Overview and Introduction

Genes and Disease Risk

Celiac disease, autoimmune hepatitis (AIH), and the inflammatory bowel diseases (IBDs), Crohn's disease and ulcerative colitis (UC), are chronic inflammatory diseases of unknown etiology. They are considered complex genetic diseases because both inherited and environmental influences appear to be important in determining risk. Complex genetic diseases are more common than Mendelian diseases in the population. Prevalence ranges for AIH, IBD and celiac disease are given in Table 1. Generally, accepted average prevalences are 1 in 1,000 persons for Crohn's disease and UC, and 3 in 1,000 for celiac disease. However, the prevalence rate of Crohn's, UC and celiac disease are much lower in some populations (e.g., 1.25 in 100,000 for Crohn's disease in Hong Kong¹). The average prevalence of AIH is 10-fold lower at 1 in 10,000.

Table 1

Epidemiologic and genetic data for IBD, celiac disease and AIH.

Some effort has been devoted to understanding the relative contribution of environmental and genetic factors to disease risk. One method for ascertaining the genetic component of a disease is to compute the risk to siblings divided by the population risk (λs). Mendelian genetic diseases have extremely high λs values (λs = 500 for cystic fibrosis), while diseases with weaker genetic components have lower values (λs = 2 for hypertension). Crohn's disease, UC, and celiac disease have sibling relative risks that are higher than most complex traits (shown in Table 1). The risk to any first-degree family member for Crohn's disease is 10–32 fold higher than in the general population; for UC it is 5–12 fold, and for celiac disease it is 20–53 fold.^2,3 Familial risk has not been reported in AIH, perhaps due to its lower prevalence. Notably, both celiac disease and AIH more commonly affect women (Table 1), suggesting that sex steroids or other female-specific factors may play a role in the etiology of these diseases.

In this chapter, we address the etiology of each disease by first providing a summary of the known environmental influences, and then reviewing the genetic studies aimed at the identification of susceptibility loci. One of the genetic loci we will give attention to is the major histocompatibility complex (MHC). The MHC is home to over 140 genes, including the eight highly variable classical human leukocyte antigen (HLA) loci. HLA genes encode cell surface molecules that present antigenic peptides to T cells, thereby initiating acquired immune response to invading pathogens and other foreign antigens. T cells determine whether antigens are “self ” or “nonself ” based on the specific antigenic peptide sequence as well as the HLA variant that presents the peptide. Given their central role in self/nonself distinction, associations between autoimmune diseases and variation in the classical HLA genes are among the most consistent findings in human genetics.⁴ The relative contribution of the MHC to disease risk for celiac disease, Crohn's disease, and UC can be determined by assessing the sibling risk based on MHC haplotype sharing (MHC λs). The ratio of the MHC λs value to the λs implies the degree to which non-MHC genes are involved in the risk to disease. We see that the non-MHC component is larger for Crohn's disease and UC risk is associated more with the MHC.

Inflammatory Bowel Diseases

Definition, Classification and Symptoms

Inflammatory bowel diseases are characterized by chronic relapsing inflammation of the gastrointestinal tract. Crohn's disease (MIM 266600) and ulcerative colitis (MIM 191390) are the two main subtypes of IBD. Crohn's disease most frequently manifests itself with abdominal pain and diarrhea and is often complicated by intestinal fistulization (an abnormal passage between an injured organ and a healthy organ), intestinal obstruction or both. Tissue damage in Crohn's patients may involve any part of the gastrointestinal tract but is frequently localized to the terminal ileum and/or colon (fig.1); inflammation is transmural and discontinuous and may contain granulomas.²¹ The major symptoms of ulcerative colitis (UC) include diarrhea, rectal bleeding, the passage of mucus and abdominal pain. Inflammation in UC patients is continuous and limited to the rectal and colonic mucosal layers (fig.1); no fistulas and granulomas are observed.²² Approximately 5–10% of IBD cases cannot be unequivocally assigned to Crohn's disease or UC and so are diagnosed with indeterminate colitis (IC). IC is often a temporary classification until a final diagnosis can be made. In two independent prospective studies, 32–50% of IC patients were classified as having either Crohn's disease or UC at follow-up that ranged from 1 month to 26 years after the diagnosis of IC.^23,24

Figure 1

Localization of Crohn's disease and ulcerative colitis in the gastrointestinal tract. Ulcerative colitis tissue damage usually begins at the rectum (arrowhead) and continues proximally in a continuous fashion throughout the colon (indicated in gray). (more...)

