certain important characteristics of IBD and concurrent presence of CRC in first-degree relatives.

2 |. MATERIALS AND METHODS

2.1 |. Study population

In Sweden, health care is tax-funded and access to care is universal. The personal identity number assigned to all residents enables linkage among registers containing information on demographics, medication, morbidity, histopathology and identity of relatives.22 Patients with CRC were drawn from the nationwide ESPRESSO (Epidemiology Strengthened by histoPathology Reports in Sweden) cohort, which included information of gastrointestinal biopsy samples from all 28 pathology departments in Sweden between 1965 and 2017.23 In ESPRESSO, histopathological findings were defined by morphology codes (a Swedish modification of the Systematized Nomenclature of Medicine [SNOMED] coding system) and topography codes. To identify patients with CRC, we used topography codes T67x (for colon) and T68x (for rectum) in combination with SNOMED codes (Table S1). For each identified CRC case in ESPRESSO, we selected up to five controls from the general population matched on age (in years), sex, year of birth and county of residence.23

For both CRC cases and matched controls, we excluded those younger than 18 years, those with hereditary syndromes of CRC, and those with a history of colectomy before CRC diagnosis. Since we had International Classification of Disease (ICD) codes recorded for all inpatient and outpatient visits of each participant, we used the codes of Z15.09 (ICD-10) and V84.09 (ICD-9) to detect those with hereditary syndromes of CRC, and the codes of 4651, 4652, 4653, 4654, 4650, JFH10, JFH11, JFH96, JFH00, JFH01, JFC40, JFC41, JFG29, JFG26, JFH30, JFH33, JGB50, JGB60, JFH40 and JFH20 to detect those with a history of colectomy, that occurred before the index date. Because the multi-generation register is confined to individuals born after 1932, we also excluded those born before January 1, 1932. In total, 69 659 CRC cases and 343 032 matched controls were included in the study (Figure S1).

2.2 |. Assessment of family histories of IBD and CRC

From the family relationship data in the Swedish multi-generation register (which is part of the Total Population register24), we retrieved information of the parents, full siblings and offspring (first-degree relatives) of our study participants. We assessed history of IBD in the first-degree relatives through linkage to national patient registers, which included IBD information between January 1969 and December 2017. Details of IBD assessment have been described previously.2,3 Briefly, we identified the first diagnosis of Crohn’s disease, ulcerative colitis or other unclassified IBD when a given first-degree relative had at least two records of a relevant ICD code, or one such record plus a colorectal biopsy report with a morphology code suggestive of IBD. This approach has been validated with a positive predictive value of 95%.25 We only counted the IBD in first-degree relatives diagnosed before the index time, which was defined as the CRC diagnosis date of the index CRC cases and their matched controls (Figure S2). For each index participant, we counted the number of first-degree relatives with an IBD diagnosis before the index time and assessed the age at the first record of IBD diagnosis across all first-degree relatives. Maximum location of Crohn’s disease and extent of ulcerative colitis were categorized according to the Montreal classification,26 using validated ICD register codes representing maximum disease extent. We also stratified the first-degree relatives by presence of primary sclerosing cholangitis (PSC) or other extraintestinal manifestations.

To comprehensively capture the CRC diagnoses including those outside ESPRESSO because of unreported histopathological information, we assessed the history of CRC in first-degree relatives based on the Cancer Register, which has recorded incident malignancies in Sweden since 1958 and has an estimated completeness of 96%.27 CRC was identified using ICD-7 (ICD seventh version) codes 153 and 154.

2.3 |. Assessment of other covariates

For each participant, we calculated the family size as the sum of the number of parents, siblings and offspring. We obtained data on education and income from the longitudinal integrated database for health insurance and labor market studies,28 which integrates annually updated administrative information form the labor market and educational and social sectors from 1990 onward on all individuals 16 years or older registered as residents in Sweden. We used the education and income data closest to the time of CRC diagnosis for both cases and their matched controls. Information on age, sex, date of birth and emigration status was collected from the Swedish Total Population Register maintained by Statistics Sweden.

We collected information on use of endoscopic examination from the Swedish National Patient Registry, which started in 1964 with complete national coverage from 1987. We used the established procedure codes to identify colonoscopy (9011, 9023, 4688, 4689, 4674, 4684, UJF32 and UJF35) and sigmoidoscopy (9012, 4685, UJF42 and UJF45).29 We counted the number of endoscopies performed before CRC diagnosis for cases and their matched controls. To avoid counting the diagnostic endoscopies for CRC, we excluded endoscopies performed within 30 days before the date of CRC diagnosis. We calculated the Charlson comorbidity score using SAS macro code developed by Turner and Burchill30 based on the established ICD-9 and ICD-10 coding algorithms for 17 comorbidities,31,32 including diabetes that has been linked to higher CRC risk (Table S2). We also calculated the total number of prior clinic visits before CRC diagnosis for cases and their matched controls using the inpatient and outpatient records.

