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Biomedical subjects

R E Ferrell

Publications and source records attributed to R E Ferrell.

At least 271 records · Page 15Linked to original sources
PubMed1988

Genetic studies of human apolipoproteins. IV. Structural heterogeneity of apolipoprotein H (beta 2-glycoprotein I).

Human beta 2-glycoprotein I has recently been identified as a component of several human plasma lipoprotein fractions and therefore termed as apolipoprotein H. Its metabolic function in lipid metabolism is not known with certainty, though it may be involved in very-low-density-lipoprotein metabolism. Previously, inherited quantitative variation in beta 2-glycoprotein I has been suggested in man. In this investigation, we document the evidence of genetically determined structural polymorphism of apolipoprotein H or beta 2-glycoprotein I by using thin-layer polyacrylamide isoelectric focusing gels followed by immunological identification by double antibody staining. The apolipoprotein H structural locus is characterized by the occurrence of three common alleles in U.S. whites and blacks. The frequency distributions of the three alleles designated APO H1, APO H2, and APO H3 are .059, .882, and .059 in whites and .017, .902, and .068 in blacks, respectively. In addition, the gene product of a fourth allele, APO H4, has been observed at polymorphic frequency in black individuals and may represent a black marker variant. Family data confirm the hypothesis of four alleles at a single APO H gene locus with an autosomal codominant pattern of inheritance.

Alleles↗
PubMed1988

A genetic study of Gardner syndrome and congenital hypertrophy of the retinal pigment epithelium.

Gardner Syndrome (GS) is an autosomal dominant variant of colorectal polyposis with essentially complete penetrance. It is distinguished from the other polyposis syndromes by its delayed age at onset, the number of polyps, and its extracolonic manifestations. The presence of epidermal cysts, bony osteomata, desmoid tumors, and dental anomalies are distinguishing features of this syndrome. Recently, multiple and bilateral patches of congenital hypertrophy of the retinal pigment epithelium (CHRPE) have been described in three families with classical GS. Tight linkage of the GS and CHRPE phenotypes (Z = 9.752; theta = 0) suggested that CHRPE is a pleiotropic effect of the Gardner mutation within the families in which the ophthalmic trait occurs and is thus a useful marker for the early detection of GS gene carriers. We have analyzed six new families segregating for classic GS and CHRPE. Linkage was tested between GS and CHRPE and between these two phenotypes and a battery of 22 informative biochemical and serological markers. We have extended the linkage analysis on two GS-CHRPE families originally reported elsewhere. Linkage between GS and CHRPE at theta = 0 was observed in all families, a result supporting our original suggestion that CHRPE is a congenital manifestation of the GS mutation. Exclusionary linkage data presented confirm that, for linkage analysis in these families, the CHRPE phenotype is a more powerful marker than other phenotypic features of GS.

Adolescent↗
PubMed1987

The reduction of aromatic alpha-keto acids by cytoplasmic malate dehydrogenase and lactate dehydrogenase.

This study demonstrates that cytoplasmic malate dehydrogenase (MDH-s) catalyzes the reduction of aromatic alpha-keto acids in the presence of NADH, that the enzyme which has been described in the literature as aromatic alpha-keto acid reductase (KAR; EC 1.1.1.96) is identical to MDH-s, and that the reduction of aromatic alpha-keto acids is due predominantly to a previously unrecognized secondary activity of MDH-s and the remainder is due to the previously recognized activity of lactate dehydrogenase (LDH) toward aromatic keto-acids. MDH-s and KAR have the same molecular weight, subunit structure, and tissue distribution. Starch gel electrophoresis followed by histochemical staining using either p-hydroxy-phenylpyruvic acid (HPPA) or malate as the substrate shows that KAR activity comigrates with MDH-s in all species studied except some marine species. Inhibition with malate, the end product of the MDH reaction, substantially reduces or totally eliminates KAR activity. Genetically determined electrophoretic variants of MDH-s seen in the fresh water bony fish of the genus Xiphophorus and the amphibian Rana pipiens exhibited identical variation for KAR, and the two traits cosegregated in the offspring from one R. pipiens heterozygote studied. Both enzymes comigrate with no electrophoretic variation among several inbred strains of mice. Antisera raised against purified chicken MDH-s totally inhibited both MDH-s and KAR activity in chicken liver homogenates. There is no evidence to suggest that any protein besides MDH-s and LDH catalyzes this reaction with the possible exception of the situation in Xiphophorus, in which a third independent zone of HPPA reduction is observed. In most species the activity formerly described as KAR appears to be due to a previously unsuspected activity of MDH-s toward aromatic monocarboxylic alpha-keto acids. In all species examined the KAR activity is associated only with MDH-s; in tissue homogenates the mitochondrial form of MDH (MDH-m) is not detected after electrophoresis using HPPA as a substrate.