Genetics

Linkage Studies

Seven genomewide scans and several targeted scans in families with Crohn's disease and/or UC have identified eight regions potentially conferring susceptibility to IBD (Table 2). The first genomewide search in Crohn's disease reported a potential locus in the pericentromeric region of chromosome 16 (LOD score = 5.79).⁴¹ This locus (IBD1) was also the first replicated through pooling genotype data from over 600 families collected by 11 centers distributed throughout North America, Europe, and Australia.⁴² This supports the hypothesis that common diseases can be explained by genetic risk factors that are common to many populations, but exist at different frequencies.

Table 2

Summary of IBD susceptibility loci.

Potential IBD susceptibility loci identified through genome scans are localized on chromosomes 3p, 7 and 12;⁴³ 5q35, 14q11, and 17q21;⁴⁵ 1, 6, 10, 22, and X;⁴⁶ 14q11;⁴⁷ and 3p, 6p, 5q31, and 19p13.⁴⁸ Some of the reported loci were replicated in follow-up studies, but no one locus was identified in every study.^49-57 This apparent lack of consistency can be explained by the modest effect of most genetic loci in complex human traits and by the modest power and significant effect of sampling variance on linkage results in a single cohort. Nonetheless, a recent meta-analysis of data from nearly 500 Crohn's families and five genomewide scans identified five top-ranking Crohn's loci: IBD1 (16q12), IBD5 (5q31), IBD3 (MHC), IBD2 (12p), and IBD6 (19p13).⁵⁸

While causal variation was identified under the IBD1 and IBD5 linkage peaks (discussed below), the etiological alleles underlying the other loci have yet to be identified. This is likely because many of the remaining linkage peaks have not yet experienced the same level of scrutiny as IBD1 and IBD5. Extensive analysis of the MHC locus on 6p has been performed, but no consistent association with disease has been found, in spite of the fact that the attention given to the MHC is similar to that in other diseases where clear associations have been defined (e.g., multiple sclerosis, systemic lupus, type 1 diabetes).

Association: Non-MHC Genes

CARD15

Parallel studies using positional mapping⁵⁹ and candidate gene analysis⁶⁰ allowed the identification of the underlying genetic variation associated with Crohn's disease at the IBD1 (16q12) locus. Strong association of three variants in CARD15 (previously known as NOD2) is observed in Crohn's patients of European descent.^59,60,69-72 Two of the three variants are missense mutations (Arg702Trp and Gly908Arg) and one is a frameshift mutation resulting in early truncation of the CARD15 protein (Leu1007fsinsC). The genotype relative risk (GRR) for heterozygotes of any of the three variants is ∼2–6 fold, while homozygotes and compound heterozygotes have a GRR of >20 fold.⁷³ These mutations are found at an appreciable frequency in European-derived Crohn's cohorts where between 30–40% of all individuals have at least one copy of one of these three variants compared with 1–7% of control individuals.⁷⁴ Interestingly, these variants are very rare in the Japanese, Chinese and Korean populations, possibly explaining the decreased disease prevalence in these populations.^72,75-78

CARD15 belongs to a large family of genes involved in the innate immune response.⁷⁹ Members of this family are also orthologues of defense genes found in a wealth of species, including plants. Specifically, CARD proteins bear sequence similarity to plant disease resistance proteins (R proteins) that detect pathogens and initiate defense mechanisms, including MAP kinase activation, oxygen radical formation, salicylate production, induced transcription of kinases and transcription factors, and rapid cell death.⁸⁰ One potential function of CARD15 is as a similar interface between pathogens and the human immune system, thus raising the possibility that Crohn's is not autoimmune per se, but rather the result of an abnormal immune response triggered by gut pathogens.

In addition to its expression in peripheral blood monocytes, CARD15 mRNA is found in primary intestinal cells,⁸¹ and specifically detected in terminal ileum Paneth cells.⁸² Overexpression of wild-type CARD15 in intestinal epithelial cells reduces bacterial survival, possibly serving as a key component of the innate mucosal responses to luminal bacteria, while the 3020insC truncation variant fails to exhibit such antibacterial properties.⁸¹ Interestingly, both CARD15 mRNA and protein are up-regulated by TNFα in colonic epithelial cell lines.⁸¹ Further understanding of CARD15 function may help reveal an aspect of the underlying etiology of Crohn's disease and clarify whether this disease is the result of a pathogenic immune reaction to antigens derived from the intestinal microflora.