2.4 |. Statistical analysis

Means (standard deviations) were calculated for continuous variables and percentages for categorical variables among cases and controls. We used conditional logistic regression to calculate the odds ratios and corresponding 95% confidence intervals of CRC according to the history of any IBD and IBD by subtype (Crohn’s disease, ulcerative colitis or unclassified IBD) in first-degree relatives (yes or no), the number of first-degree relatives with IBD (0, 1 or ≥ 2), age at the first IBD diagnosis in first-degree relatives (<18, 18–39, 40–59 or ≥60 years), maximum location or extent of IBD (L1/L3/LX/E1/E2 or L2/E3/E4/EX), and relation of first-degree relatives with IBD (parents, siblings or offspring). P values for trend were calculated by treating the number of relatives and age at diagnosis as continuous variables. We considered three models: model 1 was conditional on the matching factors, and model 2 was further adjusted for other potential confounding factors, including family size (continuous), income level (quintiles), education (≤9, 10–12, >12 years or missing), number of previous endoscopic examinations (0, 1, 2 or > 2), Charlson comorbidity index score (continuous) and major comorbidities with a prevalence of at least 1% (all binary, including diabetes, cardiovascular disease, non-CRC cancer, liver disease, chronic pulmonary disease and connective tissue disease). To address the effect of family history of IBD independent from family history of CRC, we further adjusted for the history of CRC in first-degree relatives (no CRC, CRC diagnosed at age ≥ 50 years or CRC diagnosed at age < 50 years) in the multivariable model 3.

To evaluate whether first-degree relatives are specifically at risk for early-onset CRC that was diagnosed at age < 50 years, we performed subgroup analyses focusing on early-onset CRC. To reveal any potential interaction between family history of IBD and family history of CRC, we examined the joint association of family history of IBD (yes or no) and family history of CRC (yes or no) with risk of overall CRC and early-onset CRC. We also stratified the family history of CRC by CRC diagnosis age of 50 (≥50 or <50 years). Last, we preformed several sensitivity analyses by excluding participants with a personal history of IBD (n = 3076), excluding the SNOMED code M81401 from the definition of CRC (n = 4293) since this code is generally for adenomas with severe dysplasia where the basal membrane is not covered by the specimen, and including those with a history of colectomy (n = 1418) in case the colectomy was performed for reasons of CRC. We used SAS 9.4 for the analyses. All statistical tests were two sided, with a P value of .05 considered to be significant.

3 |. RESULTS

Each CRC case was matched with a mean of 4.9 (SD 0.3) controls (Table 1). Mean (SD) age of the participants was 63 (SD 10) years and 46% were women. A total of 365 679 (33% parents, 27% siblings and 40% offspring) and 1 962 335 (33% parents, 26% siblings and 41% offspring) first-degree relatives were documented for CRC cases and matched controls, respectively. For each case, a mean of 5.3 first-degree relatives were linked, in comparison with 5.9 for each control. We found 2.2% of both cases (1566/69659) and controls (7676/343027) had at least one first-degree relative with a history of IBD. Similarly for cases and controls, mean age at the first IBD diagnosis in first-degree relatives was 42, with the majority (45%) distributed in the 18–39 age group. Among IBD subtypes, ulcerative colitis was more common than Crohn’s disease and unclassified IBD in first-degree relatives of both cases (61 vs 29 and 11%) and controls (60 vs 31 and 11%). Among the participants with information of location of Crohn’s disease or extent of ulcerative colitis in at least one first-degree relative, the first-degree relatives of CRC cases had a more common colonic Crohn’s disease/pancolitis/extent not defined colitis than terminal ileum/ileocecal/not defined Crohn’s disease/proctitis/left sided colitis (54% vs 46%) than controls (50% vs 50%). Also, compared with controls, CRC cases had a higher number of previous clinic visits (11 vs 8), comorbidities (0.8 vs 0.5) and a more common CRC history in first-degree relatives (11% vs 7%), particularly early-onset CRC diagnosed before age 50 (1.0% vs 0.4%). In cases, 2.3% had a personal history of IBD, in comparison with 0.4% in controls.

TABLE 1.

