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J I Rotter

Publications and source records attributed to J I Rotter.

At least 109 records · Page 6Linked to original sources
PubMed1990

Familial Mediterranean fever--linkage studies with genetic markers on chromosome 6.

Familial Mediterranean Fever (FMF) is an autosomal recessive disease manifested by recurrent short episodes of fever associated with polyserositis. Although the biochemical defect is unknown, there are several immunologic abnormalities which have been described in this disease. To examine critically whether there is linkage between FMF and the immunogenetic region (major histocompatibility complex-MHC) on chromosome 6, including the HLA, BF, and GLO1 loci, blood samples from members of 13 nuclear Armenian families were tested for these genetic markers. These 13 families included 28 affected and 42 unaffected family members. Linkage could be excluded at 7.5% recombination with the HLA ABC and D loci. Linkage could be excluded at 2.5% recombination for GLO1. Linkage could not be excluded with BF individually, but can be rejected based on the haplotype data. No association was found with either BF, GLO1, and HLA DQ alleles. HLA DR4 was found more often in affected cases than in controls; however, after adjusting for the number of antigens tested this was not significant. Our results would appear to exclude the immunogenetic region on chromosome 6 from linkage with FMF in the Armenian population.

Alleles↗
PubMed1990

Genetics of common diseases of adulthood. Implications for prenatal counseling and diagnosis.

Genetic factors play an important role in the development of many common diseases of adulthood that result in early morbidity and mortality. Prevention of these disorders and their sequelae is best established through early detection and early intervention. Although it may be feasible to screen the entire population for some disorders (e.g., hypertension), this approach would be expensive and impractical for others (e.g., colon cancer). The family history provides an inexpensive and convenient method of identifying families at risk for premature diseases of adulthood. Family screening for a disorder should be recommended if there is increased risk for the disorder among family members, if screening methods are available to detect the condition at an early age or preclinical stage, and if early intervention will alter the course of the disease. For many disorders screening and intervention can prevent the occurrence of clinical disease. The prenatal counseling session affords an ideal setting for identifying families at risk for diseases of adulthood with major genetic components. By reviewing the family history, key family members can be identified and investigated, in order to establish a specific genetic diagnosis. At-risk relatives can then be counseled and screened for the disorder preclinically and premorbidly. The screening and intervention available for a disease depends on the nature of the disorder, our understanding of its physiology and etiology, and our current technology. The disorders discussed earlier are typical of conditions of adulthood that are influenced strongly by genetic factors, especially when they appear in younger adults. Atherosclerosis, colon cancer, and diabetes are complex phenotypes. Each can be caused by single-gene defects, but commonly the genetics are more complex. Empiric data help to establish the risk to an individual in the latter cases. In all three examples, early detection should lead to treatment, which can prevent more serious sequelae: by treating the dyslipidemia, coronary artery disease can be prevented; by removing the benign polyp, malignant cancer can be avoided; and when impaired glucose tolerance is detected, diet and exercise can prevent or delay frank diabetes and its complications. The complete evaluation of individuals at risk for disorders such as those in Table 1 and their families can be a complicated task. Referral to a center experienced in the genetics of common diseases often may be necessary.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1989

Hypothesis: familial Mediterranean fever--a genetic disorder of the lipocortin family?

Familial Mediterranean fever is an autosomal recessively inherited disorder of unknown cause characterized by recurrent attacks of inflammation, involving mainly the peritoneum, pleura, synovia, and skin. Based on a phenotype analysis, we propose that its manifestations may be related to a genetic defect in one of the family of lipocortin proteins. Evidence is presented supporting an abnormality in the first step of prostaglandin/leukotriene synthesis.

Annexins↗
PubMed1989

Familial Mediterranean fever in Armenians: autosomal recessive inheritance with high gene frequency.

