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R E Ferrell

Publications and source records attributed to R E Ferrell.

At least 109 records · Page 6Linked to original sources
PubMed1998

Genetic structure of five susceptibility gene regions for coronary artery disease: disequilibria within and among regions.

We analyzed two-locus disequilibria for 16 polymorphic loci of seven susceptibility genes for coronary artery disease located in five chromosomal regions distributed across four chromosomes. Included were the genes coding for apolipoprotein B (ApoB, chromosome 2, four marker loci), lipoprotein lipase (LPL, chromosome 8, three marker loci), apolipoproteins AI, CIII AIV (ApoAI-CIII-AIV, chromosome 11, three marker loci), apolipoprotein E (ApoE, chromosome 19, two marker loci), and the low density lipoprotein receptor (LDLR, chromosome 19, four marker loci). Our sample included 540 unrelated individuals from the Rochester, Minn. population. There were no statistically significant deviations of single-locus genotypes from Hardy-Weinberg equilibrium. The strongest associations within genes were for composite diallelic disequilibria; 17/19 were significant (13 at Pr <0.001, 1 at Pr <0.01, 3 at Pr <0.05). These observations suggest marker alleles within genes have a shared evolutionary history reflected by disequilibria that have not been dissipated by recombination. Disequilibrium was not generally concordant with the physical orderings of markers. Only two significant higher-order disequilibria were observed although 12 triallelic disequilibria were at maximum possible values. We observed 19 statistically significant disequilibria (Pr <0.05; 4 composite diallelic, 13 triallelic, and 2 quadriallelic) between 101 pairs of marker loci, where each locus in a pair was from a different unlinked region. These unexpected results are most likely explained by recent historical factors, including worldwide population expansion and amalgamation with continuous admixture, that influence the genetic structure (organization of alleles and non-alleles into genotypes) of a population. We conclude that disequilibria between loci from unlinked regions may be more extensive than is commonly assumed. Our findings also suggest that it is, on average, at least 15 times more likely to not detect significant disequilibrium among unlinked loci when it is really present than to make a false positive inference. Disequilibria between functional loci within or between regions will impact estimates of genetic variance associated with particular functional mutations within a susceptibility gene region.

Apolipoproteins↗
PubMed1998

Trinucleotide repeat length variation in the human ribosomal protein L14 gene (RPL14): localization to 3p21.3 and loss of heterozygosity in lung and oral cancers.

Chromosome 3p is consistently deleted in lung cancer, oral squamous cell carcinoma, and renal cell carcinoma, and is believed to contain several tumor suppressor genes. We have shown a role for chromosome 3 in tumor suppression by microcell-mediated chromosome transfer experiments. We have isolated a gene that is located at 3p21.3 within the smallest region of deletion overlap in lung tumors and is the human homolog of the ribosomal protein L14 gene (RPL14). The RPL14 sequence contains a highly polymorphic trinucleotide repeat array which encodes a variable-length polyalanine tract. Genotype analysis of RPL14 shows that this locus is 68% heterozygous in the normal population, compared with 25% in non-small cell lung cancer (NSCLC) cell lines (p = 0.008). Cell cultures derived from normal bronchial epithelium show a 65% level of heterozygosity, reflecting that of the normal population. Squamous cell carcinoma of the head and neck (SCCHN), which has the same risk factors as lung cancer and is hypothesized to have a similar etiology, demonstrates 54% loss of heterozygosity at the RNA level, suggesting that transcriptional loss may be a primary mechanism of RPL14 alteration in SCCHN. In addition, RPL14 shows significant differences in allele frequency distribution in ethnically-defined populations, making this sequence a useful marker for the study of ethnicity-adjusted lung cancer risk.

Biopsy↗
PubMed1998

A novel homeobox gene PITX3 is mutated in families with autosomal-dominant cataracts and ASMD.

