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R E Ferrell

Publications and source records attributed to R E Ferrell.

At least 181 records · Page 10Linked to original sources
PubMed1993

Apo E allele frequencies in younger (age 42-50) vs older (age 65-90) women.

Allelic variation at the apolipoprotein E (Apo E) structural locus has been shown to influence concentrations of total cholesterol and low density lipoprotein cholesterol (LDL-C). Apo E has six phenotypes resulting from three common alleles at this locus. The epsilon 2 allele is associated with lower LDL-C and the epsilon 4 allele with higher LDL-C. In the current study, we compared the epsilon allele distribution in two cohorts of white women recruited from population based listing of southwestern Pennsylvania. The "younger" cohort consisted of 473 women, age 42-50; the "older" cohort, 870 women, age 65-90. A comparison of the overall distribution of allele frequencies in the two cohorts was significantly different. The allele frequency of epsilon 4 was lower in the older cohort (0.098 vs. 0.122, P = 0.08) and the epsilon 2 allele frequency was higher (0.084 vs. 0.059, P = 0.05) in the older cohort. These observations are consistent with the hypothesis that there may be a selection against individuals with the epsilon 4 allele. However, future research is needed to confirm this observation and to compare survival in individuals by their epsilon allele.

Aged↗
PubMed1993

Association of a PvuII RFLP at the lipoprotein lipase locus with fasting insulin levels in Hispanic men.

We present results from an association study between RFLPs in the lipoprotein lipase (LPL) gene and lipid and insulin levels. The study population consisted of 102 Hispanic men and 97 Hispanic women. The subjects were genotyped for two previously reported RFLPs detected with the restriction enzymes HindIII and PvuII. The frequencies of the RFLPs in the Hispanic population are similar to those seen in other Caucasian populations. Strong linkage disequilibrium was detected between the sites in Hispanics. Genotypes were used separately in analyses of variance with fasting serum triglycerides, total cholesterol, high density lipoprotein (HDL)-cholesterol, low density lipoprotein (LDL)-cholesterol, HDL2/HDL3-cholesterol, and insulin levels, as well as two measures of adiposity: waist-hip ratio and body mass index. Men and women were analyzed separately. Mean fasting insulin levels of the LPL PvuII genotypes were significantly different from each other in Hispanic men. The mean fasting insulin level of men who were homozygous for the presence of the PvuII site (+/+) was 9.20 +/- 0.24 mu units/ml, men who were heterozygous had a mean level of 10.54 +/- 0.20 mu units/ml, and men who were homozygous for the absence of the site (-/-) had a mean of 12.91 +/- 0.30 mu units/ml. This effect was not seen in Hispanic women. These results suggest that the regulation of LPL by insulin may be different in Hispanics with different LPL PvuII genotypes.

Adult↗
PubMed1993

Mutational inactivation of the p53 gene in the human erythroid leukemic K562 cell line.

The K562 human chronic myelogenous leukemia (CML) cell line has attained widespread use as a model for studying hematologic malignancy and erythroid differentiation. Sequencing of the p53 gene in the K562 cell line demonstrated a mutation in exon 5 characterized by a single base insertion (cytosine) between codons 135 and 136. This frameshift mutation leads to an N-terminal truncated protein of 147 amino acids. Only the mutated sequence was present suggesting that the normal allele has been lost. Reverse transcription PCR (RT-PCR) detected a p53 transcript but Western blotting and immunohistochemical staining of cells failed to detect p53 protein. The identification of an inactivation mutation of p53 in the K562 cell line further supports the argument that p53 mutations play a role in myeloid blast transformation of CML.

Amino Acid Sequence↗
PubMed1993

Association of lipoprotein lipase gene variation with the physiological components of the insulin-resistance syndrome in the population of the San Luis Valley, Colorado.