IBD5

Substantial effort was invested in the identification of causal variation at the IBD5 locus.⁶² This effort represents the first successful mapping of a susceptibility locus for a complex genetic disease based on haplotype analysis. Reiterative mapping with a large number of microsatellite markers allowed the definition of a 500-kb critical region. Thorough mutation screening of the genes in the region revealed no likely causal sequence variants, so a comprehensive sequence analysis of the entire critical region was performed (eight individuals sequenced for 470 kb). In this study, 301 of the 651 single nucleotide polymorphisms (SNPs) discovered were typed in Crohn's simplex families. Analysis of these data led to the discovery of a block-like haplotype structure of the genome that was reviewed in the introduction of this chapter.^17,18 A single risk haplotype (transmission ratio = 2.5:1) was identified with a frequency of 37% in controls and 75% in Crohn's patients. Current simulations show that the disease locus has a 90% probability of being within a 250-kb region where the relative risk to developing Crohn's disease is ∼2.^82a SNPs that are unique to this overtransmitted haplotype have been shown to be associated with disease in four independent studies.^83-86 Once this finding has been confirmed extensively through replication, the challenge is to demonstrate the functionality that is relevant for IBD pathogenesis and is perturbed in individuals bearing the mutated haplotype.

Candidate Genes

Additional association studies have examined gene candidates that were chosen based on their relevant immunological function. A small number of variants in these genes have been examined in multiple studies. For example, positive association was observed for identical variants of the DNA mismatch repair (MLH1) gene by two independent groups.^87,88 Conversely, seemingly significant disease associations have been challenged by subsequent studies, including those with the CD11 gene cluster,^89,90 interleukin 1 receptor antagonist (IL-1RN),^91-104 IL-1B,^92,96,98,103 IL-4R,^90,105,106IL-10,^107,108 immunoglobulin (Ig) G1 heavy chain (Gm),^109,110 vitamin D receptor (VDR),^111,112 and intercellular adhesion molecule-1 (ICAM-1).^113-116

The association with the C3435T polymorphism in the multi-drug resistance-1 (MDR1) gene identifies important caveats for the interpretation of genetic association results, therefore we discuss it in some detail. MDR1 is an interesting candidate gene since MDR1 knockout mice spontaneously develop colitis due to an intestinal epithelial barrier dysfunction¹¹⁷ (Table 3). The C3435T polymorphism was first associated with UC in a German cohort,¹¹⁸ but four independent cohorts of German, English, Greek or North American origin^119-121 could not replicate the finding (the significance of the association seen in a fifth Caucasian cohort depended on the choice of control group¹²²). C3435T is in strong linkage disequilibrium with a second polymorphism (Ala893Ser/Thr),¹²³ which was associated with IBD in a North American cohort.¹²⁰ Therefore, some of the controversy may reflect population differences in haplotype structure at the MDR1 locus. Further studies are necessary to fully delineate the MDR1 haplotype structure and whether any variation at this locus influences risk to IBD.

Table 3

Animal models for IBD.

Preliminary associations to IBD, for which replication has not yet been reported, include NRAMP-1,¹²⁴ IL-4,¹⁰⁶ IL-11,¹²⁵ IL-16,¹²⁶ Factor V (Leiden mutation),¹²⁷ microsomal epoxide hydrolase,¹²⁸ kinin receptor β1,¹²⁹ manose-binding lectin (MBL),¹³⁰ mucin-3,¹³¹ epidermal growth factor receptor (EGFR),¹¹² and NFκB.¹³² Preliminary studies for other genes show no association with IBD risk, including Ig superfamily 6,¹³³ prothrombin G20210A,¹³⁴ IL-12β,¹³⁵ IL-25,¹³⁶ interferon-γ,¹³⁷ chemokine receptor 5,^103,138 NRAMP-2,⁹⁶ β7integrin,¹³⁹ CTLA-4,¹⁴⁰ CARD4/NOD1,¹⁴¹ and STAT6.⁹⁰ However, only after the existing variation has been thoroughly sampled should a gene be confidently excluded as a susceptibility candidate.