Characteristics of study participants

Characteristics CRC cases (n = 69 659) Non-CRC controls (n = 343 032)
Women, n (%) 32 107 (46.1) 158 367 (46.2)
Mean (SD) age at index date (years) 63.3 (10.6) 63.1 (10.6)
Age groups (years), n (%)
 <50 7769 (11.2) 38 767 (11.3)
 50–59 15 492 (22.2) 77 177 (22.5)
 60–69 26 422 (37.9) 130 654 (38.1)
 ≥70 19 976 (28.7) 96 434 (28.1)
No of FDRs
 All 365 679 1 962 335
 Mean (SD) 5.3 (3.3) 5.9 (4.0)
No of FDRs according to relation
 All, n (%)
  Parent 119 708 (33) 636 138 (33)
  Sibling 97 077 (27) 519 900 (26)
  Offspring 148 894 (40) 806 297 (41)
 Mean (SD)
  Parent 1.7 (1.0) 1.9 (1.2)
  Sibling 1.4 (1.8) 1.5 (2.0)
  Offspring 2.1 (1.6) 2.4 (1.9)
No of FDRs with IBD, n (%)
 0 68 093 (97.7) 335 356 (97.7)
 1 1521 (2.2) 7399 (2.2)
 ≥2 45 (0.1) 277 (0.1)
Mean (SD) age at first IBD diagnosis in FDRs (years)a 41.5 (17.5) 41.8 (17.4)
Age at first IBD diagnosis in FDRs (years), n (%)a
 <18 99 (6.3) 430 (5.6)
 18–39 697 (44.5) 3445 (44.9)
 40–59 498 (31.8) 2463 (32.1)
 ≥60 272 (17.4) 1338 (17.4)
Type of IBD in at least one FDR, n (%)a
 Crohn’s disease 458 (29.3) 2361 (30.8)
 Ulcerative colitis 958 (61.2) 4573 (59.6)
 Unclassified 166 (10.6) 877 (11.4)
Maximum location or extent of IBD according to Montreal Classification in at least one FDR (1997-), n (%)a
 L1/L3/LX or E1/E2 (terminal ileum/ileocecal/not defined Crohn’s disease or proctitis/left sided colitis) 391 (46.4) 2107 (49.8)
 L2 or E3/E4/EX (colonic Crohn’s disease or pancolitis/extent not defined colitis) 452 (53.6) 2126 (50.2)
Extraintestinal manifestations (1987-), n (%)
 Primary sclerosing cholangitis 19 (28.4) 106 (30.5)
 Other extraintestinal manifestations 48 (71.6) 241 (69.5)
Mean (SD) total No of past clinic visits before index date 10.6 (12.4) 7.5 (10.3)
Mean (SD) Charlson comorbidity index score 0.8 (1.1) 0.5 (0.9)
CRC history in at least one FDR, n (%)
 No CRC 61 846 (88.8) 319 778 (93.2)
 CRC diagnosed at age ≥ 50 years 7145 (10.3) 21 919 (6.4)
 CRC diagnosed at age < 50 years 668 (1.0) 1335 (0.4)
Personal history of IBD diagnosis, n (%)
 No 68 060 (97.7) 341 555 (99.6)
 Yes 1599 (2.3) 1477 (0.4)
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Note: All variables of cases and their matched controls were assessed at the time of CRC diagnosis of the cases.

Abbreviations: CRC, colorectal cancer; FDR, first-degree relatives (parents, full siblings and offspring); IBD, inflammatory bowel disease.

a

Among FDRs with a history of IBD.

Overall, we found a null association between a history of IBD in first-degree relatives and risk of CRC (multivariable odds ratio 0.98, confidence interval 0.92–1.03) (Table 2). Further adjustment for family history of CRC (0.96, 0.91–1.02) did not change the observed null association. When we analyzed IBD by subtype, we found that the null association was consistent for all Crohn’s disease (0.94, 0.84–1.04), ulcerative colitis (0.97, 0.91–1.05) and unclassified IBD (0.87, 0.73–1.03) in first-degree relatives. Some 11.2% (n = 7769) of the CRC cases were early-onset CRC diagnosed before age 50. When we focused on early-onset CRC, we found a consistent null association for any IBD (1.08, 0.88–1.33) and IBD by subtype (Crohn’s disease: 1.17, 0.82–1.67; ulcerative colitis: 1.09, 0.83–1.44; unclassified IBD: 0.88, 0.46–1.67) in first-degree relatives.

TABLE 2.

Association of history of inflammatory bowel disease (IBD) in first-degree relatives (FDRs, including parents, full siblings and offspring) with risks of overall colorectal cancer (CRC) and early-onset CRC (diagnosed at age < 50 years)

