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R E Ferrell

Publications and source records attributed to R E Ferrell.

At least 235 records · Page 13Linked to original sources
PubMed1989

Phenotypic effects of apolipoprotein structural variation on lipid profiles. I. APO H and quantitative lipid measures in the healthy women study.

Apolipoprotein H (APO H), also known as beta 2-glycoprotein I, has been identified as a protein component of the major lipoprotein density fractions in human plasma. Recently, genetically determined structural polymorphism in white and black populations has been documented for this apolipoprotein. There are three common alleles in whites and blacks and a fourth allele found mainly in blacks. Family data confirm the autosomal codominant pattern of inheritance for the APO H structural gene. Little is known about the function of APO H, but it has demonstrated both lipid and platelet involvement. In this study we investigate the effect of APO H phenotypes on quantitative lipid measures in a group of 443 white women being followed through menopause for changes in cardiovascular risk. At baseline all women were premenopausal. None of the APO H phenotypes showed a statistically significant effect on lipid measures in this population.

Adult↗
PubMed1989

Phenotypic effects of apolipoprotein structural variation on lipid profiles: II. Apolipoprotein A-IV and quantitative lipid measures in the healthy women study.

Apolipoprotein A-IV (APO A-IV) is a major protein component of mesenteric lymph chylomicrons and very-low-density lipoproteins. It is found in plasma predominantly unassociated with major lipoprotein fractions and in high density lipoproteins. APO A-IV exhibits structural heterogeneity owing to two codominant alleles, APO A-IV*1 and APO A-IV*2, that occur in Caucasian and black populations. In vitro experimental evidence indicates that APO A-IV may be a cofactor for the lecithin:cholesterol acyltransferase enzyme, may be involved in reverse cholesterol transport, and may play an important role in the modulation of lipoprotein lipase activity. In this study we have investigated the effect of two APO A-IV phenotypes, APO A-IV 1-1 and APO A-IV 2-1, on quantitative lipid measures in a group of 453 white women being followed through menopause for changes in cardiovascular risk. At baseline all women were premenopausal. Of the nine lipid measures, triglycerides showed a marginally significant effect caused by phenotype. The APO A-IV 2-1 heterozygotes had lower average triglycerides than the 1-1 homozygotes (P = .053).

Adult↗
PubMed1989

Phenotypic effects of apolipoprotein structural variation on lipid profiles. IV. Apolipoprotein polymorphisms in a small group of black women from the healthy women study.

Structural variation in apolipoprotein E has been shown to influence lipid and lipoprotein concentrations. The purpose of the present study was to investigate several apolipoproteins in a group of Black women from the Healthy Women Study (HWS). HWS is a community-based prospective study of 541 premenopausal women who are being followed through the menopause to determine the influence of biological, genetic, and psychosocial phenomenon on cardiovascular risk factors. Of the 541 subjects, 48 are Black. Serum from most of these 48 Black women was used to type seven apolipoproteins (APO A-I, APO A-II, APO A-IV, APO C-II, APO D, APO E, and APO H). Five of these apolipoproteins are polymorphic in Blacks (APO A-IV, APO C-II, APO D, APO E and APO H). Only two and three individuals, respectively, were heterozygous at the APO D and APO C-II loci. APO A-IV, E, and H exhibited more variation, however, only APO E phenotypes could be used for statistical analyses. Three common phenotypes, APO E 3-2, APO E 3-3, and APO E 4-3, were used in analysis of variance on four quantitative lipid variables. Despite small numbers, the effect of APO E phenotype was apparent. The APO E 3-2 phenotype showed reduced average levels of total cholesterol, apolipoprotein B (APO B) and low-density lipoprotein cholesterol (LDLc), and the APO E 4-3 phenotype showed increased levels (P less than or equal to .0497). The APO E3-3 homozygote was intermediate on all three. Because of small numbers in the cells of APO A-IV and APO H phenotypes, these were not analyzed with respect to quantitative lipids.

Adult↗
PubMed1989

On the role of vitamin D binding globulin in glucose homeostasis: results from the San Luis Valley Diabetes Study.