Amphibians↗
PubMed1987

Von Recklinghausen neurofibromatosis: a linkage study of candidate and random marker genes.

Genotyping, using plasma proteins or DNA polymorphisms or both, was carried out on 30 families selected through probands with Von Recklinghausen disease. The data provide additional evidence for the exclusion of loci on chromosomes 3 and 5, and chromosome arms 1q, 2p, 4p, 4q, 6q, 7p, 9q, 11p, 11q, and 14q. There was no evidence for genetic heterogeneity at D1S1 (DNF15S2) on chromosome arm 3p, using the Morton test for heterogeneity.

Blood Proteins↗
PubMed1987

Human transferrin polymorphism.

The application of isoelectric focussing (IEF) has revealed a large amount of heterogeneity in the human transferrin (TF) system and has enhanced its potential value in anthropological and genetic studies. The average heterozygosity has been elevated from 0.05, observed by conventional methods of electrophoresis, to 0.29 detected by IEF. So far approximately 30,000 individuals from 122 population groups have been analyzed for TF subtypes to evaluate the magnitude of genetic variation at the TF locus. Possible environmental and biological factors, which may be operating to maintain the TF polymorphism, are discussed.

Alleles↗
PubMed1987

Genetic studies of low-abundance human plasma proteins. IV. Improved typing of alpha-1 acid glycoprotein (orosomucoid) by isoelectric focusing and immunoblotting.

The sensitivity and specificity of isoelectric focusing (IEF) and immunoblotting have been combined for the routine typing of the plasma protein alpha-1 acid glycoprotein (Orosomucoid, ORM). Optimized conditions have been determined for a reliable classification of different ORM phenotypes. Phenotypic patterns of ORM in simple IEF gels correspond to those observed by other techniques. Addition of 6 M urea in a thin-layer IEF gel revealed additional, informative microheterogeneity in the ORM system, which cannot be detected in simple IEF gels. Applying the improved method, 239 White and 181 Black Americans have been screened to determine the distribution of ORM allele frequencies. Two common alleles, ORM*1 and ORM*2, have been observed and their frequencies are 0.5592 and 0.4408, and 0.6160 and 0.3840 in Whites and Blacks, respectively. Family studies confirm the genetic basis of this variation which is compatible with autosomal, codominant inheritance.

Gene Frequency↗
PubMed1987

Genetic studies of human apolipoproteins. I. Polymorphism of apolipoprotein A-IV.

Genetic polymorphism of human apolipoprotein A-IV has been detected by means of a simple and rapid one-dimensional isoelectric-focusing technique followed by immunoblotting. In plasma samples of normal U.S. whites and blacks, the specificity and sensitivity of the technique have been demonstrated to elucidate biochemical and genetic variation present in the APO A-IV molecule. Two common alleles, APO A-IV 1 and APO A-IV 2, have been observed with respective frequencies of .909 and .088 in whites and .961 and .035 in blacks. In addition, the products of two rare alleles designated APO A-IV 3 and APO A-IV 4 also have been observed. Family studies show autosomal codominant transmission of four alleles coded by a single structural locus.

Alleles↗
PubMed1987

Genetic studies of low-abundance human plasma proteins. V. Evidence for a second orosomucoid structural locus (ORM2) expressed in plasma.

Orosomucoid (ORM) or alpha-1-acid glycoprotein is an acute-phase protein of human plasma whose function is suggested to be the competitive inhibition of cellular recognition by infective agents. Genetically determined variation in ORM has been reported, with two major alleles segregating in all populations studied to date. Isoelectric focusing-immunoblotting studies of ORM revealed the presence of isoprotein species that did not segregate with the predominant alleles at the ORM locus and suggested the expression of a second structural gene locus for orosomucoid (ORM2). Genetically independent variation consistent with expression of the ORM2 locus was observed in plasma samples from American blacks but was not observed in U.S. whites or sampled populations of North- and South-American Indians, Eskimos, Aleuts, or New Guinea Highlanders. The population allele frequencies for this locus were .958, .025, .006, and .011 for alleles ORM*1, ORM2*2, ORM2*3, and ORM2*4, respectively. Family studies confirm the autosomal codominant inheritance of the observed phenotypes.

Alleles↗
PubMed1987

Genetic studies of low-abundance human plasma proteins. VI. Polymorphism of hemopexin.

