| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 6q23.3 | {H. pylori infection, susceptibility to} | 600263 | 3 | IFNGR1 | 107470 |
A number sign (#) is used with this entry because a polymorphism in the interferon-gamma receptor-1 gene (IFNGR1; 107470) is associated with Helicobacter pylori infection. In addition, variation in the Lewis(b) blood group antigen (see 111100), an epithelial receptor for H. pylori, may be related to variation in susceptibility to H. pylori infection.
Helicobacter pylori is a microaerophilic, gram-negative bacterium that colonizes the gastric mucosa of approximately 50% of the world's population, and is a primary pathogenic factor in benign and malignant gastroduodenal disease (Warren and Marshall, 1983; Blaser and Parsonnet, 1994). Tomb et al. (1997) reported the complete sequence of the circular genome of H. pylori. The 1,667,867-bp genome contains 1,590 predicted coding sequences (genes). Sequence analysis of these genes indicated that the organism has systems for motility, for scavenging iron, and for DNA restriction and modification. Its survival in acid conditions depends, in part, on its ability to establish a positive inside-membrane potential in low pH.
Malaty et al. (1994) determined the H. pylori status in monozygotic and dizygotic twins from the Swedish Twin Registry: 36 MZ twin pairs reared apart, 64 MZ twin pairs reared together, 88 DZ twin pairs reared apart, and 81 DZ twin pairs reared together. The H. pylori status was determined by testing for anti-H. pylori IgG. The concordance rate for infection was higher in monozygotic twin pairs (81%) than in dizygotic twin pairs (63%). For 124 pairs of twins reared apart, the concordance rates were 82% and 66% for MZ and DZ twins, respectively. The correlation coefficient was 0.66 for monozygotic twins reared apart. Malaty et al. (1994) concluded that genetic effects influence the acquisition of H. pylori infection but that sharing the same rearing environment also contributes to the familial tendency.
Mendall and Northfield (1995) stated that most studies of H. pylori transmission have shown an increased rate of infection in the families of seropositive children, but there have been no controlled studies for variation in socioeconomic circumstances of the families. Hence, the findings may merely represent greater environmental exposure of the index positive children. In a large study involving 277 couples in a fertility clinic, Perez-Perez et al. (1991) found no increased rate of infection among the spouses of seropositive index cases. Mendall and Northfield (1995) noted that the study by Perez-Perez et al. (1991) was the only such study with sufficient power to detect modest effects and the only one to control for socioeconomic circumstances. Mendall and Northfield (1995) stated that it is unlikely that H. pylori could multiply in the environment, suggesting that humans were probably the only source of H. pylori infection.
Because H. pylori is rarely found in deeper portions of the gastric mucosa, where O-glycans are expressed that have terminal alpha-1,4-linked N-acetylglucosamine, Kawakubo et al. (2004) tested whether these O-glycans might affect H. pylori growth. Kawakubo et al. (2004) reported that these O-glycans have antimicrobial activity against H. pylori, inhibiting its biosynthesis of cholesteryl-alpha-D-glucopyranoside, a major cell wall component. Thus, the unique O-glycans in gastric mucin appeared to function as a natural antibiotic, protecting the host from H. pylori infection.
Peek and Blaser (2002) reviewed the relationship between H. pylori and gastrointestinal tract adenocarcinomas. Although gastric adenocarcinoma is associated with the presence of H. pylori in the stomach, only a small fraction of colonized individuals develop this common malignancy. The authors suggested that H. pylori strain and host genotypes probably influence the risk of carcinogenesis by differentially affecting host inflammatory responses and epithelial cell physiology.
Kwok et al. (2007) found that the H. pylori adhesin protein CagL was targeted to the bacterial type IV secretion pilus surface, where it bound and activated the ITGA5 (135620)/ITGB1 (135630) receptor on gastric epithelial cells through its arg-gly-asp motif. CagL interaction with the integrin receptor triggered delivery of the H. pylori oncoprotein CagA into target cells and activation of FAK (PTK2; 600758) and SRC (190090) tyrosine kinases. Kwok et al. (2007) suggested that CagL may be used as a molecular tool to better understand integrin signaling and the mechanism by which H. pylori causes gastric ulcer and cancer.
Thye et al. (2003) performed a genomewide linkage analysis among Senegalese sibs phenotyped for H. pylori-reactive serum immunoglobulin G. A multipoint lod score of 3.1 was obtained at IFNGR1. Sequencing of IFNGR1 revealed 3 variants which were found to be associated with high antibody concentrations, including a -56C-T transition (107470.0012). The inclusion of these in the linkage analysis raised the lod score to 4.2. The variants were more prevalent in Africans than in whites. The findings indicated that interferon-gamma signaling plays an essential role in human H. pylori infection and contributed to an explanation of the observations of high prevalences and relatively low pathogenicity of H. pylori in Africa.
Peek (2003) considered it possible that genetic variation in the protein-tyrosine phosphatase receptor type-zeta gene (PTPRZ; 176891) may account for some of the heterogeneity in disease presentation among H. pylori-colonized patients. Peek (2003) noted that such is the case with other immune response genes, such as interleukin 1-beta (IL1B; 147720), in which high-expression alleles increase the risk of distal gastric cancer, but only among persons infected with H. pylori.