Several studies have reported association between noninsulin-dependent diabetes mellitus and GC, the vitamin D binding protein of human plasma, with the GC 1 allele in significant excess among diabetics. Additionally, there is a considerable body of animal data suggesting that vitamin D has a significant impact on insulin secretion. Examination of the insulin levels in Dogrib Indians showed that the lowest levels of fasting insulin were associated with the GC IF-IF genotype. The present study examined levels of glucose, C-peptide, and insulin at fasting and 1 hr and 2 hr following a 75 g oral glucose challenge, in a population of Hispanic-Americans and Anglos in the San Luis Valley of southern Colorado. The sample comprised a total of 468 individuals with normal glucose tolerance. Of these, 289 were Anglos and 179 were Hispanic-Americans. An analysis of covariance was performed to determine the effect of the GC genotypes on mean levels of the primary variables--glucose, C-peptide, and insulin--and a secondary variable--insulinogenic index adjusting for the covariates age, body mass index (BMI), gender, and ethnicity. The analyses revealed that there is a significant difference in mean levels of glucose at fasting (F value = 2.46; P = 0.033) among the GC genotypes in the sample. Additionally, the differences in mean levels of 1 hr postprandial glucose among the GC genotypes although not significant at a 5% level, were significant at the 10% level. No other significant phenotypic effects were observed. These analyses are not in concordance with the results of an earlier study, where lower fasting insulin was associated with the GC 1F-1F genotype.

Blood Glucose↗
PubMed1989

Genetic studies of type 2 (non-insulin-dependent) diabetes mellitus: lack of association with seven genetic markers.

Type 2 (non-insulin-dependent) diabetes mellitus, a disease of complex aetiology, has been reported to be nonrandomly associated with several polymorphic markers in human populations. These data, plus evidence of a high prevalence of Type 2 diabetes mellitus in American Indians and mixed populations, such as Mexican-Americans, which is only partially attributable to the prevalence of obesity in these populations, makes it imperative that the nature of such associations be clarified in relation to genetic susceptibility to Type 2 diabetes mellitus. The present paper reports the results of tests of association between Type 2 diabetes mellitus and seven polymorphic markers: the blood groups - ABO, Rhesus, Duffy and Kell (K and KP) - haptoglobin and group specific component; among Anglo and Hispanic populations in the San Luis Valley of Colorado, USA. The sample population consisted of 788 individuals of which 398 were Anglo subjects (97 Types 2 diabetes mellitus patients and 301 normal individuals) and 390 Hispanic subjects (191 Type 2 diabetes mellitus patients and 199 normal individuals). Association between Type 2 diabetes mellitus and genetic markers in patients was tested using the G2 statistic within each ethnic class using normal frequencies as a comparison. Results of the tests indicated that only the Kell blood group was significantly associated with Type 2 diabetes mellitus at a 5% level among the Anglo subjects (G2 = 5.16, 1df). This significant value can be explained by chance alone, if multiple comparisons are taken into account. Our tests have not shown the previously reported haptoglobin or Rhesus blood group associations seen in Mexican-Americans in San Antonio, Texas.

Blood Group Antigens↗
PubMed1989

Genetic studies of human apolipoproteins. VIII. Role of the apolipoprotein H polymorphism in relation to serum lipoprotein concentrations.