We report here the identification of a new human homeobox gene, PITX3, and its involvement in anterior segment mesenchymal dysgenesis (ASMD) and congenital cataracts in humans. The PITX3 gene is the human homologue of the mouse Pitx3 gene and is a member of the RIEG/PITX homeobox gene family. The protein encoded by PITX3 shows 99% amino-acid identity to the mouse protein, with 100% identity in the homeodomain and approximately 70% overall identity to other members of this family. We mapped the human PITX3 gene to 10q25 using a radiation-hybrid panel. A collection of 80 DNA samples from individuals with various eye anomalies was screened for mutations in the PITX3 gene. We identified two mutations in independent patients. A 17-bp insertion in the 3'-end of the coding sequence, resulting in a frame shift, occurred in a patient with ASMD and cataracts, and a G-->A substitution, changing a codon for serine into a codon for asparagine, in the 5'-end of the gene occurred in a patient with congenital cataracts. Both mutations cosegregate with the disease phenotype in families, and neither were found in up to 300 control individuals studied. Further expression analysis of Pitx3 in the mouse supports a unique role in early ocular development, with later expression extending to the midbrain, tongue, incisors, sternum, vertebrae and limbs. These data strongly suggest a role for PITX3 in ASMD and cataracts and provide new evidence of the contribution of the RIEG/PITX gene family to the developmental program underpinning normal eye formation.

Amino Acid Sequence↗
PubMed1998

Linkage analysis of X-linked cone-rod dystrophy: localization to Xp11.4 and definition of a locus distinct from RP2 and RP3.

Progressive X-linked cone-rod dystrophy (COD1) is a retinal disease affecting primarily the cone photoreceptors. The COD1 locus originally was localized, by the study of three independent families, to a region between Xp11.3 and Xp21.1, encompassing the retinitis pigmentosa (RP) 3 locus. We have refined the COD1 locus to a limited region of Xp11.4, using two families reported elsewhere and a new extended family. Genotype analysis was performed by use of eight microsatellite markers (tel-M6CA, DXS1068, DXS1058, DXS993, DXS228, DXS1201, DXS1003, and DXS1055-cent), spanning a distance of 20 cM. Nine-point linkage analysis, by use of the VITESSE program for X-linked disorders, established a maximum LOD score (17.5) between markers DXS1058 and DXS993, spanning 4.0 cM. Two additional markers, DXS977 and DXS556, which map between DXS1058 and DXS993, were used to further narrow the critical region. The RP3 gene, RPGR, was excluded on the basis of two obligate recombinants, observed in two independent families. In a third family, linkage analysis did not exclude the RPGR locus. The entire coding region of the RPGR gene from two affected males from family 2 was sequenced and was found to be normal. Haplotype analysis of two family branches, containing three obligate recombinants, two affected and one unaffected, defined the COD1 locus as distal to DXS993 and proximal to DXS556, a distance of approximately 1.0 Mb. This study excludes COD1 as an allelic variant of RP3 and establishes a novel locus that is sufficiently defined for positional cloning.

Alleles↗
PubMed1998

Estimating African American admixture proportions by use of population-specific alleles.

We analyzed the European genetic contribution to 10 populations of African descent in the United States (Maywood, Illinois; Detroit; New York; Philadelphia; Pittsburgh; Baltimore; Charleston, South Carolina; New Orleans; and Houston) and in Jamaica, using nine autosomal DNA markers. These markers either are population-specific or show frequency differences >45% between the parental populations and are thus especially informative for admixture. European genetic ancestry ranged from 6.8% (Jamaica) to 22.5% (New Orleans). The unique utility of these markers is reflected in the low variance associated with these admixture estimates (SEM 1.3%-2.7%). We also estimated the male and female European contribution to African Americans, on the basis of informative mtDNA (haplogroups H and L) and Y Alu polymorphic markers. Results indicate a sex-biased gene flow from Europeans, the male contribution being substantially greater than the female contribution. mtDNA haplogroups analysis shows no evidence of a significant maternal Amerindian contribution to any of the 10 populations. We detected significant nonrandom association between two markers located 22 cM apart (FY-null and AT3), most likely due to admixture linkage disequilibrium created in the interbreeding of the two parental populations. The strength of this association and the substantial genetic distance between FY and AT3 emphasize the importance of admixed populations as a useful resource for mapping traits with different prevalence in two parental populations.