IBD types in FDRs Cases Controls Age adjusted odds ratio (95% CI)a Multivariable adjusted odds ratio (95% CI)b Multivariable + family historyof CRC adjusted odds ratio (95% CI)c
Overall CRC
 n 69 659 343 032
 No IBD 68 093 (97.8) 335 356 (97.8) 1.00 (Ref ) 1.00 (Ref ) 1.00 (Ref )
 Any IBD 1566 (2.2) 7676 (2.2) 1.00 (0.95–1.06) 0.98 (0.92–1.03) 0.96 (0.91–1.02)
 IBD types
  Crohn’s disease 458 (0.7) 2361 (0.7) 0.95 (0.86–1.05) 0.95 (0.86–1.06) 0.94 (0.84–1.04)
  Ulcerative colitis 958 (1.4) 4573 (1.3) 1.03 (0.96–1.10) 0.99 (0.92–1.07) 0.97 (0.91–1.05)
  Unclassified IBD 166 (0.2) 877 (0.3) 0.93 (0.79–1.10) 0.89 (0.75–1.06) 0.87 (0.73–1.03)
Early-onset CRC
 n 7769 (11.2) 38 767 (11.3)
 No IBD 7639 (98.3) 38 196 (98.5) 1.00 (Ref) 1.00 (Ref) 1.00 (Ref)
 Any IBD 130 (1.7) 571 (1.5) 1.14 (0.94–1.38) 1.11 (0.90–1.36) 1.08 (0.88–1.33)
 IBD types
  Crohn’s disease 44 (0.6) 186 (0.5) 1.17 (0.84–1.63) 1.21 (0.85–1.72) 1.17 (0.82–1.67)
  Ulcerative colitis 76 (1.0) 321 (0.8) 1.18 (0.92–1.52) 1.11 (0.85–1.47) 1.09 (0.83–1.44)
  Unclassified IBD 13 (0.2) 70 (0.2) 0.97 (0.53–1.76) 0.91 (0.48–1.70) 0.88 (0.46–1.67)
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a

Conditional logistic regression was used to account for matching on age, sex, year of birth and county of residence.

b

Multivariable model was further adjusted for family size (continuous), income levels (fifths), education (≤9 years, 10–12 years, >12 years, missing), total number of previous clinic visits (fifths), number of previous endoscopies (0, 1, 2, ≥3), Charlson comorbidity index score (continuous) and major comorbidities (all binary, including diabetes, cardiovascular disease, non-colorectal cancer, liver disease, chronic pulmonary disease and connective tissue disease).

c

Further adjusted for family history of CRC in FDRs (no CRC, CRC diagnosed at age ≥ 50 years or CRC diagnosed at age < 50 years).

The null association between history of IBD in first-degree relatives and risk of CRC was consistent across the number of first-degree relatives with IBD (1:0.97, 0.91–1.03; ≥2:0.72, 0.52–1.01; P trend = .08), age at the first IBD diagnosis in first-degree relatives (<18:1.07, 0.85–1.34; ≥60:0.92, 0.81–1.06; P trend = .93), maximum location or extent of IBD (L1/L3/LX/E1/E2: 0.90, 0.80–1.01; L2/E3/E4/EX: 0.98, 0.88–1.09) and relation type of first-degree relatives with IBD (parents: 0.94, 0.80–1.10; siblings: 0.97, 0.88–1.06; offspring: 0.95, 0.87–1.03) (Table 3). The null associations remained when we analyzed Crohn’s disease and ulcerative colitis separately (Table 3) and when we focused on early-onset CRC (Table S3).

TABLE 3.

Association of history of inflammatory bowel disease (IBD) in first-degree relatives (FDRs, including parents, full siblings and offspring) with risk of colorectal cancer (CRC) according to number of FDRs with IBD, age at the first IBD diagnosis, maximum location or extent of IBD and relation of FDR with IBDa