Apolipoprotein H (APO H) has recently been identified as a structural component of chylomicrons, very low-density lipoproteins (VLDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL). Although the precise metabolic function of APO H in lipid metabolism is not certain, it has been suggested that APO H may be involved in triglyceride (TG) metabolism. In addition to the previously described quantitative polymorphism, we have recently detected a common qualitative polymorphism at the APO H structural locus. To test the role of APO H genetic variation in determining lipoprotein and lipid levels, we have estimated the allelic effects of APO H variation on TG, VLDL, LDL, HDL, HDL3, and total cholesterol on 356 Nigerian blacks (189 males, 167 females). While no significant effect of phenotype was observed on lipoprotein levels, the effect of interaction between phenotype and gender was significant. Therefore, data on males and females were analyzed separately using analysis of variance after adjusting for age and body mass index. Logarithmic transformation of pertinent variables was done to bring the distribution of the variables closer to normality. A statistically significant effect of phenotype was observed on triglyceride levels in females only (P less than 0.05). Further analysis of this phenotypic effect revealed that it is due to the impact of the APO H*3 allele, which raises triglycerides by 9.92 mg/dl as compared to the common allele, APO H*2. These findings are in accordance with the postulated role of APO H in triglyceride metabolism. On the basis of its sex-specific effect, we propose a hypothesis that may explain the combined influence of the quantitative and qualitative polymorphisms at the APO H locus on triglyceride levels in females.

Cholesterol↗
PubMed1989

A genetic linkage study of familial breast-ovarian cancer.

Linkage analysis was conducted in 17 families identified by the familial occurrence of breast and ovarian cancer using a series of 17 serologic and biochemical markers. Lod scores suggestive of linkage of breast/ovarian cancer susceptibility to the RH blood group locus on chromosome 1p were obtained. When the presence of fibrocystic disease of the breast in a first-degree relative of an affected family member was added as an indicator of susceptibility, the evidence for linkage increased. No evidence of linkage to GPT or ABO, both previously suggested to be linked to breast cancer susceptibility, was seen in this study.

Age Factors↗
PubMed1989

Genetic studies of low-abundance human plasma proteins. XII. A new variant of corticosteroid-binding globulin detected by isoelectric focusing/immunoblotting.

Thin-layer polyacrylamide gel isoelectric focusing over the pH range 3.5-5 followed by immunoblotting was used to investigate the occurrence and frequency of genetic variation in corticosteroid-binding globulin (CBG). Plasma samples from US Caucasians (n = 105) and US Blacks (n = 106) from Pittsburgh, Pa., Canadian Indians from Vancouver Island (n = 91) and Nigerian Blacks (n = 116) were analyzed. A complex isoprotein pattern was observed in all individuals tested. Reduction of this pattern to a single primary band following neuraminidase treatment indicates that the observed intraindividual variation is due to variation in the number of sialic acid residues associated with CBG. The CBG variant pattern consisted of a series of isoprotein bands having the same mobility as the common pattern, and a second series of bands at a more acidic isoelectric point. This pattern is consistent with heterozygosity for a rare CBG allele.

Blood Proteins↗
PubMed1989

Genetic studies of low-abundance human plasma proteins. XI. Linkage analysis and population genetics of the C1S subcomponent of the first complement component.

Although subcomponents C1r and C1s of the first complement component, C1, have been established to be in the same linkage group as the proline-rich protein gene cluster on chromosome 12p13.2, no direct analysis of linkage between the C1R and C1S structural gene loci has been available. We have detected through a population screening study 5 families which are heterozygous at the structural loci for both C1R and C1S. Three of the 5 families, 21 individuals, were informative for linkage. A maximum lod score of 1.505 at theta = 0.00 was found in a two-point analysis between C1R and C1S. Ten populations were screened for structural variation at the C1S locus. Only US Whites and a Kodiak Island Eskimo group expressed heterogeneity. The frequencies of the designated alleles, C1S*1 and C1S*2, were 0.992 and 0.007, respectively, in the US White population and 0.998 and 0.002, respectively, in the Kodiak Island Eskimo population. In addition, the product of a putative new allele, designated C1S*4, was observed in a single US White individual but segregation of this variant was not observed in the limited family data available.

Blood Proteins↗
PubMed1989

Genetic analysis of childhood sarcoma.