Africa↗
PubMed1998

Hereditary lymphedema: evidence for linkage and genetic heterogeneity.

Hereditary or primary lymphedema is a developmental disorder of the lymphatic system which leads to a disabling and disfiguring swelling of the extremities. Hereditary lymphedema generally shows an autosomal dominant pattern of inheritance with reduced penetrance, variable expression and variable age at onset. Three multigeneration families demonstrating the phenotype of hereditary lymphedema segregating as an autosomal dominant trait with incomplete penetrance were genotyped for 366 autosomal markers. Linkage analysis yielded a two-point LOD score of 6.1 at straight theta = 0. 0 for marker D5S1354 and a maximum multipoint LOD score of 8.8 at marker D5S1354 located at chromosome 5q34-q35. Linkage analysis in two additional families using markers from the linked region showed one family consistent for linkage to distal chromosome 5. In the second family, linkage to 5q was excluded for all markers in the region with LOD scores Z < -2.0. The vascular endothelial growth factor C receptor ( FLT4 ) was mapped to the linked region, and partial sequence analysis identified a G-->A transition at nucleotide position 3360 of the FLT4 cDNA, predicting a leucine for proline substitution at residue 1126 of the mature receptor in one nuclear family. This study localizes a gene for primary lymphedema to distal chromosome 5q, identifies a plausible candidate gene in the linked region, and provides evidence for a second, unlinked locus for primary lymphedema.

Chromosomes, Human, Pair 5↗
PubMed1998

VO2 max is associated with ACE genotype in postmenopausal women.

Relationships have frequently been found between angiotensin-converting enzyme (ACE) genotype and various pathological and physiological cardiovascular outcomes and functions. Thus we sought to determine whether ACE genotype affected maximal O2 consumption (VO2 max) and maximal exercise hemodynamics in postmenopausal women with different habitual physical activity levels. Age, body composition, and habitual physical activity levels did not differ among ACE genotype groups. However, ACE insertion/insertion (II) genotype carriers had a 6.3 ml . kg-1 . min-1 higher VO2 max (P < 0.05) than the ACE deletion/deletion (DD) genotype group after accounting for the effect of physical activity levels. The ACE II genotype group also had a 3.3 ml . kg-1 . min-1 higher VO2 max (P < 0.05) than the ACE insertion/deletion (ID) genotype group. The ACE ID group tended to have a higher VO2 max than the DD genotype group, but the difference was not significant. ACE genotype accounted for 12% of the variation in VO2 max among women after accounting for the effect of habitual physical activity levels. The entire difference in VO2 max among ACE genotype groups was the result of differences in maximal arteriovenous O2 difference (a-vDO2). ACE genotype accounted for 17% of the variation in maximal a-vDO2 in these women. Maximal cardiac output index did not differ whatsoever among ACE genotype groups. Thus it appears that ACE genotype accounts for a significant portion of the interindividual differences in VO2 max among these women. However, this difference is the result of genotype-dependent differences in maximal a-vDO2 and not of maximal stroke volume and maximal cardiac output.

Body Composition↗
PubMed1997

Genomic structure and genetic mapping of the human neutral cysteine protease bleomycin hydrolase.

Bleomycin hydrolase (BH) is the only known eukaryotic enzyme that inactivates the widely used antineoplastic agent bleomycin (BLM) and is a primary candidate gene for protection against lethal BLM-induced pulmonary fibrosis and for BLM resistance in tumors. Human BH was found to exist as a single gene that was mapped to chromosome 17 using National Institute of General Medical Sciences human/rodent hybrid mapping panels and localized to 17q11.1-11.2 by linkage analysis using the Centre d'Etude du Polymorphisme Humain reference database. The human BH gene consisted of 11 exons ranging in size from 69-198 bp separated by introns of approximately 1 kb, reflecting the archetypal genomic structure of the cysteine protease family. A polymorphic site was identified in the eleventh exon at bp 1450 encoding either valine or isoleucine. These findings provide essential tools required to define the role of BH in BLM-induced pulmonary fibrosis and BLM resistance in tumors.

