Topic Highlight Open Access
Copyright ©2011 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Jun 14, 2011; 17(22): 2715-2722
Published online Jun 14, 2011. doi: 10.3748/wjg.v17.i22.2715
Familial aggregation in inflammatory bowel disease: Is it genes or environment?
Tiago Nunes, Miquel Sans, Department of Gastroenterology, Hospital Clinic i Provincial/IDIBAPS, CIBER EHD, 08036 Barcelona, Spain
Gionata Fiorino, Silvio Danese, Division of Gastroenterology, IRCCS Istituto Clinico Humanitas, Rozzano, Milan 20089, Italy
Author contributions: Fiorino G, Danese S, Sans M and Nunes T performed the literature review; Sans M and Nunes T wrote the manuscript.
Supported by Grants from Ministerio de Ciencia e Innovación (SAF2008/03676) and Fundació Miarnau to Sans M
Correspondence to: Miquel Sans, MD, PhD, Department of Gastroenterology, Hospital Clínic i Provincial/IDIBAPS, CIBER EHD, 170 Villarroel, 08036 Barcelona, Spain.
Telephone: +34-93-2275418 Fax: +34-93-2279387
Received: June 28, 2010
Revised: September 18, 2010
Accepted: September 25, 2010
Published online: June 14, 2011


Inflammatory bowel disease (IBD) develops in genetically susceptible individuals due to the influence of environmental factors, leading to an abnormal recognition of microbiota antigens by the innate immune system which triggers an exaggerated immune response and subsequent bowel tissue damage. IBD has been more frequently found in families, an observation that could be due to either genetic, environmental or both types of factors present in these families. In addition to expanding our knowledge on IBD pathogenesis, defining the specific contribution to familial IBD of each one of these factors might have also clinical usefulness. We review the available evidence on familial IBD pathogenesis.

Key Words: Inflammatory bowel disease, Familial aggregation, Familial clustering, Environmental factors, Genetics, Genome wide association studies


Our present understanding of inflammatory bowel disease (IBD) pathogenesis considers ulcerative colitis (UC) and Crohn’s disease (CD) as complex conditions that develop in genetically susceptible individuals due to the influence of various environmental factors[1-6]. An abnormal recognition of certain antigens of the bowel microbiota by elements of the innate immunity is thought to play a key role, leading to an exaggerated immune response, release of pro-inflammatory molecules and, ultimately, bowel tissue damage.

In past decades a greater incidence of IBD cases among UC and CD relatives, referred to as family aggregation or familial IBD, has been clearly demonstrated[7-11]. The reason for such an increased risk is not straightforward, but genes, the environment or a combination of both could, in theory, account for family aggregation, considering their contribution to the development of IBD. A better understanding of the factors leading to familial IBD might result in clinical applications.


Familial aggregation among IBD patients or “familial IBD” is defined by the occurrence of a trait in more family members than expected by chance. Multiple population studies have demonstrated that relatives of an IBD patient have a much higher risk of developing the same condition, compared to the general population[7-11]. The magnitude of familial aggregation depends on several factors, including: (1) type of IBD; (2) population studied; and (3) family relationship.

In respect to type of IBD, familial aggregation has been more frequently reported in CD than UC[7,9]. In first degree relatives, the age-adjusted relative risk of developing the same type of IBD ranges from 2-8 for UC and from 5-10 in the case of CD[7-9]. As elegantly demonstrated by Yang et al[9], affected relatives can develop both forms of IBD, although the greatest risk is associated with the appearance of the same disease type occurring in the index case. Additionally, CD patients tend to have a much higher frequency of relatives affected with UC when compared to UC patients having relatives affected with CD[7].

In respect to different populations, it has been shown that Jewish families present more than twice the number of multiple affected families when compared to the non-Jewish population[9]. However, we cannot rule out the possibility that differences amongst other geographical populations are due to their study design.

Finally, frequency of familial IBD also varies according to the degree and type of kinship. The prevalence of IBD in second-degree relatives appears to be lower than in first-degree relatives, especially in those with discordant disease[7]. In addition, although only a few studies have estimated the age-adjusted risk of IBD in relatives, it seems that the risk of IBD in offspring is higher than in parents and similar, or even slightly higher, than in siblings[8,9,11]. A potential source of bias could result from underreported cases in second-degree relatives and older generations, which might have influenced these differences.

In addition to an increased risk of developing the disease, first-degree relatives of IBD patients also have an increased likelihood of sharing the same phenotype[8,12]. This seems to be partly true in CD owing to the striking clinical concordance in families, in respect to disease location and behavior. On the contrary, literature is scarce and presents mixed results for CD severity and complications[8,9,13-16]. In UC families, the phenotype concordance data is less consistent, but a high concordance rate related to colonic extent and extra-intestinal manifestations has been reported[12,14].

The possibility that IBD develops at an earlier age in offspring than in their parents, a phenomenon known as anticipation, has been controversial[17-21]. Although different studies have reported such differences in age of onset, it seems that multiple biases could account for these findings. Whether familial IBD is a different clinical entity was the subject of debate. However, in the largest population-based study including 654 sporadic and familial IBD patients, a positive familial IBD history did not significantly influence clinical course or risk of developing IBD-related complications[22].

Evidences supporting the role of genetic factors in IBD pathogenesis

The fact that IBD is a genetically mediated disease was initially derived from the physician’s perception of a higher prevalence of UC and CD cases among the relatives of IBD patients. This hypothesis was initially supported by case report studies showing clustering in IBD families and was subsequently confirmed by several population-based studies[3-7]. In one of these studies, Yang et al[9] described a risk of developing UC and CD among first degree relatives of IBD patients of 1.6% and 5.2%, respectively. The risk of developing IBD also varies according to the ethnic origin of individuals, a fact that is likely to be linked to their genetic background. In that regard, the prevalence of IBD among the Jewish population is 2 to 4 times higher than in any other ethnic group, being greater in Ashkenazi than in Sephardic or Oriental Jewish, with no influence from their geographical location[9,11].

Another source of evidence underlying the key role of genetic factors in IBD steams from twin studies. In these studies the greatest IBD concordance rate was found in monozygotic twins, ranging from 20% to 50% in CD and from 14% to 19% in UC twins, whereas in dizygotic twins concordance rates dropped to 0%-7% in both CD and UC twins[23-26]. The degree of monozygotic-dizygotic twin concordance found in CD point towards a genetically mediated condition with a non-Mendelian inheritance pattern. Of note, the concordance rates observed in CD are greater than these found in type 1 diabetes, asthma or schizophrenia, all of them diseases with a well-established genetic background.

