Problems in the genetics of peptic ulcer. II. An analysis of the associations of the disease with certain simply heritable traits]

The research of distribution of blood group ABO, Rhesus, Lewis, Secretor, C5+-component of choline esterase and the ability to taste PTC among Moscow population patients suffering from duodenal ulcer is carried out in comparison with the control. Statistically authentic association of the disease with 0(I) blood group, unsecretor and the association of joint signs (coefficients of association are 1.32, 2.17 and 2.62 respectively) is found. Authenticity of relation with disease is not proved during the investigation of other signs. The values of risk to fall ill for the patients possessing and not possessing the signs of duodenal ulcer are obtained (concerning separate factors and joint factors). It is established that the combination of 0(I) blood group and unsecretor increases the risk of the diseases in 2.4 times as compared with the patients possessing A, B, AB blood groups and secretors.     

Risks of manifestation of Huntington chorea.

A methodology allowing the estimate of risks heterozygosity and manifestation of Huntington's chorea (HC) within preestablished periods for individuals of any age was developed. For this, the procedure was the following: 1. The variables which could influence the distribution of age frequencies were studied. 2. The error due to the exclusion of the heterozygotes dying before the manifestation of the disease from the distribution of Wendt et al. (1959) of affected persons was corrected separately for each sex. 3. The frequency of non-affected heterozygotes in each age group was calculated separately for each sex, from the corrected distribution. From those data estimates of the following parameters could be reached: a) the probability of heterozygosity for consultants of any age; b) the risks of manifestation for the gene in a given individual within a determined period, taking into account his probability of heterozygosity and survival. 4. The risks of manifestation were tabulated for making easier their use in concrete cases. Simplified tables with approximate risks are also presented for the more common cases in genetic counseling. 5. The methodology presented allows a discrimination between the probability of heterozygostiy and the risk of manifestation. This makes possible the estimate of risks of becoming affected, taking into account not only the age of the consultant at the moment, but also the period of time starting with the consultation, to which the risk applies. This is essential for adequate genetic counseling.     

A study of some immunological and clinical characteristics of gastritis, gastric ulcer, and duodenal ulcer in three racial groups of the Venezuelan population

Circulating gastric-mucosa antibodies were found more frequently among patients with different forms of chronic gastritis than among a miscellaneous control group and groups that presented prepyloric ulcer or duodenal ulcer. A higher incidence of circulating antibodies and of chronic gastritis lesions among Caucasians and “Mestizos” than among Negroes was also observed. The latter showed a higher tendency to duodenal ulcer and prepyloric ulcer. The high incidence of gastritis and gastric ulcer of the Chinese and the Mestizos support the ethnic relation between these two human groups. Our study favors the hypothesis that genetic and ethnic factors influence, on the one hand, chronic gastritis and gastric ulcer and, on the other hand, duodenal and prepyloric ulcers.     

Stasis Gastric Ulcer: A Complication of Duodenal Ulcer

A causal relation between gastric stasis and gastric ulceration is suggested by the literature reviewed. In obstructive duodenal ulcer disease it is important to know that a concomitant gastric ulcer may be present and causing the symptoms. In combined ulcers, symptoms are more severe and treatment is more difficult.A clinical study of 60 cases of stasis gastric ulcer associated with chronic duodenal ulcer disease is presented. Twenty-six of these patients with gastric ulcers were bleeding at the time of their admission. The mortality rate was at least twice that for solitary ulcer. Early warning symptoms of stasis were fatigue, anorexia, fullness and weight loss; vomiting was a late manifestation. X-ray findings were often inaccurate; evidence of retention was reported in only 21. Gastric residue measurements were particularly useful in showing gastric retention.Since the basic disease in combined ulcers is the duodenal lesion, surgical treatment is primarily that for duodenal ulcer.     

Relationship of gastric metaplasia and age, sex, smoking and Helicobacter pylori infection in patients with duodenal ulcer and duodenitis

Gastric metaplasia is one of the factors in duodenal ulcer appearance. The aim of this study was to investigate the frequency of gastric metaplasia and its connection with age, sex, cigarette smoking and H. pylori infection. In the study 216 patients were included. There were 98 patients with duodenal ulcer, 60 with duodenitis, and 58 healthy control subjects. There was no statistically significant difference in gastric metaplasia frequency according to age and sex. Gastric metaplasia was statistically more significant in patients with duodenal ulcer (p < 0.01). In all the subjects cigarette smoking did not significantly influence gastric metaplasia. In smokers with duodenal ulcer, and those who besides duodenal ulcer and smoking had H. pylori infection gastric metaplasia was more frequent (p < 0.01). However, in patients with duodenal ulcer, there was no statistically significant difference of gastric metaplasia related to H. pylori presence. It may be suggested that H. pylori infection is not of indispensable significance for gastric metaplasia appearance.     

Endogenous zinc concentrations in cysteamine-induced duodenal ulcers in the rat

Exogenously administered zinc compounds have been shown to possess anti-ulcer activity against a wide variety of ulcerogenic agents, both in laboratory animal models and in human peptic ulcer disease. However, a strong possibility exists that endogenous zinc may also play an important role during noxious events by various mechanisms. Therefore, the aim of this study was to focus on the changes of endogenous zinc serum and tissue concentrations in cysteamine-induced duodenal lesions. We used atomic absorption spectropho-tometry to determine the tissue and serum concentrations of zinc in normal (control) rats and those with cysteamine-induced duodenal ulcers. The results obtained in this study indicated that the onset, development and spontaneous healing of ulcer lesions were associated with certain shifts in zinc serum and tissue concentrations. Prior to ulcer formation, a significant increase was noted in serum zinc values. With the onset of duodenal lesions, zinc serum concentrations significantly decreased, while there was a significant increase in duodenal tissue concentrations when compared to healthy control animals. Zinc tissue concentrations decreased and returned to starting values by the end of the first week of spontaneous healing. This decrease in zinc tissue concentration corresponded to the healing rate of the duodenal ulcers. Serum zinc concentrations also returned to starting values within the first week period. These observations indicate and confirm that zinc could play an important role in duodenal ulcer disease and represent a natural defense system in the body.     

The effect of in vitro theophylline on T lymphocytes from patients with ulcers

An increase in the interest in the cellular immunity in patients with peptic and duodenal ulcers dates back to the detection of histamine H2 receptors on T-cells. In vitro effect of theophylline on T-cells in patients with peptic and duodenal ulcers was investigated. The experiment included 107 patients: 60 with peptic and duodenal ulcers and 47 controls. The experiment was carried out with theophylline test enabling to divide the whole population of T-cells forming active and "late" rosettes (ARCF and TRCF, respectively) into three subpopulations: theophylline-resistant, theophylline-sensitive, and theophylline-dependent T-cells. Increased number of theophylline-dependent T-cells and significantly reduced baseline value of rosette-forming T-cells (p greater than .02) were found in patients with duodenal ulcer. Theophylline-dependent lymphocyte number was the highest in TREC rosette fraction in patients with duodenal ulcer. Statistically significant (p greater than .01; p greater than .05) and independent of patients' age tendency to an increase in the number of theophylline-sensitive T-cells in TRFC rosettes was seen in both peptic and duodenal ulcers. Theophylline-resistant lymphocytes ratio to theophylline-sensitive ones in TRFC rosettes was also significantly lower in patients with peptic ulcer. No correlation between these results and patients age was found in both the control group and patients with the ulcerative disease. An increase in theophylline-dependent T-cells in patients with duodenal ulcer suggests an increase in the number of immature forms of T-cells and indicate an important role of T-cells maturation disorders in the pathogenesis of duodenal ulcer.     

Genetic relationship among isolates of Helicobacter pylori: evidence for the existence of a Helicobacter pylori species-complex

We investigated the population genetics of 23 isolates of H. pylori by allozyme electrophoresis using 16 enzyme loci. Isolates were obtained from adult patients of whom 48% were of Greek extraction. Eight patients (35%) had an active duodenal ulcer. Allelic variation per loci ranged from 2 to 11 alleles. Four major genetic clusters were apparent, having >75% fixed genetic differences. There was no distinct clustering (clonal structure) on the basis of the geographical origin of the persons from whom isolates were obtained, indicating that this bacterium has not recently jumped a species barrier into humans. Isolates associated with ulcer disease were not monophyletic, with isolates from ulcer patients being found in phylogenetically diverse branches of the dendogram derived from the data. Based on the genetic diversity of H. pylori isolates, we propose that isolates should be classified as belonging not to a single species but to a `Helicobacter pylori species-complex'.     

Analysis of genetic heterogeneity of bronchial asthma in relation with the age at the onset of disease

Earlier, the distribution of bronchial asthma (BA) morbidity with respect to the age of onset (AO) in the Moscow population was found to be bimodal. The distribution had two peaks (before and after 25 years of age) and a significant (P < 0.001) minimum between them. Based on these data, genetic heterogeneity of BA with respect to AO was hypothesized. The purpose of this study was to test this hypothesis via analysis of BA morbidity in families of probands with different AOs. The BA morbidity at different ages and the total recurrent risk of BA were estimated in 1518 relatives of 815 BA probands registered in several district outpatient clinics of Moscow. Based on the data obtained, phenotypic between relatives and correlation by genotype between early-onset and late-onset BA cases (with AOs under and over 25 years, respectively) were estimated. It was demonstrated for the first time that the age distribution of BA morbidity in families of probands was also bimodal. Moreover, when probands with early and late AOs were analyzed separately, proband relatives in each of the two groups exhibited these two peaks of morbidity. This suggests that BA that begins in adolescence and BA of adults are not genetically independent forms of the disease. This agrees with the data on the correlation by genotype between the "forms" with the early and late AOs, which does not significantly differ from 1. However, the prevalence of BA was higher in relatives of those probands who developed BA under the age of 25 compared to relatives of those who developed BA over the age of 25 (11.28 and 7.31%, respectively; P < 0.05). Therefore, patients with early-onset BA are more "burdened" genetically with respect to this disease. Since the BA genetic heterogeneity connected with AO has not been confirmed in this study, it is assumed that the observed bimodal distribution of BA morbidity with respect to age is accounted for by the effect of age itself. In other words, it is hypothesized that ontogenetic factors affect susceptibility to BA so that the susceptibility threshold varies with age.     

Genetic and evolutionary implications in peptic ulcer disease

The evidence for a genetic component in peptic ulcer disease has been based on twin, family, and blood group studies. A polygenic model for the inheritance of peptic ulcers has been displaced by a genetic heterogeneity model based on several lines of evidence, some of the most powerful being recent work using subclinical markers. One marker in particular, an elevated level of serum pepsinogen I (PG I), a pepsin precursor produced by the gastric mucosa, secreted into the stomach lumen and also appearing in the bloodstream, has been found to be associated with a subgroup of duodenal ulcer patients. Segregation analysis of elevated serum PG I in duodenal ulcer sibships demonstrates familial aggregation consistent with autosomal dominant inheritance. Elevated PG I is also accompanied by gastric hyperacidity and presumably indicates those individuals with an increased mass of chief and parietal cells, and thus an increased capacity for peptic activity, an important element in the pathogenesis of ulcer disease. An evolutionary hypothesis based on selection for peptic activity and acidity is offered to explain several of the epidemiologic and genetic elements of this group of chronic diseases.     

Evaluating pedigree data. I. The estimation of pedigree error in the presence of marker mistyping

Pedigrees used in the analysis of genetic or medical data are usually ascertained from sources subject to a variety of errors including misidentification of individuals, faults in historical documents or record linkage, nonpaternity, and unidentified adoption. Genetic markers can be used to verify putative family and pedigree data through the search for inconsistencies, or genetic exclusions, between putative parents and offspring. The probability of observing an exclusion given the occurrence of an error depends upon the gene frequencies at the loci under study and the forms of error. In addition, inconsistencies can arise from laboratory errors in marker determination. Together, these problems make the proper statistical analysis of such data desirable. Here we give a model that specifies the combined effects of various kinds of pedigree error along with genetic marker error. This model allows the maximum-likelihood estimation of the rates of various forms of pedigree error and laboratory error from genetic marker data collected on putative families. The method is illustrated by applying it to data obtained from a South Pacific island population, Tokelau. From the observed distribution of genetic marker inconsistencies between the parents and offspring of putative families, derived from the extensive genealogy of this population, we are able to estimate that the error of a paternal link is 4%, the error of a maternal link is zero, and the overall system typing error is 1%.     

Genetic polymorphism of interleukin-8 (IL-8) is associated with Helicobacter pylori-induced duodenal ulcer

BACKGROUND AND AIMS: Helicobacter pylori infection almost invariably causes chronic gastritis, but only a proportion of the infected subjects develop peptic ulcers. The local inflammation associated with H. pylori infection is characterized by an increased production of the proinflammatory cytokines IL-1-B, IL-6, IL-8 and TNF-alpha. Since such cytokine production is often determined by the genetic polymorphism of regions regulating cytokine gene expression, we investigated the relationship between TNF-alpha and IL-8 polymorphisms and the development of duodenal ulcer disease. We also sought a correlation between the promoter polymorphism of the lipopolysaccharide (LPS) receptor CD14 and the formation of peptic ulcer, because CD14 plays a crucial role in the initiation of the cytokine cascade. METHODS: Genomic DNA extracted from the peripheral blood of 69 patients with H. pylori-positive duodenal ulcer disease and 47 H. pylori-positive healthy controls was analyzed for TNF-alpha -308 promoter polymorphism by RFLP, and for IL-8 -251 polymorphism by ARMS. Genetic polymorphism within the promoter of the CD14 gene was identified using the LightCycler instrument via melting point analysis. RESULTS: No significant correlation could be revealed between the TNF-alpha and CD14 promoter polymorphisms and the clinical outcome of H. pylori infection. The IL-8 A/T heterozygote mutant variant was detected with a significantly higher frequency (65.22%) among the ulcer patients than among the healthy, H. pylori-positive blood donors (36.17%), while the frequency of the normal allelic genotype (TT) was significantly higher in the control group (44.6% vs 15.9%). CONCLUSION: Analysis of the genetic predisposition to enhanced cytokine production revealed a significant association only for the IL-8 polymorphism. This observation draws attention to the possible importance of IL-8 polymorphism as a genetic predisposing factor in the pathomechanism of H. pylori-induced duodenal ulcer disease, and to the relative protection from duodenal ulcer disease that is associated with the TT genotype.     

New models of inheritance of complex characteristics and their use in segregation analysis of idiopathic scoliosis]

New methods of segregation analysis of alternative traits have been developed. These methods make it possible to take into account the sex and age specificity of the disease manifestation. Hence, they extend the range of genetic hypotheses to be tested and ensure the correct analysis of inheritance of complex pathologies in humans. Segregation analysis of idiopathic scoliosis performed in this study demonstrates the possibilities of the new methods. Based on pedigrees of 93 probands, it has been demonstrated for the first time that the inheritance of severe (degrees II to IV) forms of this disease can be described by a model that assumes a dominant major gene with incomplete, sex- and age-dependent penetrances of all genotypes. According to this model, severe forms of idiopathic scoliosis do not develop if the mutant allele is absent (the penetrance of genotype A1A1 is zero). The probabilities of the disease for subjects with genotypes A1A2 and A2A2 are similar and approximately equal to 0.3 and 0.5 for males and females, respectively. Mild (degree I) forms of idiopathic scoliosis are heterogeneous. A progressive disease may be expected only in the patients that carry the mutant allele.     

Incidence of peptic ulcer disease in Gothenburg, 1985.

OBJECTIVE--To determine the incidence and age distribution of peptic ulcer disease in adults in Gothenburg. DESIGN--Retrospective study of patients with symptoms over one year. SETTING--All gastroenterology and x ray departments. PATIENTS--Any patient found to have an active ulcer crater during 1985. MAIN OUTCOME MEASURES--Sex, age, past history of gastrointestinal ulcers, and smoking habit. RESULTS--In 1985, 1402 peptic ulcers were diagnosed in 1137 adults. Over half (403; 54%) of the ulcers in men and 393 (60%) ulcers in women were in patients aged over 60. All types of ulcer showed increasing incidence with age. The sex ratio of patients aged 40-50 with peptic ulcers was 1:1. Nearly half (109; 48%) of ulcers diagnosed for the first time in men and 129 (57%) of such ulcers in women were in patients aged over 60. Elderly men and women were also more likely to develop haemorrhage. CONCLUSIONS--In Gothenburg there is a surprisingly high incidence of peptic ulcer disease, which increases considerably with age, possibly explained by the availability of modern diagnostic techniques as 1121 (80%) ulcers had been diagnosed by gastroscopy. Compared with earlier studies there was no difference in the incidence between men and women aged 40-50.     

Combined segregation and linkage analysis of genetic hemochromatosis using affection status, serum iron, and HLA.

Characterizing the distribution of parameters of iron metabolism by hemochromatosis genotype remains an important goal vis-à-vis potential screening strategies to identify individuals at genetic risk, since a specific marker to detect the abnormal gene has not been identified as yet. In the present investigation, we analyze serum iron values in ascertained families using a method which incorporates both segregation of the clinical affection status and the HLA linkage information to identify the underlying genotypes. The analysis is performed using an extension of the model presented by Bonney et al., comprising regressive models for segregation analysis and the multipoint linkage strategy implemented in LINKAGE. The gene was found to be completely recessive with respect to both clinical manifestations and serum iron abnormalities, with significant differences in expression by sex. Clinical manifestations were present for all male homozygotes in this data set, suggesting that the recessive hemochromatosis genotype is fully penetrant at all ages in males. This was not the case for younger females. Significant genotype-specific age and sex effects were found for serum iron values. It is interesting that deletion of the HLA marker information did not affect our ability to resolve the genetic model when we analyzed a bivariate phenotype. This serves as a reminder that a search for relevant biological markers can be equally important in discerning the genetic etiology of a disease trait, as a search for linked genetic markers.     

X-ray diagnosis of peptic ulcers of the jejunum

The paper is devoted to a study of the results of clinicoroentgenological and endoscopic investigation of 188 patients aged 23 to 60 who developed jejunal peptic ulcer. It was done to specify the features of an x-ray picture of jejunal peptic ulcers with relation to the cause of ulcer development and optimum methods of x-ray investigation. The predominant localization of peptic ulcer in the jejunal efferent loop and its typical ulcero-cicatricial deformity were established. Jejunal peptic ulcers developing as a result of an insufficient area of resection, are characterized by a relatively benign course of the disease. In case ulcer development was determined by the residual antral stomach mucosa at the duodenal stump or by the Zollinger-Ellison syndrome, considerable pathological changes (gigantic ulcer sizes greater than 2.5 cm and a sharp deformity of the jejunal efferent loop) were noted.     

The effect of prostaglandin E2 on duodenal ulcer healing

Oral prostaglandin E₂ (PGE₂) has specific protective effects so called cytoprotection on the gastrointestinal mucosa that are independent of the acid secretion. This has recently been documented in man. A clinical study was performed to test whether this mucosal reinforcing property also could be used to accelerate duodenal ulcer healing. Twenty-eight patients with endoscopically confirmed duodenal ulcers were randomized to treatment with PGE₂ 0.5 mg three times daily and 1 mg at night or to placebo under double-blind conditions during a four week period. To reduce antacid consumption a fluid placebo antacid was given regularly. An active antacid could be used for pain relief. Healing rate was assessed with repeated endoscopies after 2 and 4 weeks. The treatment groups were comparable with respect to age, duration of ulcer history and present ulcer symptoms, smoking habits, family history, gastric acid secretory rate and number of patients with blood group 0. There was a slight difference in sex distribution. 2 mg PGE₂ did not reduce pentagastrin-stimulated acid secretion in five of the patients. After the treatment significantly more in the PGE₂-group ( , 86%) had healed than in the placebo-group . There was no difference in pain relief between PGE₂ and placebo-treated. The antacid consumption was very low in both PGE₂ and placebo-treated. No significant side effects or changes in laboratory test-results were recorded. It is suggested that the cytoprotective effect of PGE₂ can be used to accelerate healing of duodenal ulcer.     

Changes in the intensity of protein synthesis in the gastric mucosa following the laser irradiation of a duodenal ulcer]

The intensity of protein synthesis (incorporation/pool) is usually low in normal stomach mucosa and enhanced in exacerbation of peptic ulcer; following the effective laser therapy it decreases only in one third of cases. Therefore the scarring of ulcer not always coincides with the normalization of protein synthesis. The results characterize also the community of reactions in stomach and duodenal mucose membranes. The changes in protein synthesis intensity following the laser irradiation depended neither on the initial size of ulcer nor on the age of patient and the total duration of disease.     

Presence of the cagA Gene in the Majority of Helicobacter pylori Strains Is Independent of Whether the Individual Has Duodenal Ulcer or Asymptomatic Gastritis

Background Helicobacter pylori infection presents as many different diseases, including asymptomatic gastritis, peptic ulcer disease, and gastric cancer. Although the virulence factor(s) responsible for different H. pylori-related diseases have not been identified, several candidate genes are being investigated for such an association. The polymerase chain reaction (PCR) frequently is used to assess the presence of genetic factors associated with pathogenesis of disease; the cagA gene and its product have been postulated to have a disease-specific relationship to peptic ulcer and gastric cancer because of differential expression in these diseases compared to histological gastritis alone. Materials and Methods. Genomic DNA was amplified by PCR, using synthetic oligonucleotide primers to the cagA gene to determine the prevalence of the cagA gene in 60 H. pylori isolates obtained from well-documented duodenal ulcer or asymptomatic gastritis patients (30 each). Results were confirmed by hybridization with a 1.4-Kb cagA probe. Results. The expected PCR product was obtained in 90% of isolates from duodenal ulcer patients, compared to 70% of isolates from individuals with asymptomatic gastritis. The PCR products were polymorphic in size, suggesting cagA gene sequence differences among isolates. Evaluation for the presence of the cagA gene by hybridization with a 1.4-Kb cagA probe showed a homologous product in 29 of 30 strains [96.7%; 95% confidence interval (CI) = 83–100%] from duodenal ulcer patients versus 25 of 30 strains (83.3%; 95% CI = 65–94%) obtained from individuals with asymptomatic gastritis (p= 0.19). Conclusions. The high prevalence of the cagA gene in asymptomatic gastritis suggests that it will not prove to be a useful marker to distinguish more virulent or disease-specific H. pylori strains. The genetic heterogeneity among H. pylori strains makes PCR an unwise choice as the single method to determine prevalence of a putative virulence factor. In evaluation of the prevalence of a gene or genetic factor in a population of H. pylori, hybridization with extended probes might be important to ensure that the results are representative of the organism's genotype.     

The interleukin-1 RN polymorphism and Helicobacter pylori infection in the development of duodenal ulcer

BACKGROUND: The host genetic factors that determine the clinical outcomes for Helicobacter pylori-infected individuals remain unclear. AIMS: To elucidate the relations among interleukin-1 locus polymorphisms, and H. pylori infection in the development of duodenal ulcers. MATERIALS AND METHODS: In a case-control study involving 168 control subjects and 147 patients with duodenal ulcer, biallelic polymorphisms of two interleukin-1 loci, IL-1B(-511) and IL-1B(+3954), as well as the penta-allelic variable number of tandem repeats of interleukin-1 receptor antagonist IL-1RN, were genotyped, and the H. pylori states of controls and patients were examined. RESULTS: Helicobacter pylori infection, male gender and the carriage of IL-1RN*2 independently increased the risk of duodenal ulcer with odds ratios of 6.4 (95% confidence interval, 3.7-11.0), 1.9 (95% confidence interval, 1.1-3.4) and 2.7 (95% confidence interval, 1.1-6.8), respectively. Statistical analysis revealed an interaction between IL-1RN*2 and H. pylori infection with the duodenal ulcer risk conferred by the H. pylori infection substantially increased (odds ratios, 22.6; 95% confidence interval, 5.9-86.5) by the carriage of IL-1RN*2. In addition, a synergistic interaction between IL-1RN*2 and blood group O existed. The combined risk of H. pylori infection, the carriage of IL-1RN*2 and blood group O for duodenal ulcer was 27.5 (95% confidence interval, 3.1-243.6). CONCLUSIONS: This work is the first to verify IL-1RN*2 as an independent factor that governs the development of duodenal ulcers. Our data indicate that H. pylori infection and IL-1RN*2 synergistically determine susceptibility to duodenal ulcer. The blood group phenotype is possibly a crucial determinant for the outcome of the impact of an interleukin-1 locus polymorphism on H. pylori-infected individuals.