Exclusion of atypical vitelliform macular dystrophy from 8q24.3 and from other known macular degenerative loci.
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Chromosomes, Human, Pair 8↗
Biomedical subjects
R E Ferrell
Publications and source records attributed to R E Ferrell.
The next stage: molecular epidemiology.
The traditional approach in epidemiology of relating exposure to an environmental agent such as a drug or infective agent has been to measure an overall risk (i.e., average and then "adjust risk for demographic variables and other confounders"). An attempt is sometimes made to define a "susceptible" subgroup. The analyses are usually based on good statistical methodology rather than an understanding of the interaction of body of host and agent. A twofold risk for 1000 exposed versus nonexposed people could be an average twofold risk for all 1000 exposed or a 20-fold risk for 100 exposed individuals (i.e., a drug-host interaction). Clearly, finding the 100 individuals with a 20-fold risk has much greater clinical importance than a twofold risk for 1000 people. The world of epidemiology may be changing-we may soon be able to define risk based on genetic susceptibility, at least sometimes.
Apolipoproteins E↗
Trp64Arg substitution in the beta 3-adrenergic receptor does not relate to body weight in healthy, premenopausal women.
OBJECTIVE: To examine the contribution of the substitution of arginine for tryptophan at amino acid position 64 (Trp64Arg) of the beta 3-adrenergic receptor to body weight and weight-related factors in healthy, premenopausal women. SUBJECTS: Five hundred and five healthy, premenopausal women 44-50 y, body mass index (BMI) 20-40 kg/m2. MEASUREMENTS: Subjects were genotyped for the Trp64Arg substitution using restriction fragment length polymorphism (RFLP) analysis. Measurements for weight and weight-related factors (for example, weight, waist-hip ratio, lipid levels) were also taken. RESULTS: Two women were homozygous Arg/Arg, 75 women were heterozygous Trp/Arg, and 428 women were homozygous Trp/Trp. The frequency of the Arg substitution was 0.078. When subjects with and without the arginine substitution were compared, no significant differences were found on measures of weight or weight-related risk factors. CONCLUSION: The results confirm previous studies suggesting that the Trp64Arg substitution of the beta 3-adrenergic receptor is not related to weight or weight-related phenotypes in healthy, premenopausal women.
Alleles↗
Microsatellite data support an early population expansion in Africa.
We have developed a method for the analysis of microsatellite data that is useful in the elucidation of the demographic history of populations. This method, the PK distribution method of pairwise comparisons, is analogous to the mismatch distribution of sequence comparisons developed for the analysis of mitochondrial sequence data by Rodgers and Harpending and is defined as the distribution of the number of repeat unit differences between alleles when each allele in a sample is compared with every other allele in the sample. Using computer simulations of microsatellite loci, we show that the shape of the distribution of PK changes in a distinctive manner as a function either of time since population expansion or effective population size. Increases in both of these affect the PK distribution in a similar fashion leading to a change from a steep distribution with a Po peak to one with a nonzero peak. Analysis of three data sets from surveys of microsatellite loci in ethnographically defined populations reveals that most (9/12) of the African populations analyzed, but none of the 30 non-African populations showed PK distributions with nonzero peaks. These PK distributions indicate either an earlier expansion or a larger effective population size for African populations. This observation is consistent with the hypothesized African origin of modern human.
Africa↗
The role of the apolipoprotein E polymorphism in the prediction of coronary artery disease age of onset.
We investigated the role of the apolipoprotein (Apo) E polymorphism in the prediction of CAD age of onset in a sample of unrelated living male (n = 65) and female (n = 54) Caucasian subjects diagnosed with CAD. Cumulative distributions of age at the first diagnosis of CAD were estimated for each Apo E genotype and tested for homogeneity using the log-rank test. The Apo epsilon 33 genotype was used as a reference group for all hypothesis tests. Analyses were performed separately in males and females. We found evidence suggesting that the presence of the Apo epsilon 32 genotype in males is associated with a significantly earlier CAD age of onset. These results suggest that the Apo E polymorphism may be a gender-specific predictor of CAD age of onset.
Adult↗
Vitamin D receptor gene polymorphisms, bone turnover, and rates of bone loss in older African-American women.