IBD types in FDRs Cases (n = 69 659) Controls (n = 343 032) Age adjusted odds ratio (95% CI) b Multivariable adjusted odds ratio (95% CI) c Multivariable + family history of CRC adjusted odds ratio (95% CI) d
Any IBD
No of FDRs with IBD
 0 68 093 (97.8) 335 356 (97.8) 1.00 (Ref) 1.00 (Ref) 1.00 (Ref)
 1 1521 (2.1) 7399 (2.1) 1.01 (0.95–1.07) 0.99 (0.93–1.04) 0.97 (0.91–1.03)
 ≥2 45 (0.1) 277 (0.1) 0.79 (0.58–1.09) 0.76 (0.55–1.05) 0.72 (0.52–1.01)
 P-trend - - .80 .29 .08
Age at the first IBD diagnosis (years)
 ≥60 272 (17.4) 1338 (17.4) 1.00 (0.87–1.14) 0.96 (0.84–1.10) 0.92 (0.81–1.06)
 40–59 498 (31.8) 2463 (32.1) 0.99 (0.90–1.09) 0.97 (0.88–1.07) 0.95 (0.86–1.05)
 18–39 697 (44.5) 3445 (44.9) 0.99 (0.92–1.08) 0.98 (0.90–1.06) 0.97 (0.89–1.05)
 <18 99 (6.3) 430 (5.6) 1.14 (0.91–1.41) 1.09 (0.87–1.36) 1.07 (0.85–1.34)
 P-trend - - .89 .88 .93
Maximum location or extent of IBD
 L1/L3/LX or E1/E2 (terminal ileum/ileocecal/not defined Crohn’s disease or proctitis/left sided colitis) 391 (25.6) 2107 (28.0) 0.91 (0.82–1.02) 0.91 (0.81–1.01) 0.90 (0.80–1.01)
 L2 or E3/E4/EX (colonic Crohn’s disease or pancolitis/extent not defined colitis) 452 (29.6) 2126 (28.3) 1.04 (0.94–1.15) 1.00 (0.90–1.11) 0.98 (0.88–1.09)
Relation of FDR with IBD
 Parent 198 (12.6) 988 (12.9) 0.99 (0.85–1.15) 0.96 (0.82–1.12) 0.94 (0.80–1.10)
 Sibling 638 (40.7) 3043 (39.6) 1.03 (0.94–1.12) 1.00 (0.91–1.09) 0.97 (0.88–1.06)
 Offspring 749 (47.8) 3766 (49.1) 0.97 (0.90–1.05) 0.95 (0.88–1.04) 0.95 (0.87–1.03)
Crohn’s disease
No. of FDRs with Crohn’s disease
 0 69 201 (99.3) 340 671 (99.3) 1.00 (Ref) 1.00 (Ref) 1.00 (Ref)
 1 452 (0.6) 2322 (0.6) 0.95 (0.86–1.06) 0.96 (0.86–1.06) 0.94 (0.85–1.04)
 ≥2 6 (0.01) 39 (0.01) 0.76 (0.32–1.80) 0.85 (0.35–2.09) 0.85 (0.35–2.10)
 P-trend - - .31 .36 .21
Age at the first diagnosis of Crohn’s disease (years)
 ≥60 77 (16.8) 407 (17.2) 0.93 (0.73–1.19) 0.91 (0.71–1.18) 0.89 (0.69–1.14)
 40–59 144 (31.4) 724 (30.6) 0.97 (0.81–1.16) 0.99 (0.83–1.20) 0.97 (0.80–1.17)
 18–39 204 (44.5) 1077 (45.6) 0.93 (0.80–1.08) 0.93 (0.80–1.08) 0.92 (0.78–1.08)
 <18 33 (7.2) 153 (6.5) 1.06 (0.73–1.55) 1.05 (0.71–1.55) 1.04 (0.70–1.53)
 P-trend - - .97 .70 .80
Maximum location of Crohn’s disease
 L1/L3/LX (terminal ileum/ileocecal/not defined Crohn’s disease) 196 (42.8) 1058 (44.8) 0.90 (0.78–1.05) 0.91 (0.77–1.06) 0.89 (0.76–1.05)
 L2 (colonic Crohn’s disease) 55 (12.0) 293 (12.4) 0.92 (0.69–1.23) 0.96 (0.71–1.29) 0.93 (0.69–1.25)
Relation of FDR with IBD
 Parent 74 (16.2) 314 (13.3) 1.17 (0.91–1.50) 1.15 (0.89–1.50) 1.14 (0.88–1.49)
 Sibling 162 (35.4) 877 (37.1) 0.91 (0.77–1.07) 0.93 (0.78–1.10) 0.89 (0.75–1.07)
 Offspring 224 (48.9) 1182 (50.1) 0.93 (0.80–1.07) 0.92 (0.79–1.07) 0.92 (0.79–1.06)
Ulcerative colitis
No of FDRs with ulcerative colitis
 0 68 701 (98.6) 338 459 (98.7) 1.00 (Ref) 1.00 (Ref) 1.00 (Ref)
 1 933 (1.3) 4464 (1.3) 1.03 (0.96–1.10) 0.99 (0.92–1.07) 0.97 (0.91–1.05)
 ≥2 25 (0.04) 109 (0.03) 1.12 (0.73–1.73) 1.03 (0.66–1.61) 0.98 (0.63–1.54)
 P-trend - - .41 .88 .50
Age at the first diagnosis of ulcerative colitis (years)
 ≥60 155 (16.2) 764 (16.7) 1.00 (0.84–1.19) 0.95 (0.80–1.14) 0.91 (0.76–1.09)
 40–59 316 (33.0) 1491 (32.6) 1.04 (0.92–1.17) 1.00 (0.88–1.14) 0.98 (0.87–1.12)
 18–39 437 (45.6) 2097 (45.9) 1.02 (0.92–1.14) 0.99 (0.89–1.11) 0.99 (0.88–1.10)
 <18 50 (5.2) 221 (4.8) 1.12 (0.82–1.52) 1.08 (0.78–1.48) 1.06 (0.77–1.46)
 P-trend - - .67 .47 .82
Maximum extent of ulcerative colitis
 E1/E2 (proctitis/left sided colitis) 195 (20.4) 1049 (22.9) 0.92 (0.79–1.07) 0.90 (0.77–1.06) 0.90 (0.76–1.05)
 E3/E4/EX (pancolitis/extent not defined colitis) 397 (41.4) 1833 (40.1) 1.06 (0.95–1.18) 1.00 (0.90–1.12) 0.99 (0.88–1.11)
Relation of FDR with IBD
 Parent 104 (10.9) 554(12.1) 0.93 (0.75–1.15) 0.90 (0.72–1.11) 0.87 (0.70–1.08)
 Sibling 414 (43.2) 1852 (40.5) 1.10 (0.99–1.22) 1.04 (0.93–1.16) 1.01 (0.90–1.12)
 Offspring 449 (46.9) 2206 (48.2) 1.00 (0.90–1.10) 0.98 (0.88–1.09) 0.97 (0.88–1.08)
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a