OBJECTIVE: To cross-sectionally evaluate the presence of clustering of the insulin-resistance syndrome components. Tests were conducted for association of the HindIII restriction site polymorphism at the lipoprotein lipase locus with clustering of the physiological components of the insulin resistance syndrome. RESEARCH DESIGN AND METHODS: DNA samples of 370 normoglycemic Hispanics and 520 normoglycemic non-Hispanic whites from the San Luis Valley, Colorado, were amplified by the polymerase chain reaction. Lipids and glucose were determined by the standard procedures. Cross-tabulation and chi 2 analysis were used. RESULTS: The insulin-resistance syndrome components (elevated fasting insulin, reduced high-density lipoprotein cholesterol, and elevated triglycerides) appeared together in individuals of this population sample more often than expected by chance. Individuals in the population with the (+/+) lipoprotein lipase-HindIII restriction of fragment-length polymorphism genotype were more likely to have elevated fasting insulin and triglycerides and a reduced high-density lipoprotein-cholesterol level than subjects with the (+/-) genotype (odds ratio = 2.3, 95% confidence interval 1.38-3.98). CONCLUSIONS: As expected from the physiological function of lipoprotein lipase, the primary association of lipoprotein lipase genotypes is with triglyceride and high-density lipoprotein-cholesterol levels. This appears to be the first reported genetic association with the insulin-resistance syndrome and may reflect genotype specific differences in the regulation of lipoprotein lipase by insulin.

Base Sequence↗
PubMed1993

Two DNA polymorphisms in the lipoprotein lipase gene and their associations with factors related to cardiovascular disease.

Lipoprotein lipase (LPL) plays a crucial role in plasma lipoprotein processing by catalyzing the hydrolysis of core triglycerides of chylomicrons and very low density lipoproteins. Several polymorphic restriction sites have been reported in the LPL gene, including those identified by the enzymes HindIII and PvuII. We have determined the HindIII and PvuII polymorphisms in diabetic (D) and non-diabetic (ND) Hispanics (D = 195; ND = 384) and non-Hispanic Whites (D = 76; ND = 539) from the San Luis Valley, Colorado. Both polymorphisms showed comparable gene frequencies between diabetics and non-diabetics, and between the two ethnic groups. The HindIII and PvuII polymorphisms were in strong linkage disequilibrium in both Hispanics and non-Hispanic Whites (P < 0.001). We estimated whether the two DNA polymorphisms have significant impact in determining interindividual differences in plasma levels of total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, fasting glucose, and fasting insulin. Plasma triglyceride levels varied significantly among the HindIII genotypes in the normoglycemic sample. There was a clear gene dosage effect among the three HindIII genotypes, with the (-/-) genotype having the lowest and the (+/+) genotype having the highest triglyceride levels; these levels were intermediate in the (+/-) genotype. The average effect of the (-) allele of the HindIII polymorphism was to lower triglycerides by 12.85 mg/dl in non-Hispanic White males, 8.06 mg/dl in non-Hispanic White females, 10.91 mg/dl in Hispanic males, and 12.47 mg/dl in Hispanic females. The HindIII polymorphism also showed a significant association with HDL-cholesterol levels in the normoglycemic sample.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Apolipoprotein H polymorphism and serum lipoprotein and apolipoprotein levels in two Asian populations.

The apolipoprotein H (apo H) is a constituent of several lipoprotein particles and, therefore, may play an important role in lipid metabolism. In this study, we have investigated the role of common apo H structural polymorphism in determining serum total cholesterol; high-density lipoprotein cholesterol; triglycerides; and apolipoproteins A-I, A-II, and B in 655 Chinese and 126 Dravidian Indians from Singapore. Serum lipoprotein and apolipoprotein levels were adjusted for significant concomitant variables for age and body mass index, and the quantitative mean values between different apo H genotypes were compared by an analysis of covariance. The distributions of serum lipoprotein and apolipoprotein levels were found to be comparable between the three common apo H genotypes in both ethnic groups, indicating that the apo H polymorphism may not play a significant role in lipid metabolism.