An analytical isoelectric focusing method in 3 M urea followed by immunoblotting has been devised to detect genetic and biochemical variation in the glycoprotein hemopexin (HPX) in human plasma or serum. HPX reveals extensive microheterogeneity with multiple major and minor components that are susceptible to neuraminidase treatment, suggesting that the observed biochemical variation is due to differences in sialic acid content between HPX isoproteins. However, charge differences that persist in HPX isoproteins following neuraminidase treatment suggest the presence of genetically determined HPX variation, and this is confirmed by population and family studies. HPX was found to be monomorphic, with an invariant pattern, in U.S. whites; but it is polymorphic in U.S. blacks, with three alleles controlled by a single locus, a situation that demonstrates an autosomal codominant pattern of inheritance. The HPX 1, HPX 2, and HPX 3 allele frequencies in U.S. blacks are .941, .018, and .041, respectively.

Alleles↗
PubMed1986

Individual admixture estimates: disease associations and individual risk of diabetes and gallbladder disease among Mexican-Americans in Starr County, Texas.

The ethnic and geographic distributions of several common chronic diseases show distinct patterns that are consistent with the distribution of genes and genetic admixture. For example, diabetes and gallbladder disease occur most frequently among Amerindians, while those genetically admixed with them (such as Mexican-Americans) have intermediate rates, and lowest rates are found among Whites and Blacks. Because there will be heterogeneity from individual to individual in ancestral affinity within an admixed population, a method is developed for estimating each person's admixture probability. Results confirm that there is substantial heterogeneity of individual admixture among Mexican-Americans in Starr County, Texas, with a mean value indicating that 65% of genes in this population are Caucasian derived and 35% Amerindian derived. The individual estimates are shown to be unrelated to the probability of being diabetic and only marginally related to gallbladder disease, with those having the most Amerindian affinity being at increased risk. These results are a consequence of the independent assortment of loci and indicate that unless the markers employed are related (including linkage) to the disease of interest, the method will have limited utility. Individual admixture estimates will be useful, however, for examining aspects of population structure and will find increased utility for predicting disease and examining disease associations as more and more of the genome is represented by markers, a very probable prospect with the abundance of DNA polymorphism being identified by restriction enzymes.

Adolescent↗
PubMed1986

Relationship of prevalence of non-insulin-dependent diabetes mellitus to Amerindian admixture in the Mexican Americans of San Antonio, Texas.

A genetic and epidemiological survey of non-insulin-dependent diabetes mellitus (NIDDM) was conducted among the Mexican Americans residing in three socioeconomically distinct areas of San Antonio, Texas: a low socioeconomic (SES) traditional area (barrio), a middle SES, ethnically balanced area (transitional), and a high SES, predominantly Anglo area (suburb). Seventeen polymorphic markers were used to relate the prevalences of NIDDM with the extent of Amerindian ancestry of 1,237 Mexican Americans of these three residential areas. While only the RH and haptoglobin loci showed evidence of association with NIDDM, an admixture analysis of the combined allele frequency data revealed a pattern of decreasing NIDDM prevalence with increasing socioeconomic status (as approximated by neighborhood of residence) and a parallel decrease in Amerindian ancestry. The rank-order correlation between NIDDM prevalence and Amerindian admixture is 0.943 (P less than .001) for the crude prevalence rate and 0.829 (P less than .02) for the age-adjusted rate. Nested gene diversity analysis revealed that the heterogeneity of allele frequencies is more pronounced when individuals were classified by their NIDDM disease status as compared to the classification by neighborhood. Estimation of Amerindian ancestry of each individual did not reveal any significant change in the shape of the distributions of individual admixture proportions in diabetics as compared to the controls. Nevertheless, the results suggest that genetic factors partially explain the differences in NIDDM prevalence observed between the Mexican American and Anglo populations in the southwestern United States.

Adult↗
PubMed1986

Ethnic variation in vitamin D-binding protein (GC): a review of isoelectric focusing studies in human populations.

Since the discovery in 1977 that the GC1 gene could be resolved into two common subcomponents on an isoelectric focusing (IEF) gel, a large number of ethnic groups have been screened to analyze the extent of genetic variation in human populations. Using the IEF technique, approximately 50,000 individuals from 160 different populations have been tested for the GC polymorphism. A marked variation in common GC suballele frequencies in different geographic areas seems to correlate with skin pigmentation and intensity of sun light. Pigmented (black) and keratinized (yellowish) skin type populations have a relatively high frequency of the GC*IF allele as compared to white skin populations. By comparison non-pigmented and non-keratinized white skin populations are generally characterized by having the maximum values of the GC*IS allele. The anthropologic significance of the GC locus has been enhanced further by detecting additional unique GC variants which provide useful information about evolutionary links between different populations. However, the presence of some electrophoretically identical unique variants in genetically and geographically distinct populations demand further investigation of these allelic variants to shed more light on their origins.

