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J I Rotter

Publications and source records attributed to J I Rotter.

At least 145 records · Page 8Linked to original sources
PubMed1984

Measuring the genetic contribution of a single locus to a multilocus disease.

An increasing number of diseases are being demonstrated to be due to determinants at more than one genetic locus. It thus becomes of interest to determine the genetic contribution of a specific single locus. A method of estimating a "coefficient of genetic contribution" is described herein, based on a comparison of monozygotic twin concordance data for a specific disease, the empirical sibling recurrence risks, and the sharing of identical by descent genes at the specific locus of interest by pairs of siblings who are both affected. The value of the method is that it requires relatively few assumptions, and does not require knowledge of the mode of inheritance of disease susceptibility at the gene locus of interest. If there are major environmental determinants, this method will give a lower bound for the single locus of interest. To illustrate the method, it is applied to two specific diseases, insulin dependent diabetes mellitus (IDDM) and gluten-sensitive enteropathy (GSE), and a specific locus, the HLA gene complex. The best estimates would appear to be that the HLA "genes" provide a coefficient of 60% for IDDM susceptibilty, but only 30% for GSE. A possible reason for these differences is the markedly increased disease susceptibility of the DR3/DR4 heterozygote for IDDM.

Alleles↗
PubMed1984

Estimating the recombination frequency for the MN and the Ss loci.

Linkage analysis of 146 informative families for MN and Ss resulted in an estimate of the recombination frequency greater than previously reported. Our total is 7 recombinant children out of 467 individuals, including 1 confirmed recombinant (retested and HLA-compatible) and 6 not verified. The 95% confidence interval of our estimate of recombination is 0.0033-0.0167. Our results are compared with two earlier studies.

Female↗
PubMed1984

Sample-size calculations in segregation analysis.

Segregation analysis, employing nuclear families, is the most frequently used method to evaluate the mode of inheritance of a trait. To our knowledge, there exists no tabular information regarding the sample sizes required of individuals and families needed to perform a significance test of a specific segregation ratio for a predetermined power and significance level. To fill this gap, we have developed sample-size tables based on the asymptotic variance of the maximum likelihood estimate of the segregation ratio and on the normal approximation for two-sided hypothesis testing. Assuming homogeneous sibship size, minimum sample sizes were determined for testing the null hypothesis for the segregation ratio of 1/4 or 1/2 vs. alternative values of .05-.80, for the significance level of .05 and power of .8, for ascertainment probabilities of nearly 0 to 1.0, and sibship sizes 2-7. The results of these calculations indicate a complex interaction of the null and the alternate hypotheses, ascertainment probability, and sibship size in determining the sample size required for simple segregation analysis. The accompanying tables should aid in the appropriate design and cost assessment of future genetic epidemiologic studies.

Epidemiologic Methods↗
PubMed1984

The use of association data to identify family members at high risk for marker-linked diseases.

The study of genetic markers linked and associated with disease has provided important evidence of a genetic contribution to numerous diseases and has helped to establish their modes of inheritance. However, this information has not been fully utilized in counseling individuals at risk for these disorders. In the case of recessive, marker-linked diseases, such as idiopathic hemochromatosis linked to HLA in family studies and associated with specific HLA alleles in population surveys, the only current clinical application has been to identify siblings who share both HLA-marker haplotypes with the affected proband. They are considered to be presymptomatically affected, and more definitive invasive investigations are considered appropriate. All other relatives, including parents, offspring, and other siblings, who share only one marker with the proband, have been counseled only that their risk is equivalent to the gene frequency of the disease allele, for example, 3%-6% for hemochromatosis. We have developed a generally applicable method to utilize population association data to derive more specific and accurate risk figures for these other relatives of patients with marker-linked and associated diseases. We have applied this method to idiopathic hemochromatosis. If the offspring of a patient with hemochromatosis lacks A3, B7, and B14, the risk to that offspring for developing hemochromatosis is less than 2%. On the other hand, if they receive HLA A3 from their unaffected parent, their risk climbs to 9%-10%; if they receive an A3-B14 haplotype, their risk increases to virtually 100%. As demonstrated by our example, the application of association data to family members already at a basal increased risk for marker-linked disease can significantly refine the disease risk estimates given to those relatives. This information can be utilized to select individuals in whom invasive diagnostic testing or preventative intervention is indicated.

Alleles↗
PubMed1983

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.

Biological Evolution↗
PubMed1983

A search for heterogeneity in insulin dependent diabetes mellitus (IDDM): HLA and autoimmune studies in simplex, multiplex and multigenerational families.

HLA antigens (A, B, C and DR loci), serum islet cell antibodies, thyrogastric antibodies, and insulin antibodies were studied in 77 families (25 simplex, 42 multiplex, and 10 multigenerational). In order to test for intrafamilial constancy and intergroup variation, we compared simplex with multiplex families, HLA identical and non identical siblings within families, as well as groups of families characterized by different DR alleles (DR3, DR4, and DR3/DR4) for various immunologic and clinical characteristics. These comparisons did not reveal all the distinct subgroups suggested by different cross-sectional population studies, but did provide evidence for a compound form having an aggregation of different high risk alleles. This study suggests that in many cases (and possibly especially in families with multiple affected individuals), there are several different genetic influences leading to IDDM.

Antibodies↗
PubMed1983

HLA genotypic study of insulin-dependent diabetes the excess of DR3/DR4 heterozygotes allows rejection of the recessive hypothesis.

The genetics of insulin-dependent diabetes mellitus (IDDM) is currently an area of controversy, with some investigators proposing heterogeneity within the HLA region and even the existence of non-HLA-linked susceptibility genes, and others maintaining that a simple autosomal recessive gene linked to HLA with reduced penetrance is an adequate explanation. To resolve this latter question, we report here a simple method of testing whether a single HLA-linked susceptibility gene is inherited in a recessive fashion when it is associated with two different HLA alleles, as is the case for IDDM. It is shown that if the number of DR3/DR4 heterozygotes in a diabetic population exceeds the combined sum of DR3/3 and DR4/4 homozygotes in that same diabetic population, then a recessive mode of inheritance can be rejected. The advantages of the method are that it does not depend on ratios, as do relative risk calculations, nor does it depend on control data, but is based only on studies of the diabetics themselves. With data on 193 genotyped IDDM patients, we can clearly reject the recessive mode of inheritance, since the number of heterozygotes is 68 compared with a maximum of 22 homozygotes (P less than 10(-4)). Eight other published studies are in concordance with these results. Therefore, a nonparametric test, independent of the significance of any individual study, rejects equality of heterozygotes and homozygotes (P less than 0.002) and rejects the simple recessive mode of inheritance as a direct consequence. We conclude that more complex modes of inheritance of HLA-linked IDDM susceptibility, such as two different diabetogenic alleles or multiple loci, must be entertained. DIABETES 32:169-174, February 1983.

Alleles↗
PubMed1983

Pathological acid secretion not due to gastrinoma.

There are few detailed studies of patients with pathological hypergastrinaemia of antral origin. We have identified four patients with severe acid hypersecretion associated with peptic ulcer disease and in whom no evidence for gastrinoma or isolated retained antrum could be found. Three of these patients also had hypergastrinaemia. In two patients, one with gastric ulcers and one with duodenal ulcer disease, the hypergastrinaemia appeared to be due to antral gastrin cell hyperfunction and there was also evidence for mild antral gastrin cell hyperplasia. In the other hypergastrinaemic patient, a primary intestinal gastrin cell hyperfunction syndrome was suspected, but a hidden gastrinoma could not be excluded. The remaining patient had nearly fatal hypersecretory ulcer disease and cimetidine failed to control the hypersecretory state. In this patient the hypersecretion responded to a more potent H2 antagonist with resolution of a metabolic encephalopathy. No general pathophysiological mechanism could be identified in these patients or in larger groups of patients with gastric or duodenal ulcer disease.

Adult↗
PubMed1983

The Tay-Sachs disease gene in North American Jewish populations: geographic variations and origin.