Genes involved in CD pathogenesis

Several genome linkage studies identified a number of CD susceptibility regions in chromosomes 1, 3, 4, 5, 6, 7, 10, 12, 14, 16, 19 and X[27-34]. After subsequent confirmation, regions on chromosomes 16, 12, 6, 14, 5, 19 were named IBD1 to IBD7, respectively[35]. Of these 7 original loci, only IBD1 (chromosome 16q12) was replicated in all studies, whereas another three loci, IBD2 (chromosome 12), IBD3 (chromosome 6) and IBD4 (chromosome 14) were replicated in some of the studies[36]. Later on, several CD susceptibility genes, such as NOD2, NOD1, toll-like receptors (TRLs) genes, and novel organic cation transporter (OCTN) genes were identified using either a candidate gene approach or positional cloning techniques[37].

The first and most relevant CD susceptibility gene described to date is NOD2. The carriage of one or more of the three main NOD2 variants (Arg702Trp, Gly908Arg and Leu1007incC) is found in 25%-45% of CD Caucasian patients and in only 15%-20% of healthy subjects[38]. A clear gene-dose effect has been described for NOD2 in CD patients. While the risk of developing CD is increased by 2-3-fold in subjects carrying one NOD2 variant allele, it reaches a 20-40-fold increase in subjects with two or more NOD2 variant alleles. In addition to increasing CD susceptibility, the NOD2 gene variants can also influence CD behaviour, phenotypes and need of surgery[39]. Similarly, the carriage of NOD2 variants has also been linked to a slight increase in familial CD risk[40]. In spite of being the most powerful CD susceptibility gene found to date, it must be underlined that the NOD2 gene only accounts for a small proportion of the genetic inheritance of CD in Caucasians. Moreover, NOD2 gene variants are infrequent in some geographic areas, such as Scotland, Ireland and Scandinavia, or even completely absent in subjects with an Asian and African-American genetic background[37]. In these cases other genes must account for the genetic predisposition to develop CD. This is in keeping with the highly polygenic nature of this disease.

In the last 3 years, the field of IBD genetics has experienced a dramatic transformation. Completion of the human genome project and development of tools capable of simultaneously studying a great number of genes has resulted in a much higher number of genes influencing CD and UC susceptibility than expected. Several genome-wide association studies (GWAS) have been undertaken in CD patients and healthy controls[41-45] and a meta-analysis has been recently published[46]. In this meta-analysis more than 30 independent loci are found to be convincingly associated with CD, providing an extraordinary insight into CD pathogenesis. Interestingly, most CD susceptibility genes are involved in either recognition of bowel microbiota antigens by the innate immunity, the IL-17/IL-23 pathway or autophagy, suggesting that these molecular mechanisms play a key role in CD pathogenesis.

Several studies have evaluated the frequency of CD-related mutations in affected families[47-49]. Jess et al[47] studied NOD2 mutation frequency in a population of Danish twins with IBD. In this study, a high prevalence of NOD2 mutation was observed in both CD twins and their healthy siblings. A Swedish study on monozygotic twin pairs reported a NOD2 frequency in both concordant CD siblings of only 22%, although the prevalence of NOD2 was indeed higher in concordant than in discordant twin pairs[48]. Joossens et al[49] investigated the prevalence of genetic markers (NOD2, NOD1, TLR4, CARD8) in multiplex and single-case families, healthy relatives and controls. The authors found a significant correlation between the number of genetic mutations per family and an increasing number of first-degree relatives with CD. However, these results could not discriminate between single-case and multiplex families.

Genes involved in UC pathogenesis

Two studies aimed at describing the influence in UC of the well-established CD susceptibility genes reported very interesting findings[50,51]. It became clear there is a genetic overlap between the two forms of IBD, with some genes involved in the development of both CD and UC (3p21.31, NKX2-3, CCNY). On the contrary, other genes have been only associated with UC, but not CD (ECM1 HERC2, STAT3 and PTPN2). In that regard, a very recently published UC GWAS meta-analysis has demonstrated that roughly half of the known CD susceptibility gene loci are shared by UC[52]. In addition, more than 20 exclusive UC loci have been recognized to date including, among others, IL10, ARPC2 and ECM1[52-55]. To summarize our present understanding, we believe that some genetic factors influence the global predisposition to develop IBD, whereas other genes are related to the risk of developing either UC or CD, specifically. Such genetic overlap between UC and CD probably contributes to the existence of a 5% of non-classifiable or indeterminate colitis among the IBD population. Similarly, it also contributes to the fact that first degree relatives of CD or UC patients not only have an increased risk of developing the same type of IBD, but also the other form of IBD, although with a lower frequency in the latter case.

Evidences supporting the role of environmental factors in IBD pathogenesis

The remarkable increase in the IBD incidence in the last few decades cannot be explained by changes in the genetic background of a certain population. Instead, it clearly points towards the existence of potent environmental factors playing a key role in IBD pathogenesis. Several studies performed in Europe that have evaluated IBD prevalence in immigrant populations from low IBD risk areas found that immigrants present a similar or higher risk of developing IBD when compared to the indigenous population[56-58]. These results suggest that differences in prevalence are probably associated with lifestyle and environmental factors, and not with a specific genetic background. It is remarkable though that only very few studies have addressed environmental etiologic factors in respect to familial IBD.

Eating habits, pets and previous infections

One of the largest controlled studies addressing the impact of environmental factors on familial IBD was conducted in Belgium by Van Kruiningen et al[59] who investigated 21 families with 3 or more first-degree relatives affected with CD. Subjects were interviewed using an extensive questionnaire on potential environmental factors. In this study affected families and controls presented some remarkable differences in eating habits, domestic factors and medical history. IBD patients ate fewer oats, rye and bran, consumed more unpasteurized cheese and drank more well water, compared to controls. Additionally, an increased frequency of smoking habit, appendectomy and fecal-oral transmitted infections was found in a subject who later developed CD. In respect to domestic habits, affected families also presented a lower daily contact with pets during childhood. Taken together, these results point towards a role of certain gastro-intestinal infections as triggering events contributing to the development of IBD, whereas the contact with pets during childhood seem to have a protective role favoring the immune system modulation.

Another familial aggregation study by the same Belgian group reported on a large Moroccan family with multiple CD cases[60]. Potential environmental, genetic and serological markers were studied in all family members. No differences in CD susceptibility genes or serological antibodies described in Caucasian populations were found between CD patients and healthy subjects. The study of environmental factors revealed the consumption of a large amount of unpasteurized milk in all family members, which was an environmental factor previously associated with occurrence of familial CD[59].