Time of IBD diagnosis for each FDR was the earliest time when the patient had two or more records with a relevant International Classification of Disease (ICD) code in the patient register or one such record plus a colorectal biopsy report with a morphology code suggestive of IBD.

b

Conditional logistic regression was used to account for matching on age, sex, year of birth and county of residence.

c

Multivariable model was further adjusted for family size (continuous), income levels (fifths), education (≤9 years, 10–12 years, >12 years, missing), total number of previous clinic visits (fifths), number of previous endoscopies (0, 1, 2, ≥3), Charlson comorbidity index score (continuous) and major comorbidities (all binary, including diabetes, cardiovascular disease, non-colorectal cancer, liver disease, chronic pulmonary disease and connective tissue disease).

d

Further adjusted for family history of CRC in FDRs (no CRC, CRC diagnosed at age ≥ 50 years or CRC diagnosed at age < 50 years).

We jointly examined history of IBD and history of CRC in first-degree relatives in relation to CRC risk (Table 4). Compared with individuals free of family histories of both CRC and IBD, those free of family history of CRC but only harboring a family history of IBD had no increased risk of CRC (OR = 0.98, 0.92–1.04). As expected, individuals harboring a family history of CRC but free of a family history of IBD had an increased risk of CRC (OR = 1.75, 1.70–1.80), and the risk increase was particularly strong when the family history was of an early-onset CRC (OR = 2.56, 2.32–2.83). However, we did not observe a further increased risk of CRC in individuals harboring family histories of both CRC and IBD (OR = 1.47, 1.25–1.72), including when the family history of CRC was of early-onset CRC (OR = 1.28, 0.81–2.01). Similar findings were obtained for the risk of early-onset CRC (Table 4), after excluding participants with a personal history of IBD (Table S4), excluding the SNOMED code M81401 from the definition of CRC (Table S5), and including those with a history of colectomy (Table S6).

TABLE 4.

Joint association of histories of inflammatory bowel disease (IBD) and colorectal cancer (CRC) in first-degree relatives (FDRs, including parents, full siblings and offspring) with risks of overall CRC and early-onset CRC (diagnosed at age < 50 years)

Cases Controls Age adjusted odds ratio (95% CI)a Multivariable adjusted odds ratio (95% CI)b
Overall CRC
CRC and IBD in FDR
 No CRC no IBD 60 498 (86.9) 312 840 (91.2) 1.00 (Ref) 1.00 (Ref)
 No CRC only IBD 1348 (1.9) 6938 (2.0) 1.00 (0.95–1.07) 0.98 (0.92–1.04)
 Only CRC no IBD 7595 (10.9) 22 516 (6.6) 1.75 (1.70–1.80) 1.75 (1.70–1.80)
  Only CRC <50 years no IBD 642 (0.9) 1238 (0.4) 2.66 (2.42–2.93) 2.56 (2.32–2.83)
  Only CRC ≥50 years no IBD 6953 (10.0) 21 278 (6.2) 1.69 (1.64–1.74) 1.70 (1.65–1.76)
 Both CRC and IBD 218 (0.3) 738 (0.2) 1.52 (1.31–1.77) 1.47 (1.25–1.72)
  Both CRC <50 years and IBD 26 (0.04) 97 (0.03) 1.42 (0.92–2.18) 1.28 (0.81–2.01)
  Both CRC ≥50 years and IBD 192 (0.28) 641 (0.19) 1.54 (1.31–1.81) 1.50 (1.27–1.77)
Early-onset CRC
CRC and IBD in FDR
 No CRC no IBD 6944 (89.4) 36 777 (94.9) 1.00 (Ref) 1.00 (Ref)
 No CRC only IBD 121 (1.6) 530 (1.4) 1.21 (0.99–1.48) 1.19 (0.96–1.47)
 Only CRC no IBD 695 (9.0) 1419 (3.7) 2.61 (2.37–2.87) 2.60 (2.35–2.88)
  Only CRC <50 years no IBD 176 (2.3) 152 (0.4) 6.22 (4.99–7.76) 6.45 (5.07–8.22)
  Only CRC ≥50 years no IBD 519 (6.7) 1267 (3.3) 2.18 (1.96–2.42) 2.16 (1.93–2.42)
 Both CRC and IBD 9 (0.1) 41 (0.1) 1.24 (0.60–2.57) 1.07 (0.48–2.38)
  Both CRC <50 years and IBD 2 (0.03) 7 (0.02) 1.29 (0.26–6.32) 2.06 (0.38–11.09)
  Both CRC ≥50 years and IBD 7 (0.09) 34 (0.09) 1.20 (0.53–2.73) 0.91 (0.37–2.23)
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a

Conditional logistic regression was used to account for matching on age, sex, year of birth and county of residence.

b

Multivariable model was further adjusted for family size (continuous), income levels (fifths), education (≤9 years, 10–12 years, >12 years, missing), total number of previous clinic visits (fifths), number of previous endoscopies (0, 1, 2, ≥3), Charlson comorbidity index score (continuous) and major comorbidities (all binary, including diabetes, cardiovascular disease, non-colorectal cancer, liver disease, chronic pulmonary disease and connective tissue disease).

