Genetic factors in inflammatory bowel disease

INTRODUCTION — Inflammatory bowel disease (IBD) is comprised of two major disorders: ulcerative colitis (UC) and Crohn disease (CD), and these disorders have both distinct and overlapping pathologic and clinical characteristics. (See "Definitions, epidemiology, and risk factors for inflammatory bowel disease".)

The pathogenesis of UC and CD are not well understood. The role of genetic factors will be reviewed here. Immune and microbial mechanisms are discussed separately. (See "Immune and microbial mechanisms in the pathogenesis of inflammatory bowel disease".)

GENETIC FACTORS — There are two issues related to genetic factors in IBD: factors that increase the susceptibility to IBD, which will be reviewed here; and genetic syndromes that are associated with an increased risk of IBD. However, more than 85 percent of patients with Crohn disease (CD) have no family history of IBD [1].

Genetic susceptibility — A number of observations in both humans and animal models suggest that genetically determined factors contribute to IBD susceptibility [2].

 Animal models — The ability to delete or modify genes selectively (such as interleukin [IL]-10) in animal models has contributed to the understanding of the genetic loci that may be involved in IBD pathogenesis [3,4]. These experiments have revealed several important observations:

●Colitis is a relatively nonspecific phenotype that can result from alterations in a variety of genes. Genes affecting both the adaptive and innate immune system as well as epithelial function can lead to intestinal inflammation.

●A single genetic alteration can be associated with a variable clinical presentation, depending upon the specific strain of mice used, suggesting that the actual phenotype results from interactions among multiple genetic loci.

●The lack of colitis observed in numerous susceptible strains with genetic alterations when maintained in germ-free environments demonstrates that the genes confer disease susceptibility, but actual disease is dependent upon the presence of microorganisms.

Human studies — IBD appears to follow a non-Mendelian pattern of inheritance in most affected individuals.

The most compelling clinical evidence for the heritable risk of IBD has been obtained from twin studies, which also suggest that genetic factors may be more important in CD than in ulcerative colitis (UC) [5-7]. In a study that included 80 twins with IBD, for example, the concordance rate for monozygotic twins was markedly higher in CD than UC (50 versus 19 percent) and continued to rise over time [8].

First-degree relatives of patients with IBD are approximately 3 to 20 times more likely to develop the disease than the general population [9-14]. While first-degree relatives of patients with CD have a greater increased risk of developing CD than UC, the risk of developing UC in these relatives is greater than the general population. Similarly, first-degree relatives of UC patients have a greater increased risk of developing UC than CD, and the risk of developing CD in these relatives is greater than the general population. In one report, children in whom both parents had IBD (CD or UC) had up to a 33 percent chance of developing IBD by age 28 [9]. All of the affected offspring developed CD and were born to parents who both had CD. In addition, having a sibling with CD can increase the risk of developing CD by 30 times compared with the general population [12]. Approximately two-thirds of sibling pairs are diagnosed within ten years of each other [14]. Having a positive family history of IBD remains the strongest risk factor for developing IBD.

Children of an affected parent who is Jewish may be at a higher risk of developing IBD [13].

Clinical features of the disease also demonstrate a heritable pattern. Concordance in the location (eg, ileal versus colonic) and type (eg, fibrostenotic, fistulas) of CD has been observed, as illustrated by the following findings [15-20]:

●In a series of 554 patients with CD, 17 percent had a family history of CD [15]. Concordance of the site of disease in at least two family members was observed in 86 percent of cases, and 82 percent were concordant for the clinical type of disease.

●Another report evaluated 72 families with two to five or more affected first degree relatives [16]. Concordance for disease location and type were present in 56 and 49 percent in families with two affected members compared to 83 and 76 percent in families with more than two affected members.