Bone mineral density (BMD) is under genetic control. Some studies in Caucasian and Asian women suggest that polymorphisms in the vitamin D receptor (VDR) gene are associated with BMD and the rate of postmenopausal bone loss. We determined if similar associations exist in 101 African-American women aged 65 years and older (71 +/- 5 years, mean +/- SD). We also examined the relation between VDR genotype and fractional 45Ca absorption and markers of bone formation (osteocalcin) and resorption (N-telopeptides) in these women. BMD was measured at the proximal femur and whole body at baseline and after 1.9 +/- 0.4 years (femur only) on a Hologic QDR-2000 densitometer using dual-energy X-ray absorptiometry. Calcaneal BMD was measured with single x-ray absorptiometry. VDR gene polymorphisms were defined by the endonucleases BsmI, ApaI, and TaqI. These polymorphisms were not associated with BMD at any skeletal site or with markers of bone turnover. There was a significant interaction between age and VDR genotype where the oldest women (> 70 years) with the TT genotype experienced greater hip bone loss than women with the TT genotype (-2.1%/year vs. -0.4%/year, respectively), whereas heterozygous women experienced an intermediate rate of bone loss (-1.3%/year). Women homozygous for the B allele had 14% lower fractional 45Ca absorption compared with women homozygous for the b allele, although this difference was not statistically significant (p = 0.08). We conclude that VDR gene polymorphisms are not associated with BMD or indices of bone turnover in this population of older African-American women. However, DNA sequence variation in the VDR gene or a nearby locus may influence intestinal calcium transport and the rate of postmenopausal bone loss in African-American women.
Absorption↗
Ethnic-affiliation estimation by use of population-specific DNA markers.
During the past 10 years, DNA analysis has revolutionized the determination of identity in a forensic context. Statements about the biological identity of two human DNA samples now can be made with complete confidence. Although DNA markers are very powerful for distinguishing among individuals, most offer little power to distinguish ethnicity or to support any statement about the physical characteristics of an individual. Through a search of the literature and of unpublished data on allele frequencies we have identified a panel of population-specific genetic markers that enable robust ethnic-affiliation estimation for major U.S. resident populations. In this report, we identify these loci and present their levels of allele-frequency differential between ethnically defined samples, and we demonstrate, using log-likelihood analysis, that this panel of markers provides significant statistical power for ethnic-affiliation estimation. In addition to their use in forensic ethnic-affiliation estimation, population-specific genetic markers are very useful in both population- and individual-level admixture estimation and in mapping genes by use of the linkage disequilibrium created when populations hybridize.
Alleles↗
Quantitative effects of the apolipoprotein E polymorphism in a biracial sample of 9-10-year-old girls.
Genetic polymorphism at the apolipoprotein E locus (APOE) has been shown to have a significant impact on quantitative risk factors for coronary artery disease (CAD) in diverse populations. However, despite the recognition that atherosclerosis begins in childhood and that genetic factors are related to the initial stages of atherosclerosis, prior studies were carried out mostly on adults and little attention has been paid to genetic risk factors for CAD in children. We have examined the impact of APOE polymorphism on quantitative risk factors for CAD (apoAI, apoB, TC, LDL-C, HDL-C and TG) in a sample of 647 African American and 573 White 9-10-year-old girls who were enrolled in the National Heart, Lung and Blood Institute Growth and Healthy Study. The frequencies of the APOE*2, APOE*3 and APOE*4 alleles were 0.09, 0.76 and 0.15 in Whites and 0.11, 0.70 and 0.19 in African Americans, respectively. The APOE*2 allele was significantly associated with lower mean levels of LDL-C and apoB and the APOE*4 allele with higher levels of LDL-C and apoB in both racial groups. Variation in maturation stage, body fat and fat patterning, as assessed by skin fold measures and waist/hip ratio, accounted for a significant proportion of the variation in quantitative CAD risk factors.
Alleles↗
Loss of heterozygosity of the short arm of chromosomes 3 and 9 in oral cancer.
Loss of heterozygosity (LOH) on chromosomes 3p and 9p has been documented in a variety of malignancies, which suggests the presence of tumor suppressor gene loci on these chromosomes. We have studied 77 oral carcinomas for LOH using 16 microsatellite markers distributed over 5 human chromosomes. Fifty-five (71%) of these tumors showed LOH at one or more loci. A significant proportion of LOH at the informative tumors was observed at chromosomes 3p and 9p: 58% and 48%, respectively. A majority of the tumors showed losses at multiple loci on chromosomes 3p or 9p or on both. Our results suggest that tumor suppressor genes located on the short arms of chromosomes 3 and 9 may be involved in the pathogenesis of oral carcinoma. These regions of deletion observed in oral cancers overlap those reported in other neoplasms. However, we did not find any evidence of these changