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R E Ferrell

Publications and source records attributed to R E Ferrell.

At least 91 records · Page 5Linked to original sources
PubMed1999

Aggression and anger-related traits associated with a polymorphism of the tryptophan hydroxylase gene.

BACKGROUND: Central nervous system (CNS) serotonergic activity correlates inversely with human aggressive behavior, and individual differences in aggressive disposition are at least partially heritable. This study was conducted to evaluate the possible association between measures of antagonistic behavior and an intronic polymorphism of the gene coding for tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin biosynthesis. METHODS: Locally recruited men and women (n = 251) were genotyped for the A218C polymorphism located in intron 7 of the TPH gene. All subjects were administered standard interview and questionnaire indices of aggression and anger-related traits of personality; in a portion of subjects, CNS serotonergic activity was assessed by neuropsychopharmacologic challenge (prolactin response to fenfluramine hydrochloride). RESULTS: Persons having any TPH U allele scored significantly higher on measures of aggression and tendency to experience unprovoked anger and were more likely to report expressing their anger outwardly than individuals homozygous for the alternate L allele. In men, but not women, peak prolactin response to fenfluramine was also attenuated among subjects having any U allele, relative to LL homozygotes. CONCLUSIONS: Individual differences in aggressive disposition are associated with an intronic polymorphism of the TPH gene in a nonpatient sample of community-derived volunteers.

Aggression↗
PubMed1999

Frequent allelic loss and homozygous deletion in chromosome band 8p23 in oral cancer.

Frequent loss of heterozygosity on chromosome 8p in a variety of human malignancies, including head and neck cancers, has suggested the presence of a tumor suppressor gene (or genes) associated with the pathogenesis of these cancers. To test the role of genetic alterations at 8p23 in oral carcinogenesis, we studied 51 squamous cell carcinomas of the head and neck and 29 oral squamous cell carcinoma cell lines for allelic loss using 7 microsatellite markers spanning approximately 5 cM of chromosome band 8p23. Twenty-three of 51 tumors (45%) and 23 of 29 cell lines (79%) showed allelic loss at 1 or more loci. Three cell lines showed homozygous deletion of loci within a 3 cM region defined by the markers D8S1781 and D8S262. Our results suggest that a tumor suppressor gene (or genes) is located in 8p23 and is associated with the development and/or progression of oral carcinomas.

Carcinoma, Squamous Cell↗
PubMed1999

Mitochondrial DNA variation is an indicator of austronesian influence in Island Melanesia.

Past studies have shown a consistent association of a specific set of mitochondrial DNA 9 base pair (bp) deletion haplotypes with Polynesians and their Austronesian-speaking relatives, and the total lack of the deletion in a short series of New Guinea Highlanders. Utilizing plasma and DNA samples from various old laboratory collections, we have extended population screening for the 9-bp deletion into "Island Melanesia," an area notorious for its extreme population variation. While the 9-bp deletion is present in all Austronesian, and many non-Austronesian-speaking groups, it is absent in the more remote non-Austronesian populations in Bougainville and New Britain. These results are consistent with the hypothesis that this deletion was first introduced to this region about 3,500 years ago with the arrival of Austronesian-speaking peoples from the west, but has not yet diffused through all populations there. The pattern cannot be reconciled with the competing hypothesis of a primarily indigenous Melanesian origin for the ancestors of the Polynesians. Although selection clearly has operated on some other genetic systems in this region, both migration and random genetic drift primarily account for the remarkable degree of biological diversity in these small Southwest Pacific populations.

Anthropology↗
PubMed1999

Recent progress in understanding the genetic susceptibility to osteoporosis.

