Background: The genetic background of inflammatory bowel diseases (IBDs) has been explored using genetic analysis techniques, such as genome-wide association studies for the population and whole-exome sequencing analyses of family lineages in cases of very early onset. Summary: The results of genetic analysis for IBD indicated the involvement of innate and adaptive immune system variations and epithelial abnormalities in the pathogenesis of IBD. Several associated genes were also reported, indicating that IBD occurs in a heterogeneous population with an extremely diverse background. The genetic background of IBDs is currently being studied to understand not only its onset but also its prognosis, response to treatment, and adverse effects. In the future, it will be possible to use an individual’s genetic information for determining appropriate treatment. In Japan, the NUDT15 polymorphism test is performed before administering thiopurine preparations. However, because of racial differences in genetic analysis, biased analysis toward some racial groups may result in overlooking important genetic backgrounds of IBD. Key Message: Studies of IBDs in a more diverse range of races are expected to elucidate genetic factors through a transethnic analysis, thereby aiding the development of novel treatments and precision medicine for IBDs.

Inflammatory bowel diseases (IBDs), such as Crohn’s disease (CD) and ulcerative colitis (UC), often manifest at a young age. Various studies have been conducted to clarify the factors that underlie the development of IBDs. A family history of IBD has long been considered a risk factor for IBD development, although its incidence within families is not considerably high. IBD is a multifactorial disease that involves both environmental and genetic factors [1]. Epidemiological studies have provided evidence for the involvement of genetic factors in IBD, including intrafamilial clustering, higher incidence among monozygotic twins than among dizygotic twins [2, 3], and variations in incidence and prevalence among ethnic groups [4].

Since 1996, linkage analyses have been actively conducted in IBD-affected sibling pairs of European ancestry [5‒8]. In 2001, two groups reported NOD2/CARD15 as the first susceptibility gene for CD, which was identified as such in Caucasians [9, 10]. Subsequent improvement in genetic analysis technology and the construction of various gene structure databases following the establishment of the Human Genome Project and HapMap project [11, 12] have enabled low-cost genotyping of more than hundreds of thousands of tag-single nucleotide polymorphisms at a time and prediction of individual genotypes for several million genetic polymorphisms from these data (genetic imputation) [13]. Genome-wide association analyses for IBD have been performed repeatedly, and 240 genetic loci have been reportedly associated with IBD in analyses conducted mainly in Western countries [14]. Furthermore, whole-exome or whole-genome sequencing has become relatively accessible and inexpensive since the invention of next-generation sequencing, and the association between IBD and rare functional variants, which are not included in general haplotypes, has been demonstrated [15].

In most cases of IBD, the onset typically occurs during the teenage years or later, but in cases of UC, the age of onset may be older. In general, IBD has been assumed to be a common disease, and its genetic factors include a combination of limited risks (small odds ratios) associated with frequent genetic polymorphisms [16]. Therefore, genome-wide association studies comparing the frequency of common gene polymorphisms in healthy individuals and patients with IBD have been conducted to search for these genetic factors [14, 16]. Monogenic IBD, which is presumed to occur as a result of a single genetic mutation, has been found in very early-onset IBD (VEO-IBD) cases that occur at the age of <6 years. Because whole-exome sequencing analysis has become relatively easy to perform, many disease-causing genes have been identified in the analysis of family trees. Thus, the genetic background of IBD can be analyzed on the basis of the following two major hypotheses: (1) IBD is a common disease and (2) IBD is a single-gene inherited disease (Fig. 1) [16].

Fig. 1.

Genetic background of IBD according to the age at disease onset. The graph (top) shows the ratio of genetic and environmental factors to total incidence factors according to the age at onset; with age, environmental factors predominate. Proportions of each type of genetic background in each age-group are illustrated. With age, the prevalence of monogenic IBD is decreasing in the overall population of patients with IBD; however, the backgrounds of patients with monogenic IBD remained mixed even in adult cases. The methods used for genetic analysis and diagnosis are listed in the table (bottom). WGS/WES, whole-genome/exome sequencing; GWAS, genome-wide association study.

Fig. 1.

Genetic background of IBD according to the age at disease onset. The graph (top) shows the ratio of genetic and environmental factors to total incidence factors according to the age at onset; with age, environmental factors predominate. Proportions of each type of genetic background in each age-group are illustrated. With age, the prevalence of monogenic IBD is decreasing in the overall population of patients with IBD; however, the backgrounds of patients with monogenic IBD remained mixed even in adult cases. The methods used for genetic analysis and diagnosis are listed in the table (bottom). WGS/WES, whole-genome/exome sequencing; GWAS, genome-wide association study.