Apolipoproteins↗
PubMed1993

Obesity: choosing genetic approaches from a mixed menu.

Obesity, as defined by any number of metrics, aggregates in families but does not segregate as a simple Mendelian trait. Because of the frequent association of obesity with a number of common chronic diseases, researchers are greatly interested in identifying the genes that contribute to obesity and their mode of action. The lack of a consensus regarding the biological basis of obesity makes the selection of appropriate candidate genes difficult. Several approaches to selecting plausible candidate genes for the study of obesity are outlined here. The study of rare human phenotypes that result in extreme obesity may identify genes that through polymorphic genetic variation may have an effect on body mass, body composition, or fat distribution. The study of human genes homologous to the mouse genes that lead to obesity in particular strains of inbred mice may also give clues to the location and identity of obesity-related genes. Human populations in which obesity is particularly prevalent may serve as a substrate for identifying such genes in the general population.

Animals↗
PubMed1993

Hemopexin: a unique genetic polymorphism in populations of African ancestry.

Using isoelectric focusing and immunoblotting techniques, we have screened 937 plasma or serum samples from Nigerian blacks (N = 380), Papua New Guineans (N = 110), Aleuts (N = 62), Mayans (N = 139), Dogrib Indians (N = 45), and Eskimos from Kodiak and St. Lawrence islands (N = 201) for the hemopexin (HPX) polymorphism. We compared these data with our previously published data for US whites (N = 267) and US blacks (N = 194). Except for Nigerian blacks and US blacks, HPX was found to be monomorphic for the common HPX*1 allele in all populations tested. In addition to the commonly occurring HPX*1 allele, two other less common alleles, HPX*2 and HPX*3, were observed with respective frequencies of 1.8% and 4.6% in US blacks and 1.7% and 9.0% in Nigerian blacks. These data strongly suggest that the HPX*2 and HPX*3 alleles are unique alleles restricted to the black gene pool and are of potential significance in microevolutionary studies and in defining African admixture in hybrid populations. In addition to their importance in anthropogenetic studies, these unique HPX mutations also have potential biological significance in hemolytic disorders.

Africa↗
PubMed1992

Criteria to detect minimal expressivity within families with autosomal dominant aniridia.

Autosomal dominant aniridia with complete penetrance without Wilms' tumor in five generations with 27 affected family members has been reassigned from chromosome 2p25 to chromosome 11p13. Clinically, aniridia was obvious in affected individuals with variable expressivity when they had rudimentary iris stumps, typical or atypical iris colobomata, or round, eccentric pupils. However, iris and retinal fluorescein angiography was required to detect abnormal vascular remodeling that resulted in incomplete iris collarettes and decreased retinal foveal avascular zones in 27 family members at risk with round, central pupils. These angiograms distinguished five affected and 22 unaffected individuals, and were the critical criteria required to detect minimal expressivity of aniridia in family members with round, central pupils.

Aniridia↗
PubMed1992

Genetic variation in two bone-related proteins: is there an association with bone mineral density or skeletal size in postmenopausal women?

In an effort to determine if structural variation in proteins important in bone metabolism might influence bone mineral density (BMD) and thus be a determinant of susceptibility to osteoporosis in older women, the authors typed a group of 258 non-Black women (age 65-90) participating in the Study of Osteoporotic Fractures (SOF) for two polymorphic bone-related proteins, group specific component (Gc), also known as vitamin D-binding protein, and alpha 2HS glycoprotein (AHSG). These two proteins exhibit common structural variation in populations that can be detected by isoelectric focusing/immunoblotting of serum. An important function of Gc is the binding, solubilization, and transport of vitamin D sterols in the bloodstream while AHSG is a glycoprotein constituent of calcified cortical bone matrix. There are six common phenotypes of Gc and four of AHSG. Using Gc or AHSG phenotypes as categorical variables, statistical analyses were done to determine if bone mineral density of the proximal or distal radius or calcaneus differed by phenotype. Neither Gc nor AHSG phenotype demonstrated a statistically significant relationship with BMD at any site. Adjustments for age and degree of obesity did not substantively affect these results. Subsequent analyses to determine if phenotype of either of these proteins was associated with variables related to skeletal size showed an association of AHSG with height (P less than .02). This may indicate that AHSG phenotype is related to postmenopausal loss of height, or it may be a chance statistical finding.