Family and twin studies have established a genetic contribution to the etiology of osteoporosis. The genes and allelic variants conferring osteoporotic risk are largely undefined, but the number of candidates has increased steadily in recent years (Table I). Osteoporosis is a complex disease, and allelic variation in many other candidate-genes including those that encode growth factors, cytokines, calciotropic hormones, and bone matrix proteins are likely to also play a role and warrant systematic investigation. Most family and association studies to date have focused on the genetic contributions to bone density, a major determinant of bone strength and fracture risk. Bone density is not the only determinant of skeletal fragility, however, and genetic influences on fracture risk are independent of bone density [Cummings et al., 1995]. The microarchitectural properties and overall size and geometry of bone also influence skeletal strength [Bouxsein et al., 1996], and the genetic influences on these phenotypes should be investigated more rigorously. Even fewer studies have assessed the association between candidate-gene variation and the risk of fracture, the most important clinical outcome of osteoporosis. Large-scale molecular epidemiologic studies will be increasingly necessary in the future to quantify the relative, absolute and attributable risks of fracture associated with specific genetic variants. Osteoporosis is a complex, multifactorial disease, and most candidate-gene association studies have had limited statistical power to assess gene-gene and gene-environment interaction. Although gender plays an important role in the development of osteoporosis, genetic studies have almost exclusively focused on women, and have not tested whether gender modifies the association between genetic variation and osteoporotic risk. Therefore, future genetic studies will need to recruit larger samples of individuals including men. Rapid additional progress in our understanding of the molecular basis of osteoporosis can be expected in the near future as ongoing genome-wide linkage [Spotila et al., 1996] and candidate-gene association analyses are completed. Linkage analyses in families at high-risk for rare metabolic bone diseases should also yield important clues to the pathogenesis of osteoporosis. Recent examples are the mapping of loci for both high [Johnson et al., 1997] and low [Gong et al., 1996] bone mass to chromosome 11q and osteopetrosis to chromosome 1p [Van Hul et al., 1997]. Similar ongoing studies in baboons [Rogers and Hixson, 1997] and mice [Beamer et al., 1997] may reveal additional loci whose human homologs contribute to osteoporotic risk. The improved understanding of osteoporosis that will emerge from these genetic studies should lead to better diagnosis of this disease and new treatment and prevention strategies.

Animals↗
PubMed1999

Vitamin D receptor translation initiation codon polymorphism and markers of osteoporotic risk in older African-American women.

A polymorphism at the first of two potential translation initiation codons in the vitamin D receptor (VDR) gene defined by the FokI restriction endonuclease has been associated with reduced bone mineral density (BMD) among Caucasian, Asian, and Mexican-American women. We tested the hypothesis that the FokI polymorphism is related to markers of osteoporotic risk in 104 community-dwelling African-American women aged 65 years and older. Six percent of the African-American women had the ff genotype, 32% were heterozygous, and 63% had the FF genotype. FokI genotype frequencies did not differ from Hardy-Weinberg expectations. Hip and calcaneal BMD, calcaneal ultrasound attenuation and hip geometry from pelvic radiographs did not differ significantly by FokI genotypes or between women with and without the rare FokI allele. There was also no association between the FokI polymorphism and biochemical markers of bone turnover or fractional calcium absorption. We conclude that the VDR start codon polymorphism does not have a major influence on osteoporotic risk in older African-American women.

Aged↗
PubMed1999

Correlates of quantitative ultrasound in the Women's Healthy Lifestyle Project.

Quantitative ultrasound (QUS) assessment of bone is a strong predictor of hip fractures and is currently an FDA-approved tool to identify women at risk of osteoporosis. However, few studies have investigated the lifestyle and genetic correlates of QUS in women. This study investigated the cross-sectional associates of several lifestyle, demographic and genetic factors with calcaneal QUS parameters (broadband ultrasound attenuation (BUA) and speed of sound (SOS)) in 393 women aged 45-53 years. Leisure-time and historical physical activity, dietary calcium and protein, body composition, vitamin D receptor genotypes, menopause status, other health behaviors, calcaneal QUS parameters and bone mineral density (BMD) were assessed at a single clinic visit. Lean mass, recent physical activity and African-American race were the strongest correlates of SOS whereas dietary protein, calcium and recent physical activity were the strongest correlates of BUA. These predictors explained 13% and 6% of the variance in SOS and BUA, respectively. Smoking, alcohol intake, education, hormone replacement therapy, calcium and vitamin D supplements, historical physical activity and vitamin D receptor genotypes were not significantly associated with BUA or SOS. Lean body mass and premenopausal status were the strongest correlates of lumbar BMD whereas lean body mass, physical activity, African-American race and body mass index were significantly related to femoral neck BMD. Physical activity remained predictive of SOS after controlling for lumbar BMD. The spectrum and magnitude of risk factors for SOS and BUA, including lean body mass, physical activity, race, protein and calcium intake, parallel previously observed predictors of BMD.