There is some support for "genetic anticipation," which refers to the development of earlier onset and more severe disease in offspring of affected parents in subsequent generations [14,21,22]. In one study, for example, 48 of 57 children with CD born of parents with CD developed symptoms a median of 16 years earlier than the onset of disease in their parents [21]. Rather than reflecting genetic anticipation, the preceding observations may in part be explained by ascertainment bias because children of parents with IBD may be subjected to earlier diagnostic evaluation [16,23]. In addition, apparent genetic anticipation may be explained in part by bias secondary to the lack of adjustment for different observation times among subjects [24]. Since children of affected parents are typically followed for a much shorter time span than their parents (up to a lower average age), the average age of disease onset in children may be lower than would be found if this group were followed for a longer time. However, this cannot be the entire explanation since the parents may be first diagnosed after the child (12 of 49 cases in one series) [22].

Specific genes — Although genetic alteration in any one of several individual genes in mice is sufficient to lead to an IBD-like syndrome, in humans, alterations in more than 200 distinct loci confer a modest effect by themselves; it is likely that the aggregate effect at several loci contributes to the IBD phenotype [25-27].

A variety of screening approaches, most notably genome-wide association studies (GWAS), have implicated over 200 distinct susceptibility loci for IBD, the majority associated with both CD and UC and over 70 percent associated with other immune-mediated diseases such as ankylosing spondylitis, psoriasis, and celiac disease, as well as with mycobacterial infection [28-52]. Similar studies in pediatric cohorts have identified many of the same genes associated with adult IBD risk [41,51]. Deep resequencing of genes identified by GWAS in patient cohorts have further identified rare variants within these loci adding to the overall genetic variation associated with IBD risk [53]. Such gene identification strategies have pinpointed several critical signaling pathways that have been consistently associated with IBD susceptibility. Analysis of the functional properties of the proteins encoded by these various genes has further aided in identifying specific mechanistic pathways that are important in the pathogenesis of these disorders.

●Intracellular innate immune pathways recognizing microbial products in the cytoplasm – The IBD1 locus on chromosome 16 encodes the protein NOD2 (CARD15) [32-38]. Mutations in NOD2 confer susceptibility to ileal CD [34-36]. In a prospective cohort of 186 children, the prevalence of NOD2 mutations was 42 percent, suggesting that early onset CD has a strong genetic component [38]. The wild-type NOD2 protein activates nuclear factor kappa B in response to muramyl dipeptide, a fragment of bacterial peptidoglycan [32,33]; this process is deficient in subjects with the mutant form of NOD2 [33]. (See "Immune and microbial mechanisms in the pathogenesis of inflammatory bowel disease".)

●The autophagy pathway – Several CD associated genes (ATG16L1, IRGM, and LRRK) regulate the autophagy pathway, an innate homeostatic process that permits recycling of intracellular organelles, as well as contributes to the removal of intracellular microorganisms [31,45,46,54]. NOD2 can also regulate autophagy [55,56], suggesting that these pathways are integrated and defective in some patients with CD.

●Pathways regulating adaptive immunity – Adaptive immune genes that regulate both the IL-17 and IL-23 receptor pathway have been implicated for IBD risk [43,48] including genes associated with risk for both UC and CD (eg, IL23R, IL12B, STAT3, JAK2, TNFSF15, and TYK2). Some of these genes (IL-10, STAT3, JAK2, and TYK2) also play a role in the IL-10 immunoregulatory pathway that has also been independently linked to both UC and CD.

●Pathways regulating epithelial function – A number of epithelial barrier genes have been associated with IBD (more commonly associated with ulcerative colitis as compared with Crohn disease (eg, OCTN2, ECM1, CDH1, HNF4A, LAMB1, and GNA12) [50,57]. Genes that control Paneth cell biology and the ER stress/unfolded protein response have also been identified in CD (eg, Xbp-1; NOD2, ATG16L1) [58,59]. ATG16L1 and NOD2 have been associated with changes in Paneth cell morphology. Patients with CD with a higher proportion of abnormal Paneth cells (>20 percent) had earlier disease recurrence following surgical resection compared with patients with lower proportion of abnormal Paneth cells [59,60].