The Lewis(b) antigen, Le(b) (see 111100), is an epithelial receptor for H. pylori (Boren et al., 1993). The H. pylori adhesin that binds Lewis(b) is BabA, which is encoded by babA2, a strain-specific gene (Peek, 2003). H. pylori strains that are isolated from patients with gastric cancer more commonly possess this gene than do strains isolated from patients with gastritis alone.
The Lewis(b) antigen is encoded by the FUT3 gene, which has polymorphisms affecting both the transmembrane and catalytic domains, some of which affect the activity of the Lewis enzyme. Serpa et al. (2003) studied FUT3 gene polymorphisms in a Caucasian Portuguese population with a high rate of H. pylori infection and evaluated the implications of mutant enzymes in Le(b) expression in the gastric mucosa. No relationship was observed between the FUT3 polymorphisms and the presence of H. pylori infections, although such had been suggested by the study of Ikehara et al. (2001). The results suggested that, at least in a population with a high rate of H. pylori infection, the FUT3 polymorphisms do not affect the presence or absence of infection.
Associations Pending Confirmation
Tanikawa et al. (2012) performed a genomewide association analysis in a total of 7,035 individuals with duodenal ulcer and 25,323 controls from Japan, and identified 2 susceptibility loci, one at the PSCA gene (602470) at 8q24 and another at the ABO blood group locus (110300) at 9q34. The C allele of rs2294008 at PSCA was associated with an increased risk of duodenal ulcer (odds ratio = 1.84; p = 3.92 x 10(-33)) in a recessive model but was associated with decreased risk of gastric cancer (odds ratio = 0.79; p = 6.79 x 10(-12)), as reported by Sakamoto et al. (2008). The T allele of rs2294008 encodes a translation initiation codon upstream of the reported site and changes protein localization from the cytoplasm to the cell surface. Tanikawa et al. (2012) noted that their data indicated that these SNPs are likely to be associated with duodenal ulcer development after H. pylori infection and not with susceptibility to persistent H. pylori infection per se.
Wirth et al. (2004) showed that DNA sequences from H. pylori can distinguish between closely related human populations and are superior in this respect to classic human genetic markers. H. pylori from Buddhists and Muslims, the 2 major ethnic communities in the Ladakh region of India, differed in their population-genetic structure. Moreover, the prokaryotic diversity was found to be consistent with the Buddhists having arisen from an introgression of Tibetan speakers into an ancient Ladakhi population. H. pylori from Muslims contained a much stronger ancestral Ladakhi component, except for several isolates with an Indo-European signature, probably reflecting genetic flux from the Near East. These signatures in H. pylori sequences were congruent with the recent history of population movements in Ladakh, whereas similar signatures in human microsatellites or mtDNA were only marginally significant.
The vacuolating cytotoxin VacA produced by H. pylori causes massive cellular vacuolation in vitro (Cover and Blaser, 1992) and gastric damage in vivo, leading to gastric ulcers, when administered intragastrically (Telford et al., 1994). Fujikawa et al. (2003) found that mice deficient in Ptprz do not show mucosal damage by VacA, although VacA is incorporated into the gastric epithelial cells to the same extent as in wildtype mice. Primary cultures of gastric epithelial cells from Ptprz +/+ and Ptprz -/- mice also showed similar incorporation of VacA, cellular vacuolation, and reduction in cellular proliferation, but only Ptprz +/+ cells showed marked detachment from a reconstituted basement membrane 24 hours after treatment with VacA. VacA bound to PTPRZ, and the levels of tyrosine phosphorylation of the G protein-coupled receptor kinase-interactor-1 (GIT1; 608434), a PTPRZ substrate, were higher after treatment with VacA, indicating that VacA behaves as a ligand for PTPRZ. Furthermore, pleiotrophin (PTN; 162095), an endogenous ligand of PTPRZ, also induced gastritis specifically in Ptprz +/+ mice when administered orally. Taken together, these data indicated that erroneous PTPRZ signaling induces gastric ulcers.
Falk et al. (1995) created transgenic mice with the human Le gene and showed that H. pylori attached to gastric epithelial cells in the transgenic mice but not in their normal littermates. This implies that Le/Le individuals may have an advantage in avoiding H. pylori infection.
In a study of Helicobacter infection and the immune response regulation of acid secretion, Zavros et al. (2003) demonstrated that treatment with the Th1 cytokine Ifng (147570) induced gastritis, increased gastrin (137250), and decreased somatostatin (182450) in mice, recapitulating changes seen with Helicobacter infection. In contrast, the Th2 cytokine Il4 (147780) increased somatostatin levels and suppressed gastrin expression and secretion. Il4 pretreatment prevented gastritis in infected wildtype but not in somatostatin-null mice; treatment of mice chronically infected with H. felis with a somatostatin analog resolved the inflammation. Zavros et al. (2003) concluded that IL4 resolves inflammation in the stomach by stimulating the release of somatostatin from gastric D cells.
By microarray and immunohistochemical analyses, Mueller et al. (2003) found strikingly different transcriptional profiles in stomachs of mice immunized with H. felis in conjunction with cholera toxin compared with nonprotected or control mice. Among the genes upregulated in protected mice were adipocyte-specific factors, such as adipsin (134350), resistin (RETN; 605565), and adiponectin (605441), as well as the adipocyte surface marker CD36 (173510). Potentially protective T and B lymphocytes could be found within adipose tissue surrounding protected stomachs, but never in control or unprotected stomachs, and adipsin-specific immunohistochemical staining revealed molecular cross-talk between adjacent lymphoid and adipose cell populations.
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