From data collected in a North American Tay-Sachs disease (TSD) heterozygote screening program, the TSD carrier frequency among 46,304 Jewish individuals was found to be .0324 (1 in 31 individuals). This frequency is consistent with earlier estimates based on TSD incidence data. TSD carrier frequencies were then examined by single country and single region of origin in 28,029 Jews within this sample for whom such data were available for analysis. Jews with Polish and/or Russian ancestry constituted 88% of this sample and had a TSD carrier frequency of .0327. No TSD carriers were observed among the 166 Jews of Near Eastern origins. Relative to Jews of Polish and Russian origins, there was at least a twofold increase in the TSD carrier frequency in Jews of Austrian, Hungarian, and Czechoslovakian origins (P less than .005). These findings suggest that the TSD gene proliferated among the antecedents of modern Ashkenazi Jewry after the Second Diaspora (70 A.D.) and before their major migrations to regions of Poland and Russia (before 1100 A.D.).

Female↗
PubMed1983

Pachydermoperiostosis, hypertrophic gastropathy, and peptic ulcer.

Two brothers with pachydermoperiostosis, an autosomal dominant syndrome characterized by digital clubbing, periosteal new bone formation, coarse facial features with thick, furrowed, and oily skin, presented in their twenties with severe complicated duodenal ulcer disease requiring multiple operations. Their father and one paternal uncle also had pachydermoperiostosis and a past history of ulcer dyspepsia. The mother, one sister, two maternal aunts, and one other paternal uncle were healthy. Both brothers had giant hypertrophic gastritis (Ménétrier's disease). Their pentagastrin-stimulated acid output and fasting and meal-stimulated serum gastrin levels were normal, but their serum pepsinogen I and II levels were markedly elevated. The father had hypochlorhydria and a low serum pepsinogen I/II ratio, suggesting atrophic gastritis. This family study raises the possibility that pachydermoperiostosis, hypertrophic gastropathy, and peptic ulcer may be genetically related.

Adult↗
PubMed1982

Evidence for recessive and against dominant inheritance at the HLA-"linked" locus in coeliac disease.

It has been proposed that gluten sensitive enteropathy (GSE) results from the interaction of two loci: one locus linked to HLA and associated with dominant inheritance, and the other, a non-HLA-linked GSE-associated B-cell alloantigen, exhibiting recessive inheritance. We have shown in previous analyses that a two-locus, dominant-recessive model is less compatible with the existing population prevalence and observed familial segregation data than is a recessive-recessive two-locus model. Here we present additional analyses of reported population and familial HLA data that support the recessive mode of inheritance for the HLA-linked disease locus. Reported data from HLA typing of affected sib pairs, the association of GSE with DR3 and DR7 in different populations, and the proportions of different HLA phenotypes and genotypes were compared with expected data derived by three different methods. The HLA data analyses consistently reject a dominant mode of inheritance for the presumed HLA-linked disease allele but do not reject a recessive model. The affected sib-pair data also support a recessive model. These analyses are consistent with our previous prediction that the HLA-"linked" disease allele in GSE is recessive inherited.

Celiac Disease↗
PubMed1982

Are there immunologic forms of duodenal ulcer?

The increasing evidence for etiologic and genetic heterogeneity of peptic ulcer suggests that different pathogenetic mechanisms can result in peptic disease. The existence of immunologic forms of duodenal ulcer is proposed. These disorders may account for the varied results of reported HLA association studies. One form may be characterized by antibodies to secretory immunoglobulin, be overrepresented in childhood ulcer cases and allergic populations, and lead to ulcer through a deficiency of local mucosal immune defenses. Another form may be due to the production of an immunoglobulin that is stimulatory to acid secretion, analogous to the thyroid stimulating immunoglobulins of thyrotoxicosis. Studies to further delineate these proposed disorders are suggested.

Adult↗
PubMed1982

Evidence for a major dominance component in the variation of serum pepsinogen I levels.

We report here a variance component analysis of the distribution of serum pepsinogen I levels in normal individuals, using a maximum-likelihood method on entire pedigrees. The results indicate a broad heritability of 91%, with some 74% being attributed to a dominance component. This is consistent with the hypothesis that the pepsinogen I level in normals is principally determined by the action of major genes, as also seems to be the case for duodenal ulcer patients and families.

Analysis of Variance↗