A survey of cancer in 159 3-year survivors of childhood soft tissue sarcoma and their relatives revealed a cancer excess in first-degree relatives primarily due to cancers occurring before the age of 35 years and a highly significant excess in relatives of patients with second malignant neoplasms. Tumors of soft tissue and bone, breast, and brain were in excess in relatives and as second malignant neoplasms in patients. To determine the most likely explanation for the observed cancer distribution, we applied segregation analysis under a unified version of the mixed model. The observed data were most compatible with a rare autosomal dominant gene with high penetrance (gene carriers had a 50% probability of cancer by age 30, increasing to 90% by age 60) as compared with a chance occurrence or a multifactorial explanation. We contrasted the relative odds of observing each pedigree under a sporadic, multifactorial, or major gene model, and identified 11 pedigrees in which familial clustering of cancer was significant, with the distribution of cancer strongly favoring a major gene in 9 pedigrees. The tumors in these kindreds have been associated with alterations in specific genetic loci by tumor-specific genetic analysis. In particular, we observed soft tissue sarcoma, osteosarcoma and premenopausal ductal breast carcinoma tumors, perhaps attributable to loss of the Rb-1 suppressor gene on chromosome 13q, in the same patients and families. Study of the cancer predisposition segregating in 10 families by genetic linkage with markers of chromosome 13q and the Rb-1 gene have to date given negative LOD scores at 0 = 0 of Z = -1.2 to -13.0.(ABSTRACT TRUNCATED AT 250 WORDS)

Bone Neoplasms↗
PubMed1989

Genetic studies of human apolipoproteins. X. The effect of the apolipoprotein E polymorphism on quantitative levels of lipoproteins in Nigerian blacks.

Human apolipoprotein E exhibits genetic polymorphism in all populations examined to date. By isoelectric focusing and immunoblotting, three common alleles have been demonstrated in 365 unrelated Nigerian blacks. Furthermore, the APO E genetic polymorphism's effect on quantitative levels of lipids and lipoproteins has been determined. The respective frequencies of the APO E*2, APO E*3, and APO E*4 alleles are .027, .677, and .296. The effect of APO E polymorphism is significant only on total cholesterol and low-density lipoprotein cholesterol. The average excesses of the APO E*2 allele are to lower total cholesterol and low-density lipoprotein cholesterol by 9.19 mg/dl and 11.11 mg/dl, respectively. The average excesses of the APO E*4 allele are to increase total cholesterol and low-density lipoprotein cholesterol by 5.64 mg/dl and 6.18 mg/dl, respectively. On the basis of the differences in (a) the distribution of APO E allele frequencies between the Nigerians and other populations and (b) dietary lipids, we propose a model that shows that lipid metabolism is influenced by the combined effects of the APO E polymorphism and environmental factors.

Alleles↗
PubMed1989

Gene and gene-product variation in the apolipoprotein A-I/C-III/A-IV cluster in the Dogrib Indians of the Northwest Territories.

The Dogrib, an Amerindian tribe residing in the Northwest Territories of Canada, were typed for DNA and protein polymorphism at the apolipoprotein A-I/C-III/A-IV gene cluster. Variation was seen at three previously described RFLPs detected with the enzymes SstI, PstI, and XmnI, though frequencies of these polymorphisms differ significantly from those reported in other populations. They exhibit no variation at two previously reported PvuII sites. No variation was seen in the APO A-I or APO A-IV gene products, with the Dogrib showing the most common isoelectric-focusing/immunoblot patterns of other world populations. Haplotype frequencies computed from inferred haplotypes and by maximum likelihood estimation did not differ significantly. The extent of nonrandom association of these sites is highly significant (P less than .00001), though pairwise analysis shows significance between the SstI and XmnI sites only. Levels of fasting triglyceride and fasting total cholesterol were determined for each individual. Analysis of covariance shows that fasting triglyceride levels in women vary significantly with the XmnI genotype. These results suggest that genetic variation at the APO A-I/C-III/A-IV gene cluster may be a useful tool for the study of quantitative lipoprotein variation in the Dogrib.

Adult↗
PubMed1989

Genetic studies of low-abundance human plasma proteins. XIII. Population genetics of C1R complement subcomponent and description of new variants.