Familial Mediterranean fever (FMF) is a recurrent episodic inflammatory disorder of unknown pathogenesis that occurs with high frequency in non-Ashkenazi Jews and Armenians. However, there are some differences in the clinical manifestations of FMF in these ethnic groups. FMF has been reported to be an autosomal recessive disease in non-Ashkenazi Jews, with a male/female ratio of 1.7, indicating reduced penetrance in females. However, the inheritance is less clear for Armenians. To resolve this problem, we studied prospectively families of 64 Armenian index cases randomly ascertained at the UCLA FMF clinic. Fifty-three families containing 176 sibs in addition to the probands were analyzed by genetic segregation analysis (exclusions included: six single-child families, four families in which one of the parents was also affected, and a family with incomplete information). Upper and lower bounds of the segregation ratio were estimated, and ranged from .10 +/- .03 to .18 +/- .05 when only definitely affected sibs were classified as affected; .17 +/- .04 to .27 +/- .05 when considering "possibly affected" sibs as affected; and .19 +/- .04 to .30 +/- .05 when incomplete penetrance in females was corrected. A value of .25 is the expected segregation ratio for autosomal recessive inheritance, and our data are consistent with this mode of inheritance. We can reject autosomal dominant inheritance, where the expected segregation ratio is .5. Using extended pedigree data, we calculated an FMF gene frequency of 0.073 and a carrier rate of 1/7, which is about four times the frequency in non-Ashkenazi Jews.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1989

Geographic origins of Jewish patients with inflammatory bowel disease.

Ulcerative colitis and Crohn's disease are more common among Jews than among non-Jews. Despite the existence of studies on the prevalence and incidence of inflammatory bowel disease in relation to the continent of residence or origin, there are no studies on the specific countries of origin of Ashkenazi Jewish patients. We report here the first analysis of 233 U.S. Jewish patients by defined world regions and subregions. Using two different sets of controls (a self-referred Jewish population for Tay-Sachs disease carrier detection and a sample of Jewish persons ascertained through unrelated studies from the same hospital as our patients), we found a significant excess of patients of middle European origin relative to those of Polish or Russian origin. These observations suggest that the inflammatory bowel disease gene(s) are more prevalent in the Jewish population that originated in middle Europe than in those from Poland and Russia. These results further suggest that Jewish patients with inflammatory bowel disease probably represent a nonrandom genetically predisposed subset of the Jewish population. This provides further evidence for the genetic contribution to inflammatory bowel disease in general, and to its higher risk in the Jewish population.

Colitis, Ulcerative↗
PubMed1989

Intestinal permeability in patients with Crohn's disease and their healthy relatives.

The healthy relatives of patients with Crohn's disease were previously found to have increased intestinal permeability to polyethylene glycol 400. To determine whether the abnormal permeability is uniquely detectable by polyethylene glycol 400, we studied the intestinal permeability of three new probes (lactulose, rhamnose, and mannitol) in 25 patients with Crohn's disease, 41 of their healthy relatives, and 29 normal controls without a family history of inflammatory bowel disease. Patients with Crohn's disease had increased lactulose permeability when compared with relatives or controls. Lactulose absorption by patients with Crohn's disease was 0.41% +/- 0.07% (mean +/- SE), whereas that of their relatives and unrelated controls was 0.28% +/- 0.03% and 0.26% +/- 0.03%, respectively. There was no significant difference between the relatives and controls, but both groups differed from the patients (p less than 0.05 and p less than 0.025, respectively). The patients' lactulose/rhamnose ratio was 70.5% +/- 9.2% vs. 37.2% +/- 3.3% in relatives and 40.6% +/- 5.7% in unrelated controls (p less than 0.0005 and p less than 0.0025, respectively). The two intermediate-sized probes, rhamnose and mannitol, did not detect permeability differences among the three groups. The inability of lactulose, rhamnose, or mannitol to detect permeability abnormalities in healthy relatives of patients with Crohn's disease suggests that these probes penetrate the intestinal barrier by routes or mechanisms that are different from those of polyethylene glycol 400. Lactulose, in particular, detects permeability changes in patients with intestinal inflammation, and polyethylene glycol 400 is able to detect permeability changes in the health relatives of our patients. These data indicate that permeability may be abnormal as a secondary result of inflammation, or as a result of a primary genetic abnormality.

Adult↗
PubMed1989

Familial empiric risk estimates of inflammatory bowel disease in Ashkenazi Jews.