Alleles↗
PubMed1986

A sensitive immunoblotting technique to identify thyroxin-binding globulin protein heterogeneity after isoelectric focusing.

An enzyme-linked immunoblotting technique is described to detect thyroxin-binding globulin (TBG) variation in human plasma samples after isoelectric focusing in thin-layer polyacrylamide gels followed by transfer to a nitrocellulose membrane. The technique is used to demonstrate the polymorphic variation in thyroxin-binding globulin present in populations of African and Mongoloid origin and has enabled the detection of a new TBG variant in Eskimos. This technique eliminates the use of radioactive material and related expensive equipment. The technique is specific, sensitive, and reliable for the routine detection of genetic and epigenetic variation in thyroxin-binding globulin.

Black People↗
PubMed1986

Genetic studies of low-abundance human plasma proteins. I. Microheterogeneity of zinc-alpha 2-glycoprotein in biological fluids.

A high-resolution isoelectric focusing technique followed by immunoblotting has been utilized to determine the microheterogeneity of zinc-alpha 2-glycoprotein in a large number of plasma samples from U.S. Caucasians, Blacks, and Eskimos. With the exception of one Black individual, all samples were found to contain an invariant multiple-banded pattern which, after desialylation, was reduced to a single band, suggesting that the microheterogeneity observed is due to differences in the sialic acid content of a single protein product. The asialo forms of the variant sample consist of two distinct bands, consistent with the occurrence of a rare genetic variant at the zinc-alpha 2-glycoprotein structural locus. Unfortunately family studies were not feasible. In addition to plasma, the present technique has been applied to detection of zinc-alpha 2-glycoprotein microheterogeneity in amniotic fluid, saliva, and tears. The amniotic fluid pattern is identical to that present in plasma. However, the patterns observed in saliva and tears are different from each other as well as from that in plasma and could be controlled by separate loci.

Amniotic Fluid↗
PubMed1986

Host and environmental interactions in diabetes mellitus.

A number of current issues in diabetes research are reviewed from an epidemiologic viewpoint. Though many advances have been made in our understanding of the causes of insulin-dependent diabetes mellitus (IDDM), there are many unresolved issues which could benefit from epidemiologic research. These include study of the 36-fold geographic variation in IDDM incidence seen across the world, perhaps by the development of registries, and the placing into a population perspective recent genetic and autoimmune findings concerning IDDM etiology. Epidemiologic considerations should also be incorporated into future trials of immunotherapy for IDDM. Despite considerable research, very little is known about risk factors and genetic environmental interactions in non-insulin dependent diabetes. Large scale prospective epidemiologic studies are, therefore, needed to delineate the potential roles of factors such as diet and physical activity, and how these interact with genetic predisposition.

Diabetes Complications↗
PubMed1986

Genetic polymorphism and fertility parameters in the Aymara of Chile and Bolivia.

To determine whether increased fitness in natural populations is associated with heterozygosity, several studies have attempted to correlate heterozygosity at one or a few genetic loci with fitness-related quantitative traits. The results have been equivocal at best. Furthermore, data on fertility-related parameters and the extent of genetic polymorphism at a large number of loci in man are quite scanty. This report examines the association of four fertility-related parameters (number of pregnancies, number of livebirths, number of children surviving at least one year and number of children alive at the time of the survey) with heterozygosity at 17 polymorphic immunological and biochemical systems in the Aymara of Chile and Bolivia. Women 45 years of age and above, on whom complete fertility histories and phenotype data are available, were included in the study (n = 190). None of the fertility parameters seem to be correlated with heterozygosity, as measured by the proportion of polymorphic loci. For some individual loci, however, an association between heterozygous state and fertility parameters exists. Even in these cases, heterozygosity did not always confer higher fertility. To see whether these negative results are due to heterogeneity in the data, the total sample was divided according to altitude of residence and ethnicity. The conclusions remained the same, indicating that the lack of association of these fertility parameters with genetic polymorphism is not due to population heterogeneity alone. Reproductive fitness differentials, therefore, were not detectable in the Aymara by heterozygosity determined by the polymorphic genetic systems scored by serological and electrophoretic techniques.

Adolescent↗