Isoelectric focusing and immunoblotting reveals considerable biochemical and genetic variation in the C1R subcomponent of the first complement component. The nature of the intraindividual biochemical variation can be explained by differences in sialic acid content because after digestion with neuraminidase the terminal sialic acids are removed to yield a single major band corresponding to the C1R polypeptide. Plasma samples from a large number of different ethnic groups, consisting of U.S. whites, U.S. blacks, Nigerian blacks, and Inuit, Aleut, and Amerindian populations from the Western Hemisphere have revealed genetically determined charge variation with heterozygous phenotypes consisting of two major asialo bands, indicating that the underlying variation is not due to variation in sialic acid content. Two previously reported common alleles, C1R*1 and CIR*2, have been observed in all studied populations, the notable exception being the Dogrib Indian population, which is devoid of the C1R*2 allele. Several new alleles--designated C1R*3, C1R*4, C1R*5, C1R*6, and C1R*7-have been observed, with variable frequencies ranging from the occurrence in a single individual and related family members to the polymorphic occurrence of certain alleles in several populations. Of these new alleles, the C1R*5 is of considerable interest in population and anthropological genetics studies. The C1R*5 allele is widely distributed, at a frequency of .03 to .17, in all of the North American aboriginal populations screened. This allele is not present in U.S. whites but is present at a polymorphic frequency in U.S. and Nigerian blacks.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗
PubMed1989

Genetic studies of human apolipoproteins. XI. The effect of the apolipoprotein C-II polymorphism on lipoprotein levels in Nigerian blacks.

The human apolipoprotein C-II locus exhibits genetically determined structural polymorphism in United States and African blacks. In the present study, we have investigated the effect of the apoC-II polymorphism on quantitative serum levels of total cholesterol, total high density lipoprotein (HDL) cholesterol, cholesterol in high density lipoprotein subfractions, low density lipoprotein (LDL) cholesterol, and triglycerides (TG) in a sample of 368 unrelated Nigerian blacks. The frequencies of the APOC-II*1 and APOC-II*2 alleles in the samples were 0.947 and 0.053, respectively. In males, the effect of the APOC-II*2 allele was to lower the total serum cholesterol and LDL-cholesterol levels by 13.28 mg/dl and 10.55 mg/dl, respectively, relative to the common allele, APOC-II*1. In females, the effect was to lower total plasma cholesterol by 4.49 mg/dl and LDL-cholesterol by 3.21 mg/dl. The effect of apoC-II on quantitative lipoprotein levels is shown to be independent of variation at the linked apoE locus, but the products of the two loci interact in determining overall quantitative phenotypes.

Adolescent↗
PubMed1989

Genetic studies of human apolipoproteins. IX. Apolipoprotein D polymorphism and its relation to serum lipoprotein lipid levels.

Apolipoprotein D (APO D) is a constituent of plasma high-density lipoproteins. Its precise role in lipid metabolism is not well established, though it may be involved in cholesterol esterification and cholester ester transport to the liver for catabolism. No genetic polymorphism has been reported in the APO D gene product. To investigate the extent of genetic variation at the APO D structural locus, we have developed an isoelectric focusing-immunoblotting technique and have screened a large number of plasma samples from U.S. whites, U.S. blacks, Nigerian blacks, the Aleuts of the Pribilof Islands, Eskimo groups from Kodiak Island and St. Lawrence Island, and Amerindian populations from Mexico and Canada. Except for the U.S. blacks and Nigerian blacks, the APO D locus is monomorphic in all other population groups tested. In populations with black ancestry, the products of two alleles, APO D*1 and APO D*2, have been observed at respective allele frequencies .987 and .013 in U.S. blacks and .978 and .022 in Nigerian blacks. The detection of a unique protein polymorphism in blacks makes APO D a useful black marker of significance in anthropogenetics and racial admixture studies. In addition to the interindividual variation observed, APO D reveals extensive intraindividual molecular variation with a multiple banding pattern. The basis of this molecular variation is explained, in part, by variation in the number of terminal sialic acid residues. We have investigated the effect of the APO D polymorphism on triglycerides, total cholesterol, LDL-, VLDL-, HDL-, and HDL3 cholesterol in 352 Nigerian blacks (190 males and 162 females).(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