Another questionnaire-based study on environmental factors in a large monozygotic and dizygotic twin population included more than 300 twin pairs who were discordant for IBD diagnosis[61]. Twins with UC and CD reported recurrent gastrointestinal infections more frequently than their healthy siblings. These findings are in keeping with an increased frequency of fecal-oral transmitted infections reported in multiplex CD families[59] and suggest that past gastrointestinal infections might influence the risk of IBD.


Appendectomy is associated with a lower risk of developing UC, although the exact mechanisms of this protective role are still not elucidated[62]. While controversial, it seems that the effect of appendectomy requires a certain degree of inflammation (appendicitis or lymphadenitis) and also applies to subjects undergoing appendectomy before the age of 20 years[63]. However, in a recently published study evaluating the usefulness of appendectomy as a therapeutic strategy for distal UC, 40% of patients experienced a complete symptoms resolution after elective appendectomy[64]. Conversely to UC, appendectomy seems to be associated with an increased risk of developing CD, although the studies addressing this issue yield conflicting results[65-70]. These discrepancies might be due to the inclusion of appendectomies performed at CD diagnosis or to methodological differences. More recently, data from large Swedish and Danish cohorts and a meta-analysis have demonstrated that the risk of developing CD is markedly increased only during a short period following appendectomy, disappearing after 5 years[71,72]. This behavior suggests that the association of appendectomy with CD might be a diagnostic bias, instead of a true risk factor.


Smoking habit, particularly cigarette smoking, is the most indisputable example of the influence of the environment on IBD[73,74]. Smoking has striking opposite effects on CD and UC, supporting the notion that distinct mechanisms underlie the pathogenesis of each form of IBD[74]. Subjects who have never smoked and former smokers are at a higher risk of developing UC, whereas present smokers have an increased risk of CD. In addition to the impact on disease susceptibility, smoking habit also modifies the clinical course of disease, increasing the risk of experiencing a relapse and the need for surgery[75-78]. Moreover, it has been demonstrated that tobacco discontinuation improves CD course[79]. Tuvlin et al[80] conducted a survey on tobacco use in UC and CD patients in familial IBD. In this study, smokers had double the risk of CD and former smokers had double the risk of UC, in younger age groups. A Danish case-report study on 2 monozygotic female twins with ileo-colonic CD and their non-affected brother and parents showed that though the healthy father. brother and twins all presented a NOD2 variant related to CD, only the affected twins were smokers, had undergone appendectomy and were on oral contraceptive use[81]. To further evaluate the influence of smoking habit in familial IBD, Bridger et al[82] analyzed 658 IBD patients, including 339 affected sibling pairs of whom 89 were discordant for smoking when diagnosed. Siblings who were discordant for smoking and IBD type almost always show CD in the smoker and UC in the non-smoker patient. The authors also suggest that the protective effect of tobacco on UC is due to a shift towards development of CD, in subjects prone to undergo bowel inflammation, rather than true protection of from the development of UC.

Oral contraceptive and non-steroidal anti-inflammatory drugs

Several studies have addressed the potential contribution of contraceptive pills to the development of IBD. It has been demonstrated that the risk of IBD in women taking oral contraceptives is greater that in controls, although there is no direct evidence for a causal relationship[83-85]. Data from two meta-analysis suggest a modest association between the use of oral contraceptives and development of IBD, with a pooled relative risk adjusted for smoking habit of 1.46 for CD and 1.26 for UC[86,87]. The most recent meta-analysis also suggests that the risk disappears once the medication is discontinued[87]. Other frequently used types of drug that have also been associated with IBD are non-steroidal anti-inflammatory drugs (NSAIDs)[88-95]. Due to their inhibitory action on protective prostaglandins, these drugs could enhance intestinal permeability facilitating disease activity. A growing body of evidence suggests a true association between NSAIDs and IBD activity, although the existence of multiple confounding factors makes it difficult to establish a formal relationship[96]. These confounding factors include selection of inadequate control groups, publication bias and intestinal tissue damage due not only to IBD activity but also to NSAIDs. Unfortunately, there are no studies evaluating the role of oral contraceptives and NSAIDs in familial IBD.

IBD as an infectious disease

Van Kruiningen et al[97] analyzed the pedigrees and time course of IBD development in a group of patients with familial IBD. They found that first-borns and subsequently born siblings were more frequently affected[87,97]. In addition, they described a statistically significant CD clustering that would indicate an infectious etiology supported by which family members were affected and time to develop symptomatic disease. Another study by Van Kruiningen et al[98] assessed 2 French families with multiple CD cases, in an attempt to identify the suspected infectious cause. However, Campylobacter, Yersinia, mycobacteria, mycoplasma, torovirus, coronavirus, Brucella, Influenza and animal enteropathogenic infections were all ruled out and no pathogen could be identified. Even though an abnormal recognition of antigens of the intestinal microbiota by innate immunity is thought to play a key role in IBD pathogenesis, there are no studies addressing specifically the interaction between bowel microbiota and familial IBD.

Intestinal permeability

An abnormal gut barrier function, with an increased intestinal permeability, could contribute to CD pathogenesis[99]. It that regard, it has been demonstrated that small intestinal permeability is increased not only in patients with CD but also in their healthy relatives[100,101]. Peeters et al[100] reported that 25% of healthy first-degree relatives of CD patients had an increased small intestinal permeability. The mechanisms responsible for these disturbances in bowel permeability are not fully elucidated and its pathogenesis is a much debated topic. In their study in familial and sporadic CD, Peeters et al[100] reported no specific genetic pattern accounting for the abnormal permeability found in patients and relatives. In addition, there were no significant differences between families with multiple members affected and families with only one individual affected. Interestingly, almost half of the spouses presented increased intestinal permeability, which clearly suggests that this abnormality is due to environmental and not to genetic mechanisms. In keeping with this finding, Fries et al[102] studied the prevalence of intestinal permeability and some CD genetic markers (including NOD2 main variants) in 23 families of CD patients. Authors found no association between increased intestinal permeability and genetic markers in their population. In contrast, other studies have found an association between an abnormal bowel permeability and the presence of NOD2 variations[101,103].


IBD is a complex polygenic disorder modulated by a series of environmental factors, some of which are likely yet to be determined. In spite of the significant progress done in the study of both the genetic and environmental factors associated, the exact contribution of each one of the many factors involved is still largely unknown. From a practical point of view, at present no specific recommendations to IBD families, in respect to genetic or environmental counselling, are available. Large, prospective, population-based studies following IBD patients and their healthy relatives will be necessary to untie the knots in this tangled web of genetic and environmental factors.