Close modal

IBDs include more than CD and UC; they are a heterogeneous group of diseases with a great variety of pathological manifestations, including IBD unclassified, which is difficult to categorize as either CD or UC. This suggests that the pathogenesis and genetic background of IBDs are diverse; therefore, different genetic backgrounds have been hypothesized. IBD can probably be categorized into types other than common IBD and monogenic IBD. For instance, most cases of VEO-IBD, which has a strong genetic predisposition, have not been identified as monogenic disorders. Analysis of the genetic background of IBDs is difficult because they may include oligogenic and polygenic cases that are the result of multiple rare risks and environmental factors associated with IBD, such as diet and intestinal microbiomes.

Monogenic IBD is a form of IBD that is most strongly influenced by genetic factors. While VEO-IBD is likely to be monogenic, monogenic IBD has also been found in some adult-onset cases, although less frequently [17‒19]. Nambu et al. [20] reported that out of 750 patients with monogenic IBD, 10.9% were diagnosed at older than 18 years. This indicates that monogenic IBD is present among cases that are diagnosed and treated as common IBDs by physicians rather than pediatricians. However, 10.9% is the frequency among cases of IBD that are monogenic, and the frequency of monogenic IBD among IBD cases that occur after the age of 18 years is much lower than this. Epidemiologically, the peak age of the onset of IBD is the late teenage or later years, and the frequency of monogenic IBD included in the general IBD population is extremely small.

However, identifying monogenic IBD in combination with adult-onset IBD is an important step in developing personalized medicine that would constitute appropriate treatment. At present, no consensus has been established regarding the identification of monogenic IBD in adult patients. Some characteristic findings of VEO-IBD may provide a basis for genetic diagnosis in cases with some of its features, such as early onset, family history, atypical lesions, severe anal complications, frequent extraintestinal complications (including skin lesions), other autoimmune disease complications, malignancies, and high mortality rates [15, 21‒23]. Among cases of IBD in adults, IBD-unclassified cases and atypical cases of CD or UC may include those of hidden monogenic IBD, and these cases will probably be subject to clinical sequencing analysis in the future (Fig. 2) [20].

Fig. 2.

Selection process of patients requiring genetic analysis to distinguish monogenic IBD. Candidates for clinical sequencing to diagnose monogenic IBDs are selected according to their clinical phenotypes not only at diagnosis but also at any time after diagnosis. The possibility of monogenic IBD should always be considered, even if it is not suspected at the time of diagnosis and if the subsequent course of the disease is not typical. Clinical characteristics for patient selection are anticipated from the characteristics of previously diagnosed monogenic IBD cases.

Fig. 2.

Selection process of patients requiring genetic analysis to distinguish monogenic IBD. Candidates for clinical sequencing to diagnose monogenic IBDs are selected according to their clinical phenotypes not only at diagnosis but also at any time after diagnosis. The possibility of monogenic IBD should always be considered, even if it is not suspected at the time of diagnosis and if the subsequent course of the disease is not typical. Clinical characteristics for patient selection are anticipated from the characteristics of previously diagnosed monogenic IBD cases.

Close modal

The estimated age of onset differs depending on the genetic disorders, although >80 causative genes for monogenic IBD have been reported so far, and a form of monogenic IBD that primarily affects adults may exist. In such a case, the direct clinical findings described earlier are expected to be different. Many cases of enteritis associated with MEFV mutations [17] and of small intestinal ulcers associated with SLCO2A1 mutations [19] are observed not only in children but also in adults, and the clinical manifestations are extremely different.

The genetic background of adult IBD cases has so far been analyzed mainly in terms of traditional categories (CD/UC/IBD); thus, conducting a detailed genetic analysis of individuals on a somewhat larger scale may be essential to create a database of characteristics of IBD cases.

Genetic analysis has provided important insights into the pathogenesis of IBD by showing that abnormalities in various biological mechanisms are involved in the pathogenesis of this disease.

Phagocyte Abnormalities

Chronic granulomatous disease is caused by congenital abnormalities of phagocytes, and approximately 40% of the affected patients develop CD-like enterocolitis because of genetic defects in various proteins (cytochrome b alpha and beta and neutrophil cytosolic factor 2) that make up the nicotinamide adenine dinucleotide phosphate oxidase of phagocytes [24, 25]. Reduced nicotinamide adenine dinucleotide phosphate activity results in decreased production of reactive oxygen species, which is used by phagocytes to kill pathogens and other organisms, thereby reducing their bactericidal capacity.