Major histocompatibility complex — Several studies have evaluated potential associations of IBD with major histocompatibility complex (MHC) loci [44,61-76] (see "Human leukocyte antigens (HLA): A roadmap"). Considered together, these studies have demonstrated that HLA-DR2 is associated with UC, particularly in Japanese patients, and extraintestinal manifestations of CD are more commonly observed in patients with HLA-A2, HLA-DR1, and DQw5. In a GWAS of a Japanese population, HLA-Cw*1202-B*5201-DRB1*1502 haplotype was associated with increased susceptibility to UC but decreased risk for CD [77]. The largest study examining the role of the HLA in European ancestry IBD implicated multiple HLA alleles with a primary role for HLA-DRB1*01:03. In addition, significant differences were noted at some alleles with opposite effects in UC and CD (eg, HLA-DRB1*07:01). Furthermore, the effect size in CD for both HLA-DRB1*01:03 and HLA-DRB1*07:01 depended on disease location.

The majority of advances in IBD genetics have been made in Northern European ancestry populations, but studies have been published in East Asian, Ashkenazi Jewish, and Puerto Rican populations [78-83]. These studies have identified that some IBD genes are shared across populations (eg, TNFSF15, FCGR2A, HLA alleles), while others are peculiar to different ethnic groups. This is best understood by looking at genes associated with autophagy: NOD2 and ATG16L1 appear to have no role in CD in East Asians whereas ATG16L2, implicated in Korean CD, is not associated with CD in European populations [84,85]. Genome-wide technologies have also been applied to African Americans with IBD, suggesting that many of the genes identified in Northern Europeans also contribute to the development of IBD in African Americans [83].

Genotype-phenotype associations in IBD — Genetic variation appears to influence disease location and prognosis [86,87]. For example, certain HLA alleles are associated with extensive disease and the presence of extra-intestinal manifestations. One large, genotype association study confirmed that disease location in patients with Crohn disease (CD) remains constant over time and is strongly associated with polygenic risk scores of known inflammatory bowel disease loci [86]. Another study determined that four loci (HLA, XACT, FOXO3, IGFBP1) were statistically associated, at a genome-wide level, with more severe disease in CD [87].

Pharmacogenomics in IBD — Genetic variants have been associated with increased risk of thiopurine-induced bone marrow suppression, and this is discussed separately. (See "Overview of pharmacogenomics", section on 'Thiopurines and polymorphisms in TPMT and NUDT15'.)

The development of immunogenicity to infliximab and adalimumab is a significant cause of loss of clinical response. Data have suggested that carriage of HLA-DQA1*05 was associated with the development of anti-drug antibodies to these agents [88].

GENETIC SYNDROMES ASSOCIATED WITH IBD

Very early onset IBD — There is a diverse spectrum of rare genetic disorders that produce IBD-like intestinal inflammation caused by genetic variants that have a large effect on gene function and typically present in infancy [89-92]. Over 60 unique monogenic IBD disorders have been described that affect mucosal homeostasis in diverse ways, including:

●Epithelial barrier and response defects (eg, IKBKG, TTC7, ADAM17)

●Dysfunction of neutrophil granulocytes (eg, NCF2, NCF4, SLC37A4)

●Hyper- and autoinflammatory disorders (eg, XIAP)

●Complex defects in T- and B-cell function (eg, LRBA, CD40LG; WAS)

●Regulatory T cells and IL-10 signaling (eg, IL10R, IL10, FOXP3)

Some of these disorders with gene defects that affect predominantly hematopoietic cells (eg, IL-10R, IL-10, XIAP, FOXP3) respond to stem cell transplantation.