Genotype–Phenotype and Genotype–Genotype Interactions

The identification of causal variation is by no means the end of the genetic investigation. Subsequent studies are necessary to determine whether specific variants preferentially influence discrete disease subphenotypes. In the case of IBD, CARD15 variants are associated with ileal disease localization,^{42,69,71,73,74,142-145} fibrostenosis,^146,147 and fistulization.¹⁴⁷ In addition, CARD15 variation may explain the opposite effects of smoking—which promotes Crohn's disease but prevents UC^29,30 —since the risk for ileal disease was found to be increased in Crohn's disease patients with a smoking history.¹⁴⁴

Moreover, as complex genetic diseases are thought to be the synthesis of positively and negatively acting variation, one must determine whether a causal variant influences disease independently or synergistically. For example, once identified, IBD5 and CARD15 variation could be assessed for interaction. In multiple studies, these variants seem to independently influence risk for Crohn's disease.^83-86 Linkage analyses stratified on genotype have provided additional insight into genotype–genotype interactions. CARD15-stratified genomewide scans identified suggestive linkage at 6p and 10p,⁵⁶ implicating specific interaction between these loci. Similarly, stratification by CARD15 and IBD5 variation together demonstrated linkage to chromosomes 3 and X.⁵⁷ However, much more analysis is needed to fully understand the relationship between these two variants and disease.

Celiac Disease

Definition, Classification and Symptoms

Celiac disease (also known as celiac sprue or gluten-sensitive enteropathy; MIM 212750) is a chronic gastrointestinal disease in which exposure to proteins from wheat, rye, barley and possibly oats leads to villous atrophy in the small intestine and consequent nutrient malabsorption. In wheat, such proteins are collectively known as gliadins and constitute the toxic component of gluten. Symptoms include diarrhea, general weakness, anemia and weight loss. The disease affects the mucosa of the proximal small intestine with damage gradually decreasing in severity distally (fig.2). However, in severe cases, the lesions extend to the ileum. Diagnosis of the disease is ultimately confirmed by small intestinal biopsy showing a flat mucosa that is reversed on a gluten-free diet.¹⁹⁵

Figure 2

Localization of celiac disease in the gastrointestinal tract. Tissue damage in celiac disease affects the mucosa of the proximal small intestine with damage gradually decreasing in severity distally (indicated by decreasing grayscale). In severe cases, (more...)

Genetics

Linkage Studies

Genomewide searches for genetic risk factors have identified numerous putative loci (Table 4). Confirmed linkage of the MHC region (CELIAC 1) in celiac disease exists).^10,208-214 In addition, significant linkage was shown for four non-MHC regions: 5q31-33 (CELIAC 2),²¹³ 2q23-33 (CELIAC 3),²¹⁴ 19p13 (CELIAC 4),¹⁰ and 15q12.²¹⁵ These findings need to be confirmed by replication in independent data sets. Unlike for IBD, no genes have been identified for linkage studies for celiac disease.

Table 4

Summary of celiac disease genetic linkage studies.

Association: MHC Genes

Consistent with their ability to present epitopes from deamidated gluten molecules, susceptibility to celiac disease is associated primarily with HLA-DQ2 and HLA-DQ8.²²⁸ Association has also been reported with various DR serotypes, including DR3, DR5, and DR7,^229-233 as well as variation in tumor necrosis factor-α (TNFα),^234-238 heat-shock protein 70 (HSP70-1 and HSP70-2),^239,240 inhibitor of kB-like (IKBL),²⁴¹ and the MHC class I chain-related (MICA) genes.^242,243 However, recent studies suggest that these variants are simply in linkage disequilibrium with the causal variation.²⁴⁴

Association: Non-MHC Genes

The power of a study to definitively exclude a locus of a particular strength of effect depends on two things: sample size and marker coverage. Thus, negative association studies must be interpreted cautiously since it is difficult to exclude a locus absolutely. For celiac disease, a number of genes have been reported as unassociated at various levels of statistical significance: T-cell receptors genes TCRα, TCR β, TCRγ,TCRδ,²⁴⁵ nitride oxide synthase (NOS),²⁴⁶ matrix metalloproteinase genes MMP-1 and MMP-3,²⁴⁷ IL-12B,^248,249 interferon regulatory factor 1 (IRF1),²⁴⁹ insulin (INS),²⁵⁰ and tissue transglutaminase (TGM2).^251,252 However, positive evidence for association has been observed for genes encoding Ig Gm allotypes,²⁵³ cytotoxic T-lymphocyte associated antigen 4 (CTLA-4; D2S2216,²²⁰ D2S2214,²²⁶ CT-60,²⁵⁴ and +49^*A/G see below), MBL2,²⁵⁷ inducible costimulator (ICOS),²⁵⁵ and for microsatellite markers at locus 19p13.¹⁰ Only the +49^*A/G dimorphism of CTLA-4 has been examined in numerous studies. Therefore we will restrict our discussion to this variant.