Black People↗
PubMed1999

Correlates of lipoprotein(a) levels in a biracial cohort of young girls: the NHLBI Growth and Health Study.

Elevated levels of lipoprotein(a) [Lp(a)] are associated with increased risk for coronary heart disease (CHD). However, racial differences in both Lp(a) levels and their associated CHD risk are observed, with African Americans having, on average, higher Lp(a) levels than US whites but not the expected increase in CHD risk. We determined Lp(a) levels and their correlates in a large cohort (n = 2379) of black and white girls, ages 9 to 10 years, at the baseline visit of a longitudinal study of obesity development, the National Heart, Lung, and Blood Institute Growth and Health Study. Lp(a) levels were available for 1269 girls. The median Lp(a) level in black girls was over 3-fold higher than that in white girls. Associations were examined between Lp(a) levels and low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, apolipoprotein B, triglycerides, adiposity, pubertal maturation stage, body fat patterning (triceps/truncal skinfold ratio), and dietary fat (Keys' score). In black girls multiple regression analysis identified LDL-C (P <.001) and adiposity (P =. 08) as predictors of Lp(a) levels. In white girls only LDL-C (P =. 02) was associated with Lp(a). In conclusion, the level of Lp(a) was significantly higher in black girls. Our study also revealed a racial difference in correlates of Lp(a), such as LDL-C and adiposity. Whether this racial difference is due to an underlying biologic difference or is merely a reflection of a greater statistical power to detect a relationship with the level, which was 2.5-fold higher in black girls than in white girls, needs further investigation.

Analysis of Variance↗
PubMed1999

Apolipoprotein E genotype and exercise training-induced increases in plasma high-density lipoprotein (HDL)- and HDL2-cholesterol levels in overweight men.

We determined if the apolipoprotein E (APO E) genotype affects the exercise training-induced increase in plasma high-density lipoprotein cholesterol (HDL-C) and HDL2-C. Sedentary overweight men on an American Heart Association (AHA) step I diet had plasma lipoprotein-lipids measured before and after 9 months of endurance exercise training. APO E2 (n = 6), E3 (n = 33), and E4 (n = 12) groups were similar at baseline in terms of age, body weight and composition, and plasma lipoprotein-lipid profiles. APO E2 men had a larger increase in plasma HDL-C and HDL2-C with exercise training than APO E3 and E4 men (HDL-C, 8 +/- 4 v 3 +/- 1 v 2 +/- 1 mg/dL; HDL2-C, 5 +/- 3 v 1 +/- 1 v -1 +/- 1 mg/dL; mean +/- SE, all P < .01). After adjusting for body weight changes, the increases in plasma HDL-C and HDL2-C remained greater in APO E2 versus E3 and E4 men (all P < .03). These results indicate that APO E2 men may have greater plasma HDL-C and HDL2-C increases with endurance exercise training.

Age Factors↗
PubMed1999

Association of pre-eclampsia with common coding sequence variations in the lipoprotein lipase gene.

Marked dyslipidemia may contribute to endothelial cell dysfunction in pre-eclampsia. Carriers of N291S or D9N missense mutations in the lipoprotein lipase (LPL) gene exhibit reductions in LPL activity and are predisposed to dyslipidemia and cardiovascular disease. In Caucasians, the D9N variant is in strong linkage disequilibrium with the - 93T --> G promoter variant. A fourth LPL variant, S447X, is often associated with a beneficial lipid profile. We asked if the N291S and the combination D9N/- 93T --> G variants are more prevalent, and if the S447X variant is less prevalent, in Caucasian women with pre-eclampsia as compared with normal pregnancies. DNA amplification was followed by an allele-specific oligonucleotide ligation assay. Allele frequencies were analyzed with a chi2 table and Yates' correction. The N291S variant was identified in 11.1% of pre-eclamptics as compared with 2.9% of pregnancy controls (p = 0.008). All carriers of D9N were also carriers of - 93T --> G. The D9N/ - 93T --> G combined variant was found in 7.1% of pre-eclamptics as compared with 1.4% of pregnancy controls (p = 0.02). No individuals were carriers of both N291S and D9N/ - 93T --> G. Thus, 18.2% of pre-eclamptics had either of these LPL mutations compared with 4.3% of pregnancy controls (and 4.4% of population controls). The frequency of the S447X variant did not differ among groups. We conclude that carriers of N291S or combined D9N/ - 93T --> G mutations in the LPL gene are at substantially increased risk of pre-eclampsia.