4 |. DISCUSSION

In this nationwide case-control study, using data from established national registers in Sweden, we found that a history of IBD in first-degree relatives was not associated with an increased risk of CRC. Additional adjustment for a history of CRC in first-degree relatives did not change the null association. This null association was consistently observed regardless of IBD subtypes, the number of relatives with IBD, age at the first IBD diagnosis, maximum location or extent of IBD, relation type of relatives and CRC diagnosis age. These findings provide robust evidence that a family history of IBD did not increase the risk of CRC, supporting use of the same routine CRC screening strategy in offspring, siblings and parents of IBD patients as in the general population.

Few prior studies investigated the association between family history of IBD and risk of CRC. An early study using data before 1995 reported a similar finding as ours that first-degree relatives of IBD patients were not at increased risk of CRC.19 Although that study used a cohort design, the low number of CRC events limited its study power, particularly for certain stratified analyses and the joint association of family histories of IBD and CRC. For example, only four CRC events were detected in the first-degree relatives of IBD patients diagnosed at age ≤ 19 years, and only 17 CRC events in the first-degree relatives of patients with both IBD and CRC. More importantly, that study lacked power to study the risk of early-onset CRC. A separate study based on the same data but restricted in participants with IBD observed, as a secondary finding, that family history of IBD did not increase the risk of CRC in the IBD patients.20 Another small case-control study within only 82 patients with ulcerative colitis reported that none of the 314 IBD-associated single nucleotide polymorphisms (SNPs) examined was associated with a higher risk of neoplasia development in patients with ulcerative colitis.21 But their study populations of individuals with IBD limited the generalizability of their conclusions. Given the high heritability of IBD,33 mendelian randomization design provides another good approach to detect pleiotropy between IBD and CRC. In a recent mendelian randomization study applying 289 instrumental SNPs of IBD, no significant relationship between the SNPs and CRC was found.34 This finding is consistent with our study, supporting that IBD and CRC share no horizontal pleiotropy. Therefore, our current study, which had a much better power, represents a timely revisit to this research question by comprehensively assessing the association between family history of IBD and CRC risk, particularly early-onset CRC that shows a concerning increase in the incidence in recent years worldwide.35

If our finding of the null association between family history of IBD and risk of CRC is confirmed, it has important implications. Firstly, it suggests that IBD and CRC may not have substantial familial clustering or shared genetic susceptibility, strengthening the theory that it is the actual inflammation or atypia of the colon in IBD patients that confers the increased risk of CRC. Given the high heritability of IBD33 and that IBD indeed increases the risk of IBD-associated CRC, our finding also suggests a distinction between the molecular pathways giving rise to IBD-associated CRC and sporadic CRC. For example, during the development of sporadic CRC, loss of APC function occurs at an early stage and P53 mutations or loss occurs late. However, IBD-associated CRC demonstrates a reversal sequence of the two events.36–38 Second, while first-degree relatives of IBD patients are known to have an increased risk of IBD,13–16 the lack of increase in CRC risk suggests that familial and sporadic IBD may be heterogeneous in increasing CRC risk. Indeed, familial and sporadic IBD were reported to be heterogeneous in multiple characteristics, including diagnosis age, clinical course, genetic polymorphisms, immunological dysregulation and microbial dysbiosis.39,40 More studies are needed to elucidate how these differences may modulate the carcinogenic effect of IBD. Finally, our findings provide assurance that family members of IBD patients may not have an increased risk of CRC and can follow the same CRC prevention recommendations (eg, screening when implicated) as the general population. Given the increasing incidence and prevalence of IBD worldwide,41–43 the pool of individuals with a family history of IBD is also increasing remarkably. Our current study with a much better power compared with previous study19 provides confirmative evidence supporting a null association between family history of IBD and CRC risk, shedding light on significant clinical and public health implications for CRC prevention.