In addition to chronic granulomatous disease, IBD is observed in cases of glycogen storage disease type 1b [26] and in some cases of congenital neutropenia caused due to an abnormality in G6PC3 [27‒29]. Therefore, abnormalities in both phagocyte function and innate immune system may be associated with the development of some forms of IBD. In addition, the analysis of disease susceptibility genes in IBD as a common disease has revealed that impairment of the bacterial clearance mechanism of the innate immune system is associated with IBD development [16].

NOD2, first identified as a disease susceptibility gene for CD, identifies peptidoglycans derived from intestinal bacteria, particularly muramyl dipeptide, which ultimately induces the activation of the transcriptional nuclear factor kappa light chain enhancer of activated B cells (NF-κB) via the caspase-recruitment domain protein. NOD2 has been reported to induce both ATG16L1 recruitment in the plasma membrane at the site of bacterial invasion and an autophagy-mediated immune response [30]. ATG16L1 recruitment cannot be induced and that bacterial exclusion through autophagy does not occur in cells with risk polymorphisms of fs1007insC of NOD2 [30]. Autophagy induced by muramyl dipeptide is also dysfunctional in the dendritic cells and lymphocytes of patients with CD who have ATG16L1-T300A polymorphism, which is a risk allele for CD [31, 32]. Moreover, patients with CD having NOD2 and ATG16L1 polymorphisms exhibit abnormalities in the distribution and morphology of secretory granules containing antimicrobial peptides, such as defensins and lysozymes, in Paneth cells [33‒35].

Lymphocyte Abnormalities

Primary immunodeficiency diseases with humoral immune abnormalities, such as agammaglobulinemia (associated with mutations in BTK and PIK3R1) [36, 37] and hyperimmunoglobulin M syndrome (associated with mutations in CD40LG) [38], may also manifest with IBD-like lesions. Some severe combined immunodeficiency diseases, which cause T-cell-based immune abnormalities, are associated with infantile-onset IBD, and Wiskott-Aldrich syndrome (associated with mutations in WASP) causes UC-like intestinal inflammation [39]. Various IBD-like lesions, which appear similar to those found in both CD and UC, have been noted in patients with common variable immunodeficiency (CVID). However, CVID is a multifactorial disease, and not all its symptoms can be explained by genetic abnormalities; however, complications involving IBD-like lesions have been reported in patients with monogenic CVID, especially LRBA mutations [40]. Moreover, IPEX syndrome, in which FOXP3 gene deficiency leads to regulatory T-cell abnormalities, is a major cause of autoimmune enteropathy [41]. Furthermore, abnormalities in regulatory T cells, the inflammation-regulating cytokine interleukin (IL)10, and IL10 receptors, which are derived from B cells, prompt the development of IBD within the first few months after birth [42, 43]. Such abnormalities in the adaptive immune system were observed in the susceptibility gene analysis of the disease [16]. IL23R, IL12B (p40), which codes a subunit of IL23, and various genes in the downstream Janus kinase signal transducer and activator of the transcription signaling pathway are mostly IBD susceptibility genes [44‒46]. A rare case of polymorphism (G149R) involving amino acid replacement in IL23R, which was reported in Korean and Japanese cases of CD and UC, is a protective polymorphism that reduces the disease risk, which suggests that IL23R suppression is a potential genetic treatment for CD and UC [47‒49]. Ustekinumab, which targets IL12B (p40), is used in IBD treatment, and antibody preparations targeting p19, a unit of IL23, are also being developed. TNFSF15, which is involved in the Th17 immune response, is the susceptibility gene most strongly associated with CD in Japanese patients [50, 51], and antibody preparations against TL1A [52, 53] encoded by TNFSF15 are being developed.

Intestinal Epithelial Abnormalities

IBD lesions are also observed in patients with diseases involving epithelial abnormalities. For instance, intestinal lesions have been reported in Kindler’s syndrome, a congenital epidermal hydatid disease caused by a deficiency in Kindlin-1, a protein that is involved in cell adhesion and contributes to integrin activation [54]. Enterotoxin receptors in the intestinal epithelium that are abnormal because of GUCY2C deficiency are considered to cause familial diarrhea [55]. Moreover, abnormalities in IKBKG, the X-linked gene for NF-κB essential modulator syndrome, and mutations in the autosomal-dominant inherited gene that codes for IκBα protein result in ectodermal dysplasia immunodeficiency caused by a reduction in NF-κB signaling, which in turn results in abnormalities in the intestinal epithelium and immunodeficiency as well as complicates IBD in approximately half of the affected patients [56].