Animals↗
PubMed1997

A dietary and behavioral intervention designed to lower coronary heart disease. Risk factors are unaffected by variation at the APOE gene locus.

Variation at the apolipoprotein E (APOE) gene locus has demonstrated a consistent impact on lipoprotein levels. APOE typing was performed for 488 healthy, caucasian, premenopausal women participating in the Women's Healthy Lifestyle Project (WHLP) aimed at reducing total fat, saturated fat and cholesterol intake and promoting physical activity. Women in both the intervention and control groups were included in the trial. The purpose of the present study was to determine whether the magnitude of the changes in total cholesterol (Tc), low density lipoprotein cholesterol (LDLc) and high density lipoprotein cholesterol (HDLc) due to the dietary intervention were dependent on the variation in APOE. Weight, body mass index (BMI), and lipoprotein levels were measured at baseline and at a 6 month follow-up. ANOVA was used to determine whether the change in Tc and LDLc was dependent on dietary intervention and variation at APOE levels. The levels of Tc and LDLc were higher in women with the APOE*4 genotype. There were no statistically significant effects of APOE genotype and changes in Tc and LDLc (P > 0.1). Adjusted Tc and LDLc changes were comparable in the 3 APOE subgroups (Tc = -14.3, -12.9 and -11.7 mg/dl; LDLc = -12.1, -10.7 and -10.7 mg/dl, respectively as above). In conclusion, the genetic (APOE) background of premenopausal women in this study did not have a significant effect on their response to dietary intervention.

Apolipoproteins E↗
PubMed1997

Mitochondrial versus nuclear admixture estimates demonstrate a past history of directional mating.

Six blood group antigens (ABO, RH, MNS, KK, KP, FY) and five plasma proteins (HP, GC, APOA4, FXIIIB, C1R) were typed in 790 individuals, and 12 mtDNA RFLP and deletion polymorphisms were typed in 657 individuals from the San Luis Valley, Colorado. The 790 nuclear typings were conducted on 399 Anglos and 391 Hispanics, while the 657 mitochondrial haplotypes were generated from 207 Anglos and 450 Hispanics. Chakraborty's ADMIX2 FORTRAN program was used to estimate the average Amerindian admixture using all nuclear loci simultaneously. Since there is no recombination in mtDNA, the sum of the frequencies of the Amerindian/Asian-specific mitochondrial haplotypes represents the level of Amerindian admixture. The nuclear estimates of Amerindian admixture were 33.15 +/- 2.41% for the Hispanics and 9.72 +/- 1.90% for the Anglos, while the strictly maternally inherited mtDNA estimates of Amerindian admixture were 85.11% for the Hispanics and 0.97% for the Anglos. This dramatic difference in estimated levels of admixture between the biparentally derived nuclear estimates and the uniparentally derived mtDNA estimates is indicative of past directional matings between Hispanic males and Amerindian females.

Blood Group Antigens↗
PubMed1997

Two discrete regions of deletion at 7q in uterine leiomyomas.

This study further defines the region of consistent deletion of chromosome 7 in uterine leiomyomas. We have examined 74 leiomyomas for allelic loss of markers spanning the 7q22 region defined by markers D7S518 and D7S471. Forty tumors with cytogenetically defined 7q deletions, twenty-nine tumors without cytogenetically visible 7q deletions, and five tumors with no cytogenetic information were examined for allelic loss of D7S518, D7S666, D7S515, D7S658, D7S496, D7S692, and D7S471. Loss of heterozygosity for one or more of these loci was observed in twenty-eight leiomyomas with cytogenetically defined 7q deletions and in three leiomyomas with a normal karyotype. Allelic loss of D7S666 was common and was observed in all twenty-three informative tumors with 7q deletions and in two tumors with normal karyotypes. This study indicates the presence of a tumor suppressor gene in close proximity to the D7S666 locus. Eight tumors followed an unusual pattern of allelic loss. These tumors showed retention of heterozygosity for at least one locus flanked by deleted loci. These results suggest the possibility that two discrete regions of deletion at 7q22 are involved in the development of a subset of leiomyomas.