Aged↗
PubMed1992

Estimation of the frequency of isoform-genotype discrepancies at the apolipoprotein E locus in heterozygotes for the isoforms.

Estimates of the impact of apolipoprotein E (apo E) alleles coding for the three common isoforms on plasma lipid levels assume genetic homogeneity among the genotype classes. To test this assumption, we have determined the apo E genotype at the two common polymorphic sites (amino acids 112 and 158) by DNA amplification and hybridisation with allele-specific oligoprobes, in 195 unrelated Caucasian participants of the Rochester Family Heart Study previously classified as heterozygotes by isoelectric focusing (IEF). Fourteen discordant samples were initially detected. Repeat typing of these samples by both methods resolved nine discrepancies and analysis of additional blood samples from the remaining five individuals eliminated a further four discrepancies. The only truly discordant allele was found in a female subject who had an E3 isoform with the common E2 (Cys112, Cys158) genotype. Transmission of this allele from the mother was demonstrated. From these results, we estimate the frequency of discrepancies between isoforms and common genotypes to be 0.25% in this population. Allele misclassification was caused by poor amplification of the DNA in six samples and superimposition of glycosylated and nonglycosylated apo E isoforms on isoelectric focusing gels in five samples. We conclude that the assumption of genetic homogeneity among genotype classes is valid and that misclassification due to technical difficulties is more frequent than true discordancies.

Adult↗
PubMed1992

Two common polymorphisms in the APO A-IV coding gene: their evolution and linkage disequilibrium.

Human apolipoprotein A-IV (APO A-IV) exhibits a common protein polymorphism detectable by isoelectric focusing (IEF) due to a single base substitution at codon 360 which replaces the frequently occurring glutamine residue (allele 1) with histidine (allele 2). Recently, sequence analysis of the APO A-IV coding region has revealed another common nucleotide substitution at codon 347 which converts the commonly present threonine residue (allele A) into serine (allele T). In order to investigate the extent of genetic variation at codon 347, we screened DNA samples from 192 unrelated individuals using a polymerase chain reaction based assay. The frequencies of the two alleles, A-IV*A and A-IV*T, were 0.81 and 0.19, respectively, with average heterozygosity 0.31. Genetic screening of the corresponding 192 plasma samples by IEF gave frequencies of 0.922 and 0.078 for the A-IV*1 and A-IV*2 alleles, respectively, at codon 360 with average heterozygosity 0.14. Genotype data at the two polymorphic sites were used to assign unequivocal haplotypes to all the 384 chromosomes. Of the expected four haplotypes (A1, T1, A2, and T2) only three were observed and their frequencies were 0.732 for A1, 0.190 for T1 and 0.078 for A2, with average heterozygosity 0.42. Although our data indicate significant linkage disequilibrium between the two sites (chi 21 = 7.65, P < 0.006, standardized disequilibrium constant phi = -0.14) the degree of nonrandom association varied between alleles at the two sites. Based upon allele frequency data and variable linkage disequilibrium between alleles, we propose that the A2 and T1 haplotypes may have evolved from the parental A1 haplotype by two independent mutations.

Apolipoproteins A↗
PubMed1992

Molecular basis of a unique African variant (A-IV 5) of human apolipoprotein A-IV and its significance in lipid metabolism.