As described earlier, genetic analysis has confirmed that abnormalities in the intestinal epithelium and responses of the innate and adaptive immune systems against the intestinal environment, such as intestinal bacteria, play an important role in IBD development, although such abnormalities occur in varying degrees. In particular, differences in the function of these mechanisms are associated with susceptibility to IBD.

IBD develops in an individual who is born with genetic risk factors and is postnatally exposed to various environmental factors, such as intestinal flora, diet, medications, and smoking. After disease onset, such environmental factors and IBD treatment continue to affect the prognosis of IBD. Other genetic factors, such as pharmacogenetic genes, also affect the prognosis through their interaction with environmental factors and IBD treatment. These genetic factors are associated with disease progression after onset despite being determined at birth. Therefore, studies investigating the genetic factors associated with IBD have focused on differences in germline-derived nucleotide sequences (Fig. 3).

Fig. 3.

Pathogenesis of IBD as a multifactorial disease. In the pathogenesis of IBD, both genetic and environmental factors play a role. Previous analyses of genetic factors in IBD have focused on germline-derived nucleotide sequence differences, and somatic mosaic alterations, which may affect the disease onset, disease course, or both, have been reported in patients with IBD.

Fig. 3.

Pathogenesis of IBD as a multifactorial disease. In the pathogenesis of IBD, both genetic and environmental factors play a role. Previous analyses of genetic factors in IBD have focused on germline-derived nucleotide sequence differences, and somatic mosaic alterations, which may affect the disease onset, disease course, or both, have been reported in patients with IBD.

Close modal

Recently, a case of VEO-IBD was reported in which mosaicism of the CYBB mutation might have been involved in the pathogenesis of the disease [57]. Mosaic chromosomal alterations (mCAs), such as copy number abnormalities, have been observed in normal individuals with an increase in their age [58, 59], but among patients with IBD, the prevalence of mCAs in peripheral blood is reported to be higher in patients with CD than that in patients with UC [60]. Whether mCAs are the result of IBD inflammation or a factor in IBD pathogenesis remains unclear. However, CD and UC arise from different genetic backgrounds, and genes occurring in the regions altered in these diseases include those involved in bacterial defense mechanisms and innate immunity in the mucosa as well as Paneth cells. The pathogenesis of CD and the biological response after disease onset are interesting areas of research. Considering the possibility of mosaicism, deep (high read count) whole-genome sequencing analysis, rather than simply focusing on gene sequences, may also reveal new genetic backgrounds of IBD.

The actual IBD course can change over a long period. Many of these changes are caused by changes in environmental factors, and some are caused by various mechanisms and functional changes in the body; somatic mutation mosaicism may lead to such changes. The phenomenon of carcinogenesis arising as a result of genetic abnormalities associated with inflammation (inflammatory carcinogenesis) is well known, but the type of changes undergone by the mutant clones selected under persistent inflammation is not yet well understood. Nanki et al. [61] analyzed clones with somatic mutations in intestinal epithelial cells from patients with UC using the latest organoid culture technology and found that persistent inflammation caused the intestinal epithelium to acquire genetic mutations that made it resistant to inflammation. Inflammation causes the normal epithelium to drop off while the clone with the mutation expands. However, the tumor cells themselves contain few of these mutations, although patients with UC-associated tumors have many of these clones. This suggests that mutant clones induced by inflammation are resistant to inflammation and protect against carcinogenesis. This proliferation of acquired gene mutant clones as a biological response provides an important insight into the maintenance and alteration of the pathogenesis of UC [62]. Therefore, future studies are expected to focus on the relationship between germline-derived disease susceptibility gene polymorphisms involved in pathogenesis and genetic mutations induced by inflammation after disease onset because some genetic mutations involve disease susceptibility genes.

Genetic analysis has been conducted to investigate not only the pathogenesis of IBD but also genetic factors associated with prognosis, treatment efficacy, and adverse effects of treatment. In particular, several exploratory analyses of genetic backgrounds in association with the efficacy of infliximab and other drugs and associations of antitumor necrosis factor α drugs with TNFα, FCGR3A, and TNFR1 polymorphisms have been conducted [63‒65]. However, no clinically useful level of correlation has been established because many factors other than genetic background are involved in drug efficacy, and selecting a drug on the basis of a single genetic background may be difficult. Constructing a prediction model by combining information about multiple genetic polymorphisms, such as polygenic risk score (PRS), and clinical information will be essential because the associations among genetic polymorphisms are weak.