Peer reviewer: Alessandro Fichera, MD, FACS, FASCRS, Assistant Professor, Department of Surgery, University of Chicago, 5841 S. Maryland Ave, MC 5031, Chicago, IL 60637, United States

S- Editor Sun H L- Editor Rutherford A E- Editor Zheng XM

1.  Fiocchi C. Inflammatory bowel disease: etiology and pathogenesis. Gastroenterology. 1998;115:182-205.  [PubMed]  [DOI]  [Cited in This Article: ]
2.  Cortot A, Pineton de Chambrun G, Vernier-Massouille G, Vigneron B, Gower Rousseau C. [Inflammatory bowel disease: genetic or environmental diseases?]. Gastroenterol Clin Biol. 2009;33:681-691.  [PubMed]  [DOI]  [Cited in This Article: ]
3.  Abraham C, Cho JH. Inflammatory bowel disease. N Engl J Med. 2009;361:2066-2078.  [PubMed]  [DOI]  [Cited in This Article: ]
4.  Lakatos PL. Environmental factors affecting inflammatory bowel disease: have we made progress? Dig Dis. 2009;27:215-225.  [PubMed]  [DOI]  [Cited in This Article: ]
5.  Fiocchi C. Susceptibility genes and overall pathogenesis of inflammatory bowel disease: where do we stand? Dig Dis. 2009;27:226-235.  [PubMed]  [DOI]  [Cited in This Article: ]
6.  Braus NA, Elliott DE. Advances in the pathogenesis and treatment of IBD. Clin Immunol. 2009;132:1-9.  [PubMed]  [DOI]  [Cited in This Article: ]
7.  Orholm M, Munkholm P, Langholz E, Nielsen OH, Sørensen TI, Binder V. Familial occurrence of inflammatory bowel disease. N Engl J Med. 1991;324:84-88.  [PubMed]  [DOI]  [Cited in This Article: ]
8.  Peeters M, Nevens H, Baert F, Hiele M, de Meyer AM, Vlietinck R, Rutgeerts P. Familial aggregation in Crohn's disease: increased age-adjusted risk and concordance in clinical characteristics. Gastroenterology. 1996;111:597-603.  [PubMed]  [DOI]  [Cited in This Article: ]
9.  Yang H, McElree C, Roth MP, Shanahan F, Targan SR, Rotter JI. Familial empirical risks for inflammatory bowel disease: differences between Jews and non-Jews. Gut. 1993;34:517-524.  [PubMed]  [DOI]  [Cited in This Article: ]
10.  Freeman HJ. Familial Crohn's disease in single or multiple first-degree relatives. J Clin Gastroenterol. 2002;35:9-13.  [PubMed]  [DOI]  [Cited in This Article: ]
11.  Roth MP, Petersen GM, McElree C, Vadheim CM, Panish JF, Rotter JI. Familial empiric risk estimates of inflammatory bowel disease in Ashkenazi Jews. Gastroenterology. 1989;96:1016-1020.  [PubMed]  [DOI]  [Cited in This Article: ]
12.  Annese V, Andreoli A, Astegiano M, Campieri M, Caprilli R, Cucchiara S, D'Incà R, Giaccari S, Iaquinto G, Lombardi G. Clinical features in familial cases of Crohn's disease and ulcerative colitis in Italy: a GISC study. Italian Study Group for the Disease of Colon and Rectum. Am J Gastroenterol. 2001;96:2939-2945.  [PubMed]  [DOI]  [Cited in This Article: ]
13.  Colombel JF, Grandbastien B, Gower-Rousseau C, Plegat S, Evrard JP, Dupas JL, Gendre JP, Modigliani R, Bélaïche J, Hostein J. Clinical characteristics of Crohn's disease in 72 families. Gastroenterology. 1996;111:604-607.  [PubMed]  [DOI]  [Cited in This Article: ]
14.  Satsangi J, Grootscholten C, Holt H, Jewell DP. Clinical patterns of familial inflammatory bowel disease. Gut. 1996;38:738-741.  [PubMed]  [DOI]  [Cited in This Article: ]
15.  Bayless TM, Tokayer AZ, Polito JM 2nd, Quaskey SA, Mellits ED, Harris ML. Crohn's disease: concordance for site and clinical type in affected family members--potential hereditary influences. Gastroenterology. 1996;111:573-579.  [PubMed]  [DOI]  [Cited in This Article: ]
16.  Polito JM 2nd, Childs B, Mellits ED, Tokayer AZ, Harris ML, Bayless TM. Crohn's disease: influence of age at diagnosis on site and clinical type of disease. Gastroenterology. 1996;111:580-586.  [PubMed]  [DOI]  [Cited in This Article: ]
17.  Heresbach D, Gulwani-Akolkar B, Lesser M, Akolkar PN, Lin XY, Heresbach-Le Berre N, Bretagne JF, Katz S, Silver J. Anticipation in Crohn's disease may be influenced by gender and ethnicity of the transmitting parent. Am J Gastroenterol. 1998;93:2368-2372.  [PubMed]  [DOI]  [Cited in This Article: ]
18.  Grandbastien B, Peeters M, Franchimont D, Gower-Rousseau C, Speckel D, Rutgeerts P, Belaïche J, Cortot A, Vlietinck R, Colombel JF. Anticipation in familial Crohn's disease. Gut. 1998;42:170-174.  [PubMed]  [DOI]  [Cited in This Article: ]
19.  Lee JC, Bridger S, McGregor C, Macpherson AJ, Jones JE. Why children with inflammatory bowel disease are diagnosed at a younger age than their affected parent. Gut. 1999;44:808-811.  [PubMed]  [DOI]  [Cited in This Article: ]
20.  Faybush EM, Blanchard JF, Rawsthorne P, Bernstein CN. Generational differences in the age at diagnosis with Ibd: genetic anticipation, bias, or temporal effects. Am J Gastroenterol. 2002;97:636-640.  [PubMed]  [DOI]  [Cited in This Article: ]
21.  Hampe J, Heymann K, Kruis W, Raedler A, Fölsch UR, Schreiber S. Anticipation in inflammatory bowel disease: a phenomenon caused by an accumulation of confounders. Am J Med Genet. 2000;92:178-183.  [PubMed]  [DOI]  [Cited in This Article: ]
22.  Henriksen M, Jahnsen J, Lygren I, Vatn MH, Moum B. Are there any differences in phenotype or disease course between familial and sporadic cases of inflammatory bowel disease? Results of a population-based follow-up study. Am J Gastroenterol. 2007;102:1955-1963.  [PubMed]  [DOI]  [Cited in This Article: ]