Human apolipoprotein A-IV (apoA-IV) exhibits a genetically determined structural polymorphism amenable to analysis by isoelectric focusing and immunoblotting techniques. We have determined the allele frequency and molecular basis of a unique ApoA-IV*5 allele which is widely distributed among blacks but is absent in other populations. The frequency of the ApoA-IV*5 allele in blacks (N = 308) was estimated to be 3.2%. In comparison to the common ApoA-IV*1 allele, analysis of coding and non-coding sequences of the ApoA-IV*5 allele revealed an in-frame insertion of 12 nucleotides near the carboxyl terminal region of the mature protein. The insertion involves an exact duplication of the second of the four repeats and codes for 4 amino acids glutamic acid (GAA), glutamine (CAG), glutamine (CAG), and glutamine (CAG) and is responsible for the charge shift of the the apoA-IV 5 isoform slightly toward the anode as compared to the wild type apoA-IV 1 isoform on the isoelectric focusing gel. This in-frame insertion occurs in a region which is highly conserved among rat, mouse, and humans. In addition to the 12 nucleotide insertion, the four individuals sequenced for the ApoA-IV*5 allele also revealed a same-sense mutation by replacing G to T at the third position of codon 316. Our preliminary data suggest that this unique black allele marker may be of potentially significance in studies of human lipid metabolism and in microevolution.

Adolescent↗
PubMed1992

The impact of the apolipoprotein E polymorphism on the lipoprotein profile in insulin-dependent diabetes: the Pittsburgh Epidemiology of Diabetes Complications Study IX.

The apolipoprotein (apo) E polymorphism has been related to differences in lipoprotein metabolism and lipid/lipoprotein concentrations in a number of studies. Whether these associations are seen in insulin-dependent diabetes mellitus (IDDM), which itself affects many of the same aspects of lipoprotein metabolism as does the apo E polymorphism, is unknown. The present study is an investigation into the influence of apo E phenotype on lipoprotein concentrations in a large group of IDDM patients (n = 433) participating in the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study. The frequency of the three apo E alleles 2, 3, and 4 did not differ in this population from that reported in general white populations. Although the diabetic subjects show the same trends as seen in the general population, ie, apo E-2 is associated with lower and apo E-4 with higher low-density lipoprotein cholesterol (LDLc) compared with apo E3 (P less than .03), they also show relationships with glycemic control that influence the relative levels of lipid measures with respect to apo E phenotype. Results also raise the possibility that lipoprotein composition varies according to apo E phenotype in IDDM.

Adult↗
PubMed1992

Resolution of the two loci for autosomal dominant aniridia, AN1 and AN2, to a single locus on chromosome 11p13.

Two distinct loci have been proposed for aniridia; AN1 for autosomal dominant aniridia on chromosome 2p and AN2 for the aniridia in the WAGR contiguous gene syndrome on chromosome 11p13. In this report, the kindred segregating for autosomal dominant aniridia, which suggested linkage to acid phosphatase-1 (ACP1) and led to the assignment of the AN1 locus on chromosome 2p, has been updated and expanded. Linkage analysis between the aniridia phenotype and ACP1 does not support the original linkage results, excluding linkage up to theta = 0.17 with Z = -2. Tests for linkage to other chromosome 2p markers. APOB, D2S71, D2S5, and D2S1, also excluded linkage to aniridia. Markers that have been isolated from the chromosome 11p13 region were then analyzed in this aniridia family. Two RFLPs at the D11S323 locus give significant evidence for linkage. The PvuII polymorphism detected by probe p5S1.6 detects no recombinants, with a maximum lod score of Z = 6.97 at theta = 0.00. The HaeIII polymorphism detected by the probe p5BE1.2 gives a maximum lod score of Z = 2.57 at theta = 0.00. Locus D11S325 gives a lod score of Z = 1.53 at theta = 0.00. These data suggest that a locus for aniridia (AN1) on chromosome 2p has been misassigned and that this autosomal dominant aniridia family is segregating for an aniridia mutation linked to markers in the 11p13 region.

Alkaline Phosphatase↗