Our study has several strengths, including the nationwide population-based design, large sample size, high validity of the cancer and IBD diagnoses, comprehensive assessment of the number of first-degree relatives with IBD, their age at diagnosis and IBD characteristics. Particularly, our use of the multi-generation register and the objective register-based data enabled us to have a decent power to study early-onset CRC and joint association of family history of IBD and family history of CRC with CRC risk, representing a major advantage over previous studies.19–21 Notably, our study also has several limitations. Firstly, we lacked information on some other factors that might influence the risk of CRC, for example, cigarette smoking and obesity. However, we adjusted for the Charlson comorbidity index score and several major individual comorbidities that are strongly associated with the lacked factors. Second, we lacked information on indications of endoscopic examination for CRC detection. As organized screening did not start regionally in Sweden until 2008 and then only in part of Sweden, individuals with family history of IBD might be more likely to undertake screening and have CRC diagnosed at an early stage compared with those without family history of IBD. However, such detection bias could only have led to a spurious positive association between family history of IBD and CRC risk. The consistent null association we observed indicates a minimal influence of such detection bias on our findings. Thirdly, because of a low number with information on the extraintestinal manifestations, degree of inflammation, treatment prescribed to assess severity of IBD, and subsite information of CRC, we lacked sufficient power to conduct subgroup analyses according to these characteristics. Additionally, as a case-control study, we were unable to calculate absolute risk or risk difference of CRC. But a case-control design with a large number of CRC cases enabled us to analyze some specially concerning cancer type, for example, early-onset CRC.

In conclusion, a history of IBD in first-degree relatives was not associated with an increased risk of CRC, and this null association was independent of family history of CRC. Our finding supports a similar utilization of routine CRC screening in offspring, siblings and parents of patients with IBD as in the general population.

Supplementary Material

Supplementary Material

What’s new?

Patients with inflammatory bowel disease are at an increased risk of colorectal cancer. However, the association between family history of inflammatory bowel disease and risk of colorectal cancer remains unclear. In this nationwide case-control study, a history of inflammatory bowel disease in first-degree relatives was not associated with an increased risk of colorectal cancer. The null association was consistent irrespective of various characteristics of inflammatory bowel disease and colorectal cancer history. The findings suggest that extra screening for colorectal cancer may not be needed in the first-degree relatives of patients with inflammatory bowel disease.

ACKNOWLEDGEMENT

The authors thank the participants and staff of the ESPRESSO for their continued contributions. The authors assume full responsibility for analyses and interpretation of these data.

FUNDING INFORMATION

This work was supported by the National Institutes of Health (R00 CA215314, U01 CA261961 and R01 CA263776 to Mingyang Song), American Cancer Society (MRSG-17-220-01-NEC to Mingyang Song), ALF funding (Dnr 20190638 to Ola Olén), the Swedish Research Council (Dnr 2020-02002 to Ola Olén) and the Swedish Cancer Foundation (Jonas F. Ludvigsson). The funding sources did not participate in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; or decision to submit the manuscript for publication.

ALF funding, Grant/Award Number: Dnr 20190638; American Cancer Society, Grant/Award Number: MRSG-17-220-01-NEC; National Institutes of Health, Grant/Award Numbers: R00 CA215314, R01 CA263776, U01 CA261961; Swedish Cancer Foundation; Vetenskapsrådet, Grant/Award Number: Dnr 2020-02002

Abbreviations:

CRC

colorectal cancer

ESPRESSO

Epidemiology Strengthened by histoPathology Reports in Sweden

GWAS

genome-wide association studies

IBD

inflammatory bowel disease

ICD

International Classification of Disease

PSC

primary sclerosing cholangitis

SNOMED

systematized nomenclature of medicine

Footnotes

CONFLICT OF INTEREST

Jonas F. Ludvigsson has coordinated an unrelated study on behalf of the Swedish IBD quality register (SWIBREG). That study received funding from Janssen corporation. Ola Olén has been PI on projects at Karolinska Institute partly financed by grants from Janssen, Takeda, AbbVie, Pfizer, Galapagos, BMS, Vifor Pharma and Ferring. Jonas Halfvarson has served as speaker and/or advisory board member for Abbvie, Aqilion, BMS, Celgene, Celltrion, Dr Falk Phrma, Ferring, Galapagos, Gilead, Hospira, Index Pharma, Janssen, MEDA, Medivir, MSD, Novartis, Prometheus Laboratories Inc. Sandoz, Shire, Takeda, Thermo Fisher Scientific, Tillotts Pharma, Vifor Pharma, UCB and received grant support from Janssen, MSD and Takeda. No other conflict of interest exists.

ETHICS STATEMENT

This study was approved by the Stockholm ethical review board (2014/1287–31/4 and 2018/972–32). Informed consent from participants was waived by the Stockholm ethics review board because the study was strictly register-based.44

SUPPORTING INFORMATION

Additional supporting information can be found online in the Supporting Information section at the end of this article.

DATA AVAILABILITY STATEMENT

The data underlying this article will be shared on reasonable request to the corresponding author.

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Associated Data

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Supplementary Materials

Supplementary Material
NIHMS1994767-supplement-Supplementary_Material.pdf (413.6KB, pdf)

Data Availability Statement

The data underlying this article will be shared on reasonable request to the corresponding author.

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