23.  Halfvarson J, Bodin L, Tysk C, Lindberg E, Järnerot G. Inflammatory bowel disease in a Swedish twin cohort: a long-term follow-up of concordance and clinical characteristics. Gastroenterology. 2003;124:1767-1773.  [PubMed]  [DOI]  [Cited in This Article: ]
24.  Orholm M, Binder V, Sørensen TI, Rasmussen LP, Kyvik KO. Concordance of inflammatory bowel disease among Danish twins. Results of a nationwide study. Scand J Gastroenterol. 2000;35:1075-1081.  [PubMed]  [DOI]  [Cited in This Article: ]
25.  Thompson NP, Driscoll R, Pounder RE, Wakefield AJ. Genetics versus environment in inflammatory bowel disease: results of a British twin study. BMJ. 1996;312:95-96.  [PubMed]  [DOI]  [Cited in This Article: ]
26.  Spehlmann ME, Begun AZ, Burghardt J, Lepage P, Raedler A, Schreiber S. Epidemiology of inflammatory bowel disease in a German twin cohort: results of a nationwide study. Inflamm Bowel Dis. 2008;14:968-976.  [PubMed]  [DOI]  [Cited in This Article: ]
27.  Cho JH, Nicolae DL, Gold LH, Fields CT, LaBuda MC, Rohal PM, Pickles MR, Qin L, Fu Y, Mann JS. Identification of novel susceptibility loci for inflammatory bowel disease on chromosomes 1p, 3q, and 4q: evidence for epistasis between 1p and IBD1. Proc Natl Acad Sci USA. 1998;95:7502-7507.  [PubMed]  [DOI]  [Cited in This Article: ]
28.  Barmada MM, Brant SR, Nicolae DL, Achkar JP, Panhuysen CI, Bayless TM, Cho JH, Duerr RH. A genome scan in 260 inflammatory bowel disease-affected relative pairs. Inflamm Bowel Dis. 2004;10:513-520.  [PubMed]  [DOI]  [Cited in This Article: ]
29.  Vermeire S, Rutgeerts P, Van Steen K, Joossens S, Claessens G, Pierik M, Peeters M, Vlietinck R. Genome wide scan in a Flemish inflammatory bowel disease population: support for the IBD4 locus, population heterogeneity, and epistasis. Gut. 2004;53:980-986.  [PubMed]  [DOI]  [Cited in This Article: ]
30.  Paavola P, Heliö T, Kiuru M, Halme L, Turunen U, Terwilliger J, Karvonen AL, Julkunen R, Niemelä S, Nurmi H. Genetic analysis in Finnish families with inflammatory bowel disease supports linkage to chromosome 3p21. Eur J Hum Genet. 2001;9:328-334.  [PubMed]  [DOI]  [Cited in This Article: ]
31.  Rioux JD, Daly MJ, Green T, Stone V, Lander ES, Hudson TJ, Steinhart AH, Bull S, Cohen Z, Greenberg G. Absence of linkage between inflammatory bowel disease and selected loci on chromosomes 3, 7, 12, and 16. Gastroenterology. 1998;115:1062-1065.  [PubMed]  [DOI]  [Cited in This Article: ]
32.  Williams CN, Kocher K, Lander ES, Daly MJ, Rioux JD. Using a genome-wide scan and meta-analysis to identify a novel IBD locus and confirm previously identified IBD loci. Inflamm Bowel Dis. 2002;8:375-381.  [PubMed]  [DOI]  [Cited in This Article: ]
33.  Duerr RH, Barmada MM, Zhang L, Pfützer R, Weeks DE. High-density genome scan in Crohn disease shows confirmed linkage to chromosome 14q11-12. Am J Hum Genet. 2000;66:1857-1862.  [PubMed]  [DOI]  [Cited in This Article: ]
34.  Ma Y, Ohmen JD, Li Z, Bentley LG, McElree C, Pressman S, Targan SR, Fischel-Ghodsian N, Rotter JI, Yang H. A genome-wide search identifies potential new susceptibility loci for Crohn's disease. Inflamm Bowel Dis. 1999;5:271-278.  [PubMed]  [DOI]  [Cited in This Article: ]
35.  Zheng CQ, Hu GZ, Zeng ZS, Lin LJ, Gu GG. Progress in searching for susceptibility gene for inflammatory bowel disease by positional cloning. World J Gastroenterol. 2003;9:1646-1656.  [PubMed]  [DOI]  [Cited in This Article: ]
36.  Tamboli CP, Cortot A, Colombel JF. What are the major arguments in favour of the genetic susceptibility for inflammatory bowel disease? Eur J Gastroenterol Hepatol. 2003;15:587-592.  [PubMed]  [DOI]  [Cited in This Article: ]
37.  Henckaerts L, Figueroa C, Vermeire S, Sans M. The role of genetics in inflammatory bowel disease. Curr Drug Targets. 2008;9:361-368.  [PubMed]  [DOI]  [Cited in This Article: ]
38.  Roussomoustakaki M, Koutroubakis I, Vardas EM, Dimoulios P, Kouroumalis EA, Baritaki S, Koutsoudakis G, Krambovitis E. NOD2 insertion mutation in a Cretan Crohn's disease population. Gastroenterology. 2003;124:272-273; author reply 273-274.  [PubMed]  [DOI]  [Cited in This Article: ]
39.  Annese V, Lombardi G, Perri F, D'Incà R, Ardizzone S, Riegler G, Giaccari S, Vecchi M, Castiglione F, Gionchetti P. Variants of CARD15 are associated with an aggressive clinical course of Crohn's disease--an IG-IBD study. Am J Gastroenterol. 2005;100:84-92.  [PubMed]  [DOI]  [Cited in This Article: ]
40.  Heliö T, Halme L, Lappalainen M, Fodstad H, Paavola-Sakki P, Turunen U, Färkkilä M, Krusius T, Kontula K. CARD15/NOD2 gene variants are associated with familially occurring and complicated forms of Crohn's disease. Gut. 2003;52:558-562.  [PubMed]  [DOI]  [Cited in This Article: ]
41.  Rioux JD, Xavier RJ, Taylor KD, Silverberg MS, Goyette P, Huett A, Green T, Kuballa P, Barmada MM, Datta LW. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat Genet. 2007;39:596-604.  [PubMed]  [DOI]  [Cited in This Article: ]