Adult↗
PubMed1999

Neuroticism is not associated with the serotonin transporter (5-HTTLPR) polymorphism.

A deletion/insertion polymorphism in the transcriptional control region of the serotonin transporter gene (5-HTTLPR) was reported to be associated with dimensional measures of neuroticism, although subsequent replication attempts have failed. These replication attempts, however, have been dissimilar to the initial study in sample size, distribution of allelic frequency and/or assessment of neuroticism. The current study was conducted in a further attempt to replicate the initial finding using: (a) a sample that was more comparable to each of the individual samples in the initial report; and (b) identical psychometric methodology to assess neuroticism. Two hundred and twenty-five Caucasian adults were genotyped for the 5-HTTLPR polymorphism and completed the NEO Personality Inventory. Results did not replicate the association between the 5-HTTLPR polymorphism and neuroticism; individuals with the short form of this variant did not report higher NEO Neuroticism. Indeed, men with the short form reported lower Anxiety, a finding that is directionally opposite to the initial results. These findings, combined with other failures to replicate, indicate that the reproducibility of the association between the 5-HTTLPR polymorphism and neuroticism must be regarded as questionable. The contradictory findings suggest the need for a replication attempt in a large, normative sample that is stratified by ethnicity and sex.

Adult↗
PubMed1999

Influence of apolipoprotein E genotype variation on the means, variances, and correlations of plasma lipids and apolipoproteins in children.

The impact of the three most common apolipoprotein E (APOE) genotypes (epsilon 32, epsilson 33, and epsilon 43) on means, variances, and correlations of nine plasma lipid and apolipoprotein traits (total cholesterol, InTriglycerides, HDL cholesterol, and apolipoproteins AI, AII, B, CII, CIII, and InE) was studied in 212 unrelated female and 219 unrelated male children aged 5-21.5 years from 278 pedigrees ascertained without regard to health status from Rochester, Minnesota. There was significant heterogeneity (p < or = 0.05) among genotypes for the mean plasma levels of InApo E, Apo CII, Apo CIII, and InTriglycerides (InTrig) in females, and for the means of InApo E, Apo B, and total cholesterol (Total-C) in males. Significant heterogeneity of intragenotypic variance was observed in males for Apo CII, InTrig, and HDL-C; no significant heterogeneity was observed in females. Pairwise correlations between traits differed significantly among APOE genotypes in both females (6 of 36 pairs) and males (5 of 36 pairs). These results differ from those obtained from studies of the parental generation from the same sample of pedigrees. Our study further demonstrates that, with the exception of mean InApo E levels, the univariate and bivariate distributions of traits that are measures of lipoprotein metabolism are influenced by variation in the APOE gene in a gender- and generation-dependent manner.

Adolescent↗
PubMed1999

The relationship between risk factor levels and presence of coronary artery calcification is dependent on apolipoprotein E genotype.

An important research question in the study of the genetics of coronary artery disease (CAD) is whether information about genetic variation will improve our ability to predict CAD beyond established risk factors. This question is especially relevant to the goal of identifying young, asymptomatic adults with coronary atherosclerosis who would benefit most from interventions to reduce risk. Coronary artery calcification (CAC) detected by electron-beam computed tomography is a relatively new method for detecting coronary atherosclerosis in asymptomatic individuals that has been shown to be a more accurate indicator of coronary atherosclerosis in asymptomatic individuals than other noninvasive techniques. In a study of asymptomatic women (n=169) and men (n=160) between the ages of 20 and 59 representative of the Rochester, Minnesota population, we used logistic regression to ask whether the most common Apolipoprotein (Apo) E genotypes (epsilon3/2, epsilon3/3, and epsilon4/3) predict the presence of CAC. The addition of information about ApoE genotypes to logistic models containing each separate risk factor did not improve prediction of CAC (P>0.10 in both women and men). However, there was significant evidence (P<0.10) that associations between variation in the probability of having CAC and variation in body mass index, plasma total cholesterol, and plasma ApoB in men and body mass index, plasma triglycerides, plasma ApoA1, and plasma ApoE in women were dependent on ApoE genotype. Thus, variation in the gene coding for ApoE may play a role in determining the contribution of established risk factors to risk of CAC.