Adverse effects that are directly linked to drugs or related to a well-defined phenotype, such as antidrug antibody production, are often strongly associated with the genetic background. Differences in susceptibility to thiopurine drugs are largely determined by genetic factors, such as the TPMT polymorphism in Caucasians and the NUDT15 polymorphism in Asians and others [66, 67]. Adverse effects in patients homozygous for the NUDT15 R139C polymorphism are severe and relatively common (affecting approximately 1% of the Japanese population); thus, the NUDT15 polymorphism test can be used as a screening tool before the administration of thiopurine preparations in Japan [68, 69]. Thiopurine-induced pancreatitis is also associated with human leukocyte antigens in Caucasians [70]. The personalized anti-TNF therapy in Crohn’s disease study (PANTS) has shown that HLA-DQA1*05 carriers are also at a risk for production of antibodies to antitumor necrosis factor α drugs [70]. Meanwhile, although adverse effects such as high fever and worsening diarrhea caused by mesalamine preparations are relatively common in Japanese patients, a genetic analysis did not reveal any strong association with specific genes; therefore, a prediction model based on a combination of PRS and clinical information has been proposed [71].

Racial differences must be considered while investigating genetic factors. Previous studies on the genetic analyses of IBD have been conducted mostly in Europeans [14], with only limited studies having been conducted on other races with much smaller sample sizes [48, 49, 72‒74]. Discussion that is based solely on the results of such biased racial genetic analyses overlooks important genetic backgrounds. For example, almost no Asians have causative mutations of NOD2, a disease susceptibility gene that is most strongly associated with CD in Caucasians. Conversely, TNFSF15 is strongly associated with CD in Asians, and the odds ratios of the risk variants are extremely different between Asians and Caucasians (Fig. 4). The NUDT15 polymorphism described earlier had demonstrated an extremely strong association with thiopurine-induced leukopenia in a small Asian sample set because it is common in Asians, but such an association was not observed in Europeans for a long time because NUDT15 polymorphism is extremely rare in this population [66, 75].

Fig. 4.

Comparison of Manhattan plots of GWAS for IBD in patients of Japanese and European ancestries. SNPs are plotted according to chromosomal location, in which the −log10(P) is calculated from GWAS study. The red line indicates the threshold for genome-wide significance (P= 5E−8). The blue line indicates the threshold for nominal significance (P= 5E−6). The SNPs most common in CD differ completely between patients of European and Japanese ancestries. In addition, signals, except for HLA regions in UC, are different. Plots were redrawn by the authors using their published data [49, 74] and publicly available data [14] (ftp://ftp.sanger.ac.uk/pub/project/humgen/summary_statistics/human/2016-11-07/).

Fig. 4.

Comparison of Manhattan plots of GWAS for IBD in patients of Japanese and European ancestries. SNPs are plotted according to chromosomal location, in which the −log10(P) is calculated from GWAS study. The red line indicates the threshold for genome-wide significance (P= 5E−8). The blue line indicates the threshold for nominal significance (P= 5E−6). The SNPs most common in CD differ completely between patients of European and Japanese ancestries. In addition, signals, except for HLA regions in UC, are different. Plots were redrawn by the authors using their published data [49, 74] and publicly available data [14] (ftp://ftp.sanger.ac.uk/pub/project/humgen/summary_statistics/human/2016-11-07/).

Close modal

Some polymorphisms are not detected because of their absence in people of different races, whereas others are not detected because, despite their presence, they interact differently with genetic and environmental factors. Although studies on the genetic analysis of IBD have been conducted in East Asians, such as Koreans, Chinese, and Japanese populations, the sample sizes in these studies were smaller than those in previous studies on Caucasians. Conducting a meta-analysis on populations with similar genetic backgrounds would be useful in resolving these problems, and future analyses are expected.

The genetic background of IBD has been analyzed in populations and individuals according to two different hypotheses, and numerous associated genes have been identified. However, analyses considering racial differences are insufficient, and more studies should be performed in this regard. In addition, the genetic information accumulated is expected to be used in various ways in the future, such as in PRS and Mendelian randomization analysis, which will result in the development of novel therapeutic methods and provide a foundation for further research.

We thank all members of the MENDEL study group.

The authors have no conflicts of interest to declare.

The authors have not received any funding for this review.

Yoichi Kakuta drafted the article. Takeo Naito and Yoshitaka Kinouchi were responsible for the critical revision and final approval of the article. Atsushi Masamune provided final approval of the article.

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