42.  Hampe J, Franke A, Rosenstiel P, Till A, Teuber M, Huse K, Albrecht M, Mayr G, De La Vega FM, Briggs J. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat Genet. 2007;39:207-211.  [PubMed]  [DOI]  [Cited in This Article: ]
43.  Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ, Steinhart AH, Abraham C, Regueiro M, Griffiths A. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science. 2006;314:1461-1463.  [PubMed]  [DOI]  [Cited in This Article: ]
44.  Libioulle C, Louis E, Hansoul S, Sandor C, Farnir F, Franchimont D, Vermeire S, Dewit O, de Vos M, Dixon A. Novel Crohn disease locus identified by genome-wide association maps to a gene desert on 5p13.1 and modulates expression of PTGER4. PLoS Genet. 2007;3:e58.  [PubMed]  [DOI]  [Cited in This Article: ]
45.  Parkes M, Barrett JC, Prescott NJ, Tremelling M, Anderson CA, Fisher SA, Roberts RG, Nimmo ER, Cummings FR, Soars D. Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility. Nat Genet. 2007;39:830-832.  [PubMed]  [DOI]  [Cited in This Article: ]
46.  Barrett JC, Hansoul S, Nicolae DL, Cho JH, Duerr RH, Rioux JD, Brant SR, Silverberg MS, Taylor KD, Barmada MM. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat Genet. 2008;40:955-962.  [PubMed]  [DOI]  [Cited in This Article: ]
47.  Jess T, Riis L, Jespersgaard C, Hougs L, Andersen PS, Orholm MK, Binder V, Munkholm P. Disease concordance, zygosity, and NOD2/CARD15 status: follow-up of a population-based cohort of Danish twins with inflammatory bowel disease. Am J Gastroenterol. 2005;100:2486-2492.  [PubMed]  [DOI]  [Cited in This Article: ]
48.  Halfvarson J, Bresso F, D'Amato M, Järnerot G, Pettersson S, Tysk C. CARD15/NOD2 polymorphisms do not explain concordance of Crohn's disease in Swedish monozygotic twins. Dig Liver Dis. 2005;37:768-772.  [PubMed]  [DOI]  [Cited in This Article: ]
49.  Joossens M, Van Steen K, Branche J, Sendid B, Rutgeerts P, Vasseur F, Poulain D, Broly F, Colombel JF, Vermeire S. Familial aggregation and antimicrobial response dose-dependently affect the risk for Crohn's disease. Inflamm Bowel Dis. 2010;16:58-67.  [PubMed]  [DOI]  [Cited in This Article: ]
50.  Anderson CA, Massey DC, Barrett JC, Prescott NJ, Tremelling M, Fisher SA, Gwilliam R, Jacob J, Nimmo ER, Drummond H. Investigation of Crohn's disease risk loci in ulcerative colitis further defines their molecular relationship. Gastroenterology. 2009;136:523-529.e3.  [PubMed]  [DOI]  [Cited in This Article: ]
51.  Franke A, Balschun T, Karlsen TH, Hedderich J, May S, Lu T, Schuldt D, Nikolaus S, Rosenstiel P, Krawczak M. Replication of signals from recent studies of Crohn's disease identifies previously unknown disease loci for ulcerative colitis. Nat Genet. 2008;40:713-715.  [PubMed]  [DOI]  [Cited in This Article: ]
52.  McGovern DP, Gardet A, Törkvist L, Goyette P, Essers J, Taylor KD, Neale BM, Ong RT, Lagacé C, Li C. Genome-wide association identifies multiple ulcerative colitis susceptibility loci. Nat Genet. 2010;42:332-337.  [PubMed]  [DOI]  [Cited in This Article: ]
53.  Fisher SA, Tremelling M, Anderson CA, Gwilliam R, Bumpstead S, Prescott NJ, Nimmo ER, Massey D, Berzuini C, Johnson C. Genetic determinants of ulcerative colitis include the ECM1 locus and five loci implicated in Crohn's disease. Nat Genet. 2008;40:710-712.  [PubMed]  [DOI]  [Cited in This Article: ]
54.  Silverberg MS, Cho JH, Rioux JD, McGovern DP, Wu J, Annese V, Achkar JP, Goyette P, Scott R, Xu W. Ulcerative colitis-risk loci on chromosomes 1p36 and 12q15 found by genome-wide association study. Nat Genet. 2009;41:216-220.  [PubMed]  [DOI]  [Cited in This Article: ]
55.  Franke A, Balschun T, Karlsen TH, Sventoraityte J, Nikolaus S, Mayr G, Domingues FS, Albrecht M, Nothnagel M, Ellinghaus D. Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility. Nat Genet. 2008;40:1319-1323.  [PubMed]  [DOI]  [Cited in This Article: ]
56.  Montgomery SM, Morris DL, Pounder RE, Wakefield AJ. Asian ethnic origin and the risk of inflammatory bowel disease. Eur J Gastroenterol Hepatol. 1999;11:543-546.  [PubMed]  [DOI]  [Cited in This Article: ]
57.  Probert CS, Jayanthi V, Pinder D, Wicks AC, Mayberry JF. Epidemiological study of ulcerative proctocolitis in Indian migrants and the indigenous population of Leicestershire. Gut. 1992;33:687-693.  [PubMed]  [DOI]  [Cited in This Article: ]
58.  Carr I, Mayberry JF. The effects of migration on ulcerative colitis: a three-year prospective study among Europeans and first- and second- generation South Asians in Leicester (1991-1994). Am J Gastroenterol. 1999;94:2918-2922.  [PubMed]  [DOI]  [Cited in This Article: ]
59.  Van Kruiningen HJ, Joossens M, Vermeire S, Joossens S, Debeugny S, Gower-Rousseau C, Cortot A, Colombel JF, Rutgeerts P, Vlietinck R. Environmental factors in familial Crohn's disease in Belgium. Inflamm Bowel Dis. 2005;11:360-365.  [PubMed]  [DOI]  [Cited in This Article: ]
60.  Joossens M, Simoens M, Vermeire S, Bossuyt X, Geboes K, Rutgeerts P. Contribution of genetic and environmental factors in the pathogenesis of Crohn's disease in a large family with multiple cases. Inflamm Bowel Dis. 2007;13:580-584.  [PubMed]  [DOI]  [Cited in This Article: ]