Adult↗
PubMed1999

Exercise training-induced blood pressure and plasma lipid improvements in hypertensives may be genotype dependent.

Exercise training improves cardiovascular disease risk, but individual responses are highly variable. We hypothesized that common polymorphic gene variations would affect these responses. Sedentary obese hypertensive older men who had undergone exercise training were typed at the apolipoprotein (apo) E, angiotensin-converting enzyme (ACE), and lipoprotein lipase (LPL) loci. Individuals of all genotype subgroups were generally similar before training; they also changed body weight, body composition, and &f1;O(2)max similarly with training. ACE insertion/insertion (II) and insertion/deletion (ID) genotype individuals (n=10) tended to reduce systolic blood pressure more with training than deletion/deletion (DD) individuals (n=8) (-10 versus -5 mm Hg, P=0. 16). ACE II and ID individuals decreased diastolic blood pressure more with training than DD individuals (-10 versus -1 mm Hg, P<0. 005). Systolic blood pressure reductions with training were also larger in apoE3 and E4 (n=15) than apoE2 men (n=3) (-10 versus 0 mm Hg, P<0.05). The same trend was evident for diastolic blood pressure (-7 versus -3 mm Hg), but the difference was not significant. Systolic (14 versus -6 mm Hg, P=0.08) and diastolic (-9 versus -5 mm Hg, P=0.10) blood pressure reductions tended to be greater in LPL PvuII +/+ (n=4) than +/- and -/- individuals (n=14). Systolic (-10 versus 3 mm Hg, P<0.05) and diastolic (-9 versus 2 mm Hg, P<0.05) blood pressure reductions were larger in LPL HindIII +/+ and +/- (n=15) than -/- persons (n=3), respectively. LPL PvuII -/- individuals (n=3) had larger increases in HDL cholesterol (11 versus 2 mg/dL, P<0.05) and HDL(2) cholesterol (8 versus 0 mg/dL, P<0.05) than LPL PvuII +/- and +/+ individuals (n=15). These results are consistent with the possibility that apoE, ACE, and LPL genotypes may identify hypertensives who will improve blood pressure, lipoprotein lipids, and cardiovascular disease risk the most with exercise training.

Apolipoproteins E↗
PubMed1999

Functional polymorphism in the matrix metalloproteinase-9 promoter as a potential risk factor for intracranial aneurysm.

BACKGROUND AND PURPOSE: There is convincing evidence that susceptibility to intracranial aneurysms (ICAs) has a genetic component. However, few studies have sought to identify functional variation in specific candidate genes that may predispose individuals to develop an ICA. METHODS: ICA cases and controls were genotyped for a simple length polymorphism in the promoter of matrix metalloproteinase-9 (MMP-9) to test for association between variation in the promoter and the occurrence of ICA. Alternative alleles were cloned into an in vitro reporter vector, transfected into human HT1080 fibroblasts, and assayed for promoter activity by beta-gal and luciferase assays. Electrophoretic gel shift assays were used to assess nuclear factor binding. RESULTS: A length polymorphism in the promoter of MMP-9 was nonrandomly associated with the occurrence of ICA in a case-control study. This polymorphism was shown, by direct sequencing of 36 individuals, to be the only sequence variation within a 736-base pair region proximal to the transcriptional start site of the gene. Variation in the length of this repetitive element was shown to modulate promoter activity in an in vitro reporter assay, with the highest promoter activity being observed in constructs bearing the longest [(CA)23] element. Electrophoretic mobility shift assays were used to show that the (CA) element is bound by a sequence-specific DNA-binding protein. CONCLUSIONS: Genetic variation in the promoter of the MMP-9 gene results in variation in its expression at the level of transcription. This may result in subtle differences in MMP-9 activity within the circle of Willis, leading to increased susceptibility to ICA formation.

Alleles↗
PubMed1999

Apolipoprotein E polymorphism: A new genetic marker of hip fracture risk--The Study of Osteoporotic Fractures.