Genetic factors have been implicated in the etiology of inflammatory bowel disease (IBD) because of the increased occurrence of IBD in relatives. To further characterize the familial aggregation of IBD, we obtained family histories by interview on 188 IBD patients, including 154 Ashkenazi Jews (82%), ascertained through a Los Angeles gastroenterology practice. Thirty-three index cases (17.6%) had at least one affected first-degree relative; an additional 11 had more distant affected relatives. Thus, 23.4% of our sample had a positive family history. The quantification of empiric risk estimates for various classes of relatives has been quite limited and has been reported in only a few series. An important goal of our study was the determination of the specific empiric risk figures for relatives. We obtained uncorrected risk estimates of 2.5% to off-spring, 5.2% to siblings, and 2.9% to parents. Although the highest risk we observed is to siblings, IBD has a variable and often late age of onset, and it is likely that many relatives, particularly offspring, of patients in this sample have not reached the age at which they will manifest clinical disease. Thus, these uncorrected risks as well as those reported in the literature are an underestimate of the true empiric risks. To provide an estimate of the true lifetime risks, we utilized age-specific incidence data to calculate the following age-corrected empiric risk estimates for IBD: 8.9% to offspring, 8.8% to siblings, and 3.5% to parents. It is these latter age-corrected estimates that are most appropriate for both genetic counseling and genetic modeling.

Adolescent↗
PubMed1989

Lack of an association between polymorphisms of the T-cell receptor alpha-chain and ulcerative colitis.

It was recently reported that, using a T-cell receptor alpha-chain complementary deoxyribonucleic acid probe (pGA5) and the restriction enzyme Eco RV, a 10-kilobase restriction fragment length polymorphism was detected significantly more frequently in patients with ulcerative colitis than in patients with Crohn's disease and controls. This finding had great potential importance, as no gene marker had previously been found to be strongly associated with inflammatory bowel disease. Therefore, an attempt to confirm it in an independent laboratory and patient population has been made in this study. Thirty patients with ulcerative colitis, 30 with Crohn's disease, and 30 healthy control subjects were studied using the Eco RV restriction enzyme and the same T-cell receptor alpha-chain complementary deoxyribonucleic acid probe as was used in the prior report. No 10-kilobase fragment or any other polymorphism using this probe-enzyme combination was found in any of the individuals studied. Polymorphisms were observed with the restriction enzyme Bgl II, but their frequencies did not distinguish between cases and controls. Therefore, there is as yet no evidence for an association between polymorphisms of Eco RV-digested genomic DNA probed with the pGA5 T-cell receptor alpha-chain complementary deoxyribonucleic acid and the predisposition to inflammatory bowel disease.

Blotting, Southern↗
PubMed1988

Serum pepsinogen I in familial multiple endocrine neoplasia type I.

An increased serum pepsinogen I (PG I) concentration has been reported to be a marker of inherited peptic ulcer disease. Since both the Zollinger-Ellison syndrome and hyperparathyroidism, components of the familial multiple endocrine neoplasia type I syndrome (MEN I), are often associated with peptic ulcer, we have studied serum PG I concentrations in members of six well-defined families with MEN I. Serum PG I concentrations in 20 family members with hyperparathyroidism ranged from 35 to 864 ng/ml compared to 21-92 ng/ml in 16 nonaffected MEN I members. However, serum PG I levels were significantly higher (P less than 0.01) in the hyperparathyroid patients with hypergastrinemia (PGI median 192, range 75-864 ng/ml) than in those with normogastrinemia (PGI median 75, range 35-139 ng/ml). In fact, five of seven patients with hyperparathyroidism and hypergastrinemia compared to only one of 13 hyperparathyroid patients without hypergastrinemia had increased serum PG I levels above 130 ng/ml. We conclude that in the MEN I syndrome, increased serum PG I levels are found in patients with Zollinger-Ellison syndrome but not in hyperparathyroid patients with normogastrinemia and not in nonaffected MEN I members. The results indicate that in familial MEN I, hyperpepsinogenemia I is not inherited as a genetic trait but suggest that the elevated serum PG I levels are secondary to chronic hypergastrinemia.

Female↗
PubMed1988

Gastrin cell function in familial multiple endocrine neoplasia type I.