Turner syndrome — Turner syndrome is caused by the absence of an X chromosome (45 XO) or by the presence of an abnormal, dysfunctional X chromosome. One of these abnormalities is present in approximately 1:5000 live female births. Common features of Turner syndrome include short stature, webbed neck, widely spaced nipples, cubitus valgus, and cardiac defects (especially bicuspid aortic valve, coarctation, and aortic stenosis). (See "Clinical manifestations and diagnosis of Turner syndrome".)

An association with IBD has also been reported [93-95]. In one of the largest series, 4 of 135 (3 percent) adults with Turner syndrome developed IBD (two with UC and two with CD), an incidence much higher than an age-matched population [93].

Hermansky-Pudlak syndrome — Granulomatous colitis similar to CD has been reported in individuals with Hermansky-Pudlak syndrome (HPS) [96,97]. HPS is an autosomal recessive disorder characterized by oculocutaneous albinism, abnormal platelet aggregation with bleeding diathesis, and pulmonary fibrosis. Genetic linkage analysis has identified a candidate gene for HPS on chromosome 10q23. In one study, 8 of 49 (16 percent) patients with HPS had IBD; four of the eight had a mutation in this gene [97].

Glycogen storage disease type 1b — Patients with glycogen storage disease type 1b present in infancy with hypoglycemia, growth failure, hepatomegaly, and neutropenia, secondary to a deficiency of the glucose-6-phosphate translocase (transport protein). (See "Glucose-6-phosphatase deficiency (glycogen storage disease I, von Gierke disease)".)

These patients develop a granulomatous colitis pathologically similar to CD [98], which responds to treatment with granulocyte-macrophage colony stimulating factor [99]. Interestingly, a case report described the use of granulocyte colony-stimulating factor to treat fistulae in an adolescent boy with CD, suggesting altered neutrophil function may be a contributing factor to the pathogenesis of idiopathic CD [100].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Ulcerative colitis in adults" and "Society guideline links: Crohn disease in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Crohn disease in adults (The Basics)" and "Patient education: Ulcerative colitis in adults (The Basics)")

●Beyond the Basics topics (see "Patient education: Crohn disease (Beyond the Basics)" and "Patient education: Ulcerative colitis (Beyond the Basics)")

SUMMARY

●Studies of humans and animal models suggest that genetically determined factors contribute to inflammatory bowel disease (IBD) susceptibility. The colitis phenotype results from interactions among multiple genetic loci but actual disease is likely dependent upon the presence of microorganisms. (See 'Genetic susceptibility' above.)

●Clinical evidence for the heritable risk of IBD is suggested by the high concordance rate for Crohn disease (CD) in monozygotic twins and a 3 to 20-fold increased risk of IBD in first-degree relatives of patients with IBD. Clinical features of CD also demonstrate a heritable pattern with concordance in disease location (eg, ileal versus colonic) and type (eg, fibrostenotic, fistulas). Furthermore, the presence of "genetic anticipation," which refers to the development of earlier onset and more severe disease in offspring of affected parents in subsequent generations, also suggests a heritable cause for IBD. (See 'Genetic factors' above.)

●Genome-wide association studies (GWAS) have implicated over 200 distinct susceptibility loci for IBD. Rare variants within these loci have been identified adding to the overall genetic variation associated with IBD risk. The functional properties of the proteins encoded by these genes has aided in identifying specific mechanistic pathways that are important in the pathogenesis of IBD. (See 'Specific genes' above.)

●Several studies have evaluated potential associations of IBD with major histocompatibility complex (MHC) loci. However, results among studies have varied. Some variation may be due to differences in methods used to assess MHC and in population groups studied. (See 'Major histocompatibility complex' above.)

●Several genetic syndromes have been associated with IBD. These include Turner syndrome, Hermansky-Pudlak syndrome, and glycogen storage disease type 1b. (See 'Genetic syndromes associated with IBD' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Dr. Daniel K Podolsky, MD, who contributed to an earlier version of this topic review.

The UpToDate editorial staff also acknowledges Paul Rutgeerts, MD (deceased), who contributed as a section editor for UpToDate in Gastroenterology.