61.  Halfvarson J, Jess T, Magnuson A, Montgomery SM, Orholm M, Tysk C, Binder V, Järnerot G. Environmental factors in inflammatory bowel disease: a co-twin control study of a Swedish-Danish twin population. Inflamm Bowel Dis. 2006;12:925-933.  [PubMed]  [DOI]  [Cited in This Article: ]
62.  Andersson RE, Olaison G, Tysk C, Ekbom A. Appendectomy and protection against ulcerative colitis. N Engl J Med. 2001;344:808-814.  [PubMed]  [DOI]  [Cited in This Article: ]
63.  Frisch M, Pedersen BV, Andersson RE. Appendicitis, mesenteric lymphadenitis, and subsequent risk of ulcerative colitis: cohort studies in Sweden and Denmark. BMJ. 2009;338:b716.  [PubMed]  [DOI]  [Cited in This Article: ]
64.  Bolin TD, Wong S, Crouch R, Engelman JL, Riordan SM. Appendicectomy as a therapy for ulcerative proctitis. Am J Gastroenterol. 2009;104:2476-2482.  [PubMed]  [DOI]  [Cited in This Article: ]
65.  Andersson RE, Olaison G, Tysk C, Ekbom A. Appendectomy is followed by increased risk of Crohn's disease. Gastroenterology. 2003;124:40-46.  [PubMed]  [DOI]  [Cited in This Article: ]
66.  Frisch M, Johansen C, Mellemkjaer L, Engels EA, Gridley G, Biggar RJ, Olsen JH. Appendectomy and subsequent risk of inflammatory bowel diseases. Surgery. 2001;130:36-43.  [PubMed]  [DOI]  [Cited in This Article: ]
67.  Frisch M, Gridley G. Appendectomy in adulthood and the risk of inflammatory bowel diseases. Scand J Gastroenterol. 2002;37:1175-1177.  [PubMed]  [DOI]  [Cited in This Article: ]
68.  Radford-Smith GL, Edwards JE, Purdie DM, Pandeya N, Watson M, Martin NG, Green A, Newman B, Florin TH. Protective role of appendicectomy on onset and severity of ulcerative colitis and Crohn's disease. Gut. 2002;51:808-813.  [PubMed]  [DOI]  [Cited in This Article: ]
69.  Reif S, Lavy A, Keter D, Broide E, Niv Y, Halak A, Ron Y, Eliakim R, Odes S, Patz J. Appendectomy is more frequent but not a risk factor in Crohn's disease while being protective in ulcerative colitis: a comparison of surgical procedures in inflammatory bowel disease. Am J Gastroenterol. 2001;96:829-832.  [PubMed]  [DOI]  [Cited in This Article: ]
70.  Russel MG, Dorant E, Brummer RJ, van de Kruijs MA, Muris JW, Bergers JM, Goedhard J, Stockbrügger RW. Appendectomy and the risk of developing ulcerative colitis or Crohn's disease: results of a large case-control study. South Limburg Inflammatory Bowel Disease Study Group. Gastroenterology. 1997;113:377-382.  [PubMed]  [DOI]  [Cited in This Article: ]
71.  Kaplan GG, Jackson T, Sands BE, Frisch M, Andersson RE, Korzenik J. The risk of developing Crohn's disease after an appendectomy: a meta-analysis. Am J Gastroenterol. 2008;103:2925-2931.  [PubMed]  [DOI]  [Cited in This Article: ]
72.  Kaplan GG, Pedersen BV, Andersson RE, Sands BE, Korzenik J, Frisch M. The risk of developing Crohn's disease after an appendectomy: a population-based cohort study in Sweden and Denmark. Gut. 2007;56:1387-1392.  [PubMed]  [DOI]  [Cited in This Article: ]
73.  Calkins BM. A meta-analysis of the role of smoking in inflammatory bowel disease. Dig Dis Sci. 1989;34:1841-1854.  [PubMed]  [DOI]  [Cited in This Article: ]
74.  Mahid SS, Minor KS, Soto RE, Hornung CA, Galandiuk S. Smoking and inflammatory bowel disease: a meta-analysis. Mayo Clin Proc. 2006;81:1462-1471.  [PubMed]  [DOI]  [Cited in This Article: ]
75.  Breuer-Katschinski BD, Holländer N, Goebell H. Effect of cigarette smoking on the course of Crohn's disease. Eur J Gastroenterol Hepatol. 1996;8:225-228.  [PubMed]  [DOI]  [Cited in This Article: ]
76.  Sutherland LR, Ramcharan S, Bryant H, Fick G. Effect of cigarette smoking on recurrence of Crohn's disease. Gastroenterology. 1990;98:1123-1128.  [PubMed]  [DOI]  [Cited in This Article: ]
77.  Lindberg E, Järnerot G, Huitfeldt B. Smoking in Crohn's disease: effect on localisation and clinical course. Gut. 1992;33:779-782.  [PubMed]  [DOI]  [Cited in This Article: ]
78.  Cottone M, Rosselli M, Orlando A, Oliva L, Puleo A, Cappello M, Traina M, Tonelli F, Pagliaro L. Smoking habits and recurrence in Crohn's disease. Gastroenterology. 1994;106:643-648.  [PubMed]  [DOI]  [Cited in This Article: ]
79.  Cosnes J, Beaugerie L, Carbonnel F, Gendre JP. Smoking cessation and the course of Crohn's disease: an intervention study. Gastroenterology. 2001;120:1093-1099.  [PubMed]  [DOI]  [Cited in This Article: ]
80.  Tuvlin JA, Raza SS, Bracamonte S, Julian C, Hanauer SB, Nicolae DL, King AC, Cho JH. Smoking and inflammatory bowel disease: trends in familial and sporadic cohorts. Inflamm Bowel Dis. 2007;13:573-579.  [PubMed]  [DOI]  [Cited in This Article: ]
81.  Vind I, Jespersgaard C, Hougs L, Riis L, Dinesen L, Andersen PS, Locht H, Jess T, Munkholm P. Genetic and environmental factors in monozygotic twins with Crohn's disease and their first-degree relatives: a case report. Digestion. 2005;71:262-265.  [PubMed]  [DOI]  [Cited in This Article: ]
82.  Bridger S, Lee JC, Bjarnason I, Jones JE, Macpherson AJ. In siblings with similar genetic susceptibility for inflammatory bowel disease, smokers tend to develop Crohn's disease and non-smokers develop ulcerative colitis. Gut. 2002;51:21-25.  [PubMed]  [DOI]  [Cited in This Article: ]
83.  Lesko SM, Kaufman DW, Rosenberg L, Helmrich SP, Miller DR, Stolley PD, Shapiro S. Evidence for an increased risk of Crohn's disease in oral contraceptive users. Gastroenterology. 1985;89:1046-1049.  [PubMed]  [DOI]  [Cited in This Article: ]