Alleles↗
PubMed1997

Gender-specific nonrandom association between the alpha 1-antichymotrypsin and apolipoprotein E polymorphisms in the general population and its implication for the risk of Alzheimer's disease.

A common polymorphism in the alpha 1-antichymotrypsin (ACT) gene has been found co modify the APOE*4-associated risk of Alzheimer's disease due to an apparent interaction between the two loci. This study was undertaken to determine the gender- and age-related distributions of these two polymorphisms in two large population-based samples of Caucasians (n = 803) and Nigerian Blacks (n = 730). Significantly higher frequencies of the ACT*A (78.6% vs. 48.4%; P < 0.001) and APOE*4 (25.6% vs. 15.6%; P < 0.001) alleles were observed in Nigerian Blacks than in Caucasians. In Caucasian women but not in men, the frequency of the APOE*4 allele was significantly lower in the ACT/AA genotype as compared to the ACT/AT and ACT/TT genotypes, while a reverse trend was seen for the APOE*3 allele frequency among the ACT genotypes. The distribution of the ACT*A allele between the APOE*4 carriers and non-APOE*4 carriers was also different in Caucasian women but not in men. A similar gender-specific nonrandom association between the two polymorphisms was observed in Black women but this was not as strong as observed in Caucasian women. When the two samples were stratified by age group, an association or trend of association was observed in all age groups in women only. These data indicate the existence of a nonrandom association between the APOE and ACT loci in women which may have an important implication for the higher prevalence of Alzheimer's disease in women.

Adult↗
PubMed1997

The epidemiology of quantitative ultrasound: a review of the relationships with bone mass, osteoporosis and fracture risk.

Quantitative ultrasound (QUS) is a simple, inexpensive and non-invasive measure of bone which has been used in research settings for the prediction of osteoporosis. This review summarizes the current status of the epidemiology of QUS analysis, including its relationship with bone mineral density (BMD), risk of osteoporotic fracture and risk factors for osteoporosis. Although only moderately correlated with BMD, QUS appears to be as strong a predictor of osteoporotic fracture as BMD and may predict fracture independent of BMD. Risk factors for low QUS, including age, menopause, body composition and physical inactivity, seem to parallel those of low BMD. More longitudinal research is needed to confirm the clinical utility of QUS and more experimental and population-based studies are needed to determine whether the etiology of low QUS values is different from that of low bone mass.

Bone Density↗
PubMed1997

The high mobility group I-C gene (HMGI-C): polymorphism and genetic localization.

We have identified a highly informative dinucleotide repeat in the 5'-flanking region of the human high mobility group I-C (HMGI-C) gene. This polymorphism consists of 18-37 copies of a (CT) repeat with an observed heterozygosity of 82-83% in African Americans and Caucasians. Linkage analysis in CEPH pedigrees localized the HMGI-C gene to chromosome region 12q13-15 with no recombination observed between HMCI-C and markers D12S102 and D12S8.

Black or African American↗
PubMed1997

Association between common alleles of the low-density lipoprotein receptor gene region and interindividual variation in plasma lipid and apolipoprotein levels in a population-based sample from Rochester, Minnesota.

This paper presents an analysis of the relationship between variation in the low-density lipoprotein receptor (LDLR) gene region and interindividual variation in plasma lipid and apolipoprotein levels in a sample representative of the adult population of Rochester, Minn. (217 females and 187 males aged 26 to 63). This relationship was analyzed by estimating the average excesses of alleles of the LDLR gene defined using RFLP markers both singly and simultaneously. We also used a cladistic approach to illustrate the consequences of incorporating evolutionary information into the analysis of genotype-phenotype relationships. Although results from both approaches supported the inference that common variation in the LDLR gene region associates with small effects on plasma lipid and apolipoprotein levels, only the cladistic approach provides direction for further work aimed at identifying the functional DNA sequence variations responsible for the observed associations.

Adult↗