The evidence for association with +49^*A is not consistent across studies,^{220-222,226,227,256- 260} but a meta-analysis shows modest association for CTLA-4+49^*A in celiac disease.²¹⁴ Importantly, variation contained in the CTLA-4 gene has been reported to confer susceptibility to many autoimmune genetic diseases, including insulin-dependent diabetes mellitus (IDDM), Grave's disease, and Hashimoto's hypothyroidism.²⁶¹ However, a recent positional mapping association study of 109 polymorphisms in the 330-kb region surrounding the CTLA-4 gene strongly suggests that a yet unidentified common variant in the 6.1-kb region 3' of CTLA-4 is responsible for the association with IDDM, Grave's and autoimmune hypothyrodism.²⁶² Moreover, these data firmly rejected +49A/G as IDDM's causal SNP,²⁶² a result which raises the possibility that +49^*A is simply linked to the causal variant in celiac disease as well.

Autoimmune Hepatitis

Definition, Classification and Symptoms

Autoimmune hepatitis (AIH) is a chronic inflammation of the liver (fig.3) for which early symptoms are fatigue, jaundice and anorexia.²⁶⁵ AIH accounts for 10–20% of chronic hepatitis cases in North America, but less than 4% of patients in India.^266,267 AIH is diagnosed based on criteria defined by the International Autoimmune Hepatitis Group.²⁶⁸ A scoring system for these criteria allows the classification of cases as definite AIH or probable AIH. These criteria include the absence of infection with hepatitis viruses (i.e., exclusion of viral nucleic acids, antigens and antibodies), the presence of circulating autoantibodies (see below), hypergammaglobulinemia, and being of the female sex.

Figure 3

Localization of autoimmune hepatitis. Inflammation in autoimmune hepatitis is observed throughout the liver (gray). Compared to primary biliary cirrhosis and primary sclerosing cholangitis, which affect the bile ducts, autoimmune hepatitis affects hepatocytes. (more...)

Genetics

Linkage Studies

Given the limited number of families with multiple members affected with AIH, no whole-genome linkage scans have been performed to date, and all genetic studies for AIH are based on case–control association analysis of candidate genes with known immunoregulatory functions.

Association: MHC Locus

Larger cohorts and more complete analysis of the variation at the MHC locus will be required to precisely identify the genetic variation that influences risk for AIH. However, some studies provide preliminary insight into the search for susceptibility loci.

MHC variants that have been associated with risk to AIH-1 include HLA-DR3, HLA-DR4, and DRB1^*1301.^275,276 Interestingly, the particular DR4 suballeles associated with AIH-1 appear to differ in different populations, suggesting that risk is associated with the larger DR4 superclass and not a particular allele. Genetic studies in AIH-2 are limited by its rarity and regional occurrence. However, the DRB1^*07, DRB1^*15, DQB1^*06, and DRB1^*03 alleles have been shown to be associated with risk for disease.275

Association: Non-MHC Loci

Among the potential non-MHC susceptibility factors (Table 5) are the CTLA-4 +49G allele,^277,278 the VDR Fok polymorphism,²⁷⁹ and the CD45 tyrosine phosphatase +77C/G mutation.²⁸⁰ In addition, genetic variants for the heavy chain constant regions of both TCRβ²⁸¹ and IgG1²⁸² were reportedly associated with AIH. Interestingly, the association with TCRβ was strongest in patients without HLA-DR3 and DR4, and is significantly decreased in early onset cases.²⁸¹ These associations remain to be confirmed in larger samples. Other studies of candidate genes, such as IL-1B, IL-1RN, and IL-10,^283,284 and the autoimmune regulator AIRE,²⁸⁵ failed to identify an association with disease susceptibility. Caveats for the apparent lack of association in negative studies might be the limited number of samples available for study and the heterogeneity of the sample population (e.g., in the AIRE study of 85 AIH cases, 14% of individuals were seropositive for AIH-2, while the remaining 86% were diagnosed as AIH-1).

Table 5

AIH non-MHC association studies.

Conclusions

Acknowledgments

We thank Cisca Wijmenga, Leslie Gaffney, Philip De Jager, Lisa Farwell and Tracey Petryshen for critical reading of this manuscript. ECW is supported by a Cancer Research Institute Fellowship. This work was supported by NIH-R01#DK64869 (JDR).

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