Hip fractures are common and devastating events. The apolipoprotein E*4 (APOE) allele, associated with Alzheimer's disease, has also been associated with osteoporosis in hemodialysis patients. We prospectively studied 1750 women, age >/=65 years, who underwent measurements of hip and calcaneal bone mineral density (BMD), were typed for APOE and followed for approximately 7.0 years for the occurrence of fractures and falls. Women with at least one APOE*4 allele had an increased risk of hip fracture, relative hazard (RH) (95% confidence interval) = 1.90 (1.05-3.41) and wrist fracture, RH = 1.67 (1.01-2.77) compared with women without APOE*4, even after adjusting for age, cognitive function, falling, and BMD. The effect of APOE*4 on hip fracture was greatest among women with additional (>/=3) other risk factors. Women with an APOE*4 allele were also likely to report a maternal history of fracture. The average number of falls per year did not differ by APOE*4: 0.46 for APOE*4 women and 0.41 for women without an APOE*4 allele. Women with an APOE*4 allele experienced greater weight loss which contributed to faster rates of bone loss. We conclude that women with the APOE*4 polymorphism are at substantially increased risk of hip and wrist fracture that is not explained by bone density, impaired cognitive function, or falling. Possible alternate explanations include an effect of APOE on vitamin K, bone turnover, or weight loss. The APOE polymorphism may be a candidate gene for hip fractures among community dwelling nondemented women.

Accidental Falls↗
PubMed1998

Genetic association studies between Alzheimer's disease and two polymorphisms in the low density lipoprotein receptor-related protein gene.

The E*4 allele of apolipoprotein E (APOE) is a major risk factor for Alzheimer's disease (AD) but the underlying mechanism is unknown. The low density lipoprotein receptor-related protein (LRP) is directly involved in APOE metabolism and therefore may alter the risk of AD associated with APOE. Two common polymorphisms, a tetranucleotide repeat in the 5'-region and a same-sense mutation in exon 3, are present in the LRP gene. Three studies have reported conflicting association of the tetranucleotide polymorphism with AD. The only study of the exon 3 polymorphism found a significant association with AD. In this study we examined the association of these two LRP polymorphisms with sporadic late-onset AD. No significant association was observed between the tetranucleotide polymorphism and AD. While the overall genotype and allele frequencies for the LRP exon 3 polymorphism were comparable between AD cases and controls, the frequency of the TT genotype was significantly higher in controls than AD (5.7% vs. 2.5%; P < 0.01). Stratification of the data by APOE genotypes indicated that the protective effect associated with the TT genotype was confined to APOE*4 carriers. Although the effect of the exon 3 polymorphism in our sample is small compared to the previous study, this warrants additional studies to confirm this putative association.

Age of Onset↗
PubMed1998

Genetic variation in alpha 2HS-glycoprotein is related to calcaneal broadband ultrasound attenuation in older women.

Calcaneal broadband ultrasound attenuation (BUA) is an independent predictor of hip and vertebral fractures. BUA is under genetic control, but the specific genes contributing to BUA are not well defined. We examined the relationship between genetic variation in alpha2HS-glycoprotein (AHSG), an abundant noncollagenous protein of bone matrix, and calcaneal BUA. Genetic polymorphism in AHSG was determined in 222 Caucasian women (age 66-92) enrolled in the Pittsburgh Study of Osteoporotic Fractures clinical center by isoelectric focusing of serum samples. Calcaneal BUA and bone mineral density (BMD) were measured on the same foot with a Walker Sonix UBA 575(+) and single X-ray absorptiometry. Hip and spine BMD were determined with a Hologic QDR-1000 densitometer using dual-energy X-ray absorptiometry. AHSG polymorphism was not significantly related to hip, lumbar spine, or calcaneal BMD. Compared with the homozygous AHSG*2 women, calcaneal BUA was 13% lower in heterozygous (P < 0.05) and 16% lower in homozygous AHSG*1 women (P < 0.05). This relationship persisted after controlling for age, weight, height, walks for exercise, and calcaneal BMD. Current and self-reported height were also lowest in homozygous AHSG*1 women, intermediate in heterozygous women, and highest among homozygous AHSG*2 subjects. These results suggest that the AHSG polymorphism may contribute to the genetic influence on calcaneal BUA and stature.

Aged↗