Recent studies have suggested that patients with multiple endocrine neoplasia type I (MEN I) may have abnormal serum gastrin secretion in the absence of gastrin producing tumours. G-(gastrin) cell function by three provocation tests in 20 patients with hyperparathyroidism from six MEN I-families were studied: each patient was an obligate carrier of the MEN I-gene. The serum gastrin response to secretin was used to identify the presence of gastrinoma, that to a test meal of G-cell hyperfunction of the antral and/or duodenal mucosa, and that to bombesin to differentiate antral from duodenal G-cell hyperfunction. Seven patients had basal hypergastrinaemia and hyperchlorhydria. These patients had increased serum gastrin responses to secretin (p less than 0.01) and to bombesin (p less than 0.02), but normal postprandial responses. In the 13 normogastrinaemic patients the responses to the three stimuli were normal. In families with MEN-I gastrinoma is the only endocrine disorder accounting for abnormal gastrin secretion. G-cell function is normal in obligate carriers of the MEN I-gene.

Adult↗
PubMed1987

Genetic factors in Haemophilus influenzae type b disease susceptibility and antibody acquisition.

Because Alaskan Eskimos have the greatest known endemic risk of Haemophilus influenzae type b (Hib) disease and represent a comparatively homogeneous population, we selected this population to evaluate the presence or absence of an association of 35 genetic markers (alleles or allotypes) at 12 chromosomal loci with susceptibility to both invasive Hib disease risk and level of Hib anticapsular antibody. We studied nearly all Alaskan Eskimo children who had had invasive Hib disease between 1971 and 1982 in southwestern Alaska (n = 103) and an equivalent number of controls matched for age, race, and village of residence, and verified not to have had proved or suspected Hib disease. We found no significant associations with Hib disease for the single alleles of HLA-A, -B, -C, -DR, Gm, Km, Am, Kidd, MNSs, ABO, esterase D, or glutamate pyruvate transaminase loci. However, we observed a significant interaction of two loci, Gm(a;..;g,s,t) allotype and HLA-DR8 (P = 0.002), with increased Hib disease susceptibility, and an interaction of the same Gm allotype and HLA-DR5 with decreased disease susceptibility (P = 0.01). We also compared the level of anticapsular antibody to Hib with each genetic marker and two-locus interactions, but no genetic association with antibody level was found. We conclude that some genetic factors contribute to the susceptibility to invasive Hib disease in this population.

Alaska↗
PubMed1986

Preferential transmission of diabetic alleles within the HLA gene complex.

Several studies suggest a higher incidence of insulin-dependent diabetes mellitus (IDDM) among the offspring of men with the disease than among those of female diabetics. Differential transmission by the father of genes that predispose to diabetes may explain this phenomenon. To test this hypothesis, we examined parent-to-offspring transmission of HLA haplotypes and DR (D-related) alleles in 107 nuclear families in which a child had IDDM. We observed that fathers with a DR4 allele were significantly more likely to transmit this allele to their diabetic or nondiabetic children than were mothers with a DR4 allele (72.1 vs. 55.6 percent, P less than 0.001). No differences between parents were observed for HLA-DR3; however, DR3 was transmitted significantly more than 50 percent of the time from either parent (P less than 0.001). These data suggest that differential parental transmission of the HLA-DR4-linked diabetes-predisposing allele may explain the higher risk of diabetes among children of diabetic fathers than among those of diabetic mothers. In addition, the excess transmission of diabetogenic HLA alleles from parent to offspring may explain how these deleterious genes continue to recur at such high frequencies in the general population.

Alleles↗
PubMed1986

HLA haplotype sharing and proband genotype in IDDM.

We previously proposed that the HLA-related genetic susceptibility to insulin dependent diabetes mellitus (IDDM) is best explained by at least two different susceptibility alleles, one preferentially associated with DR3, the other with DR4. This IDDM HLA heterogeneity model predicts that HLA haplotype sharing among affected sibpairs will be increased when the index case is a compound heterozygote (i.e., DR3/DR4). This prediction was tested and confirmed using the GAW IV IDDM data set. A significantly increased sharing of HLA haplotypes was seen when the index sib was DR3/DR4 compared to those of other genotypes (68% versus 37% sharing 2 haplotypes, p less than .01).

Alleles↗