84.  Sandler RS, Wurzelmann JI, Lyles CM. Oral contraceptive use and the risk of inflammatory bowel disease. Epidemiology. 1992;3:374-378.  [PubMed]  [DOI]  [Cited in This Article: ]
85.  Vessey M, Jewell D, Smith A, Yeates D, McPherson K. Chronic inflammatory bowel disease, cigarette smoking, and use of oral contraceptives: findings in a large cohort study of women of childbearing age. Br Med J (Clin Res Ed). 1986;292:1101-1103.  [PubMed]  [DOI]  [Cited in This Article: ]
86.  Godet PG, May GR, Sutherland LR. Meta-analysis of the role of oral contraceptive agents in inflammatory bowel disease. Gut. 1995;37:668-673.  [PubMed]  [DOI]  [Cited in This Article: ]
87.  Cornish JA, Tan E, Simillis C, Clark SK, Teare J, Tekkis PP. The risk of oral contraceptives in the etiology of inflammatory bowel disease: a meta-analysis. Am J Gastroenterol. 2008;103:2394-2400.  [PubMed]  [DOI]  [Cited in This Article: ]
88.  Gleeson MH, Davis AJ. Non-steroidal anti-inflammatory drugs, aspirin and newly diagnosed colitis: a case-control study. Aliment Pharmacol Ther. 2003;17:817-825.  [PubMed]  [DOI]  [Cited in This Article: ]
89.  Gleeson MH, Lim SH, Spencer D. Non-steroidal anti-inflammatory drugs, salicylates, and colitis. Lancet. 1996;347:904-905.  [PubMed]  [DOI]  [Cited in This Article: ]
90.  Tanner AR, Raghunath AS. Colonic inflammation and nonsteroidal anti-inflammatory drug administration. An assessment of the frequency of the problem. Digestion. 1988;41:116-120.  [PubMed]  [DOI]  [Cited in This Article: ]
91.  Evans JM, McMahon AD, Murray FE, McDevitt DG, MacDonald TM. Non-steroidal anti-inflammatory drugs are associated with emergency admission to hospital for colitis due to inflammatory bowel disease. Gut. 1997;40:619-622.  [PubMed]  [DOI]  [Cited in This Article: ]
92.  Bonner GF, Walczak M, Kitchen L, Bayona M. Tolerance of nonsteroidal antiinflammatory drugs in patients with inflammatory bowel disease. Am J Gastroenterol. 2000;95:1946-1948.  [PubMed]  [DOI]  [Cited in This Article: ]
93.  Gibson GR, Whitacre EB, Ricotti CA. Colitis induced by nonsteroidal anti-inflammatory drugs. Report of four cases and review of the literature. Arch Intern Med. 1992;152:625-632.  [PubMed]  [DOI]  [Cited in This Article: ]
94.  Felder JB, Korelitz BI, Rajapakse R, Schwarz S, Horatagis AP, Gleim G. Effects of nonsteroidal antiinflammatory drugs on inflammatory bowel disease: a case-control study. Am J Gastroenterol. 2000;95:1949-1954.  [PubMed]  [DOI]  [Cited in This Article: ]
95.  Sandborn WJ, Stenson WF, Brynskov J, Lorenz RG, Steidle GM, Robbins JL, Kent JD, Bloom BJ. Safety of celecoxib in patients with ulcerative colitis in remission: a randomized, placebo-controlled, pilot study. Clin Gastroenterol Hepatol. 2006;4:203-211.  [PubMed]  [DOI]  [Cited in This Article: ]
96.  Singh S, Graff LA, Bernstein CN. Do NSAIDs, antibiotics, infections, or stress trigger flares in IBD? Am J Gastroenterol. 2009;104:1298-1313; quiz 1314.  [PubMed]  [DOI]  [Cited in This Article: ]
97.  Van Kruiningen HJ, Joossens M, Vermeire S, Joossens S, Debeugny S, Gower-Rousseau C, Cortot A, Colombel JF, Rutgeerts P, Vlietinck R. Familial Crohn's disease in Belgium: pedigrees, temporal relationships among cases, and family histories. J Clin Gastroenterol. 2007;41:583-590.  [PubMed]  [DOI]  [Cited in This Article: ]
98.  Van Kruiningen HJ, Colombel JF, Cartun RW, Whitlock RH, Koopmans M, Kangro HO, Hoogkamp-Korstanje JA, Lecomte-Houcke M, Devred M, Paris JC. An in-depth study of Crohn's disease in two French families. Gastroenterology. 1993;104:351-360.  [PubMed]  [DOI]  [Cited in This Article: ]
99.  Peeters M, Ghoos Y, Maes B, Hiele M, Geboes K, Vantrappen G, Rutgeerts P. Increased permeability of macroscopically normal small bowel in Crohn's disease. Dig Dis Sci. 1994;39:2170-2176.  [PubMed]  [DOI]  [Cited in This Article: ]
100.  Peeters M, Geypens B, Claus D, Nevens H, Ghoos Y, Verbeke G, Baert F, Vermeire S, Vlietinck R, Rutgeerts P. Clustering of increased small intestinal permeability in families with Crohn's disease. Gastroenterology. 1997;113:802-807.  [PubMed]  [DOI]  [Cited in This Article: ]
101.  D'Incà R, Annese V, di Leo V, Latiano A, Quaino V, Abazia C, Vettorato MG, Sturniolo GC. Increased intestinal permeability and NOD2 variants in familial and sporadic Crohn's disease. Aliment Pharmacol Ther. 2006;23:1455-1461.  [PubMed]  [DOI]  [Cited in This Article: ]
102.  Fries W, Renda MC, Lo Presti MA, Raso A, Orlando A, Oliva L, Giofré MR, Maggio A, Mattaliano A, Macaluso A. Intestinal permeability and genetic determinants in patients, first-degree relatives, and controls in a high-incidence area of Crohn's disease in Southern Italy. Am J Gastroenterol. 2005;100:2730-2736.  [PubMed]  [DOI]  [Cited in This Article: ]
103.  Buhner S, Buning C, Genschel J, Kling K, Herrmann D, Dignass A, Kuechler I, Krueger S, Schmidt HH, Lochs H. Genetic basis for increased intestinal permeability in families with Crohn's disease: role of CARD15 3020insC mutation? Gut. 2006;55:342-347.  [PubMed]  [DOI]  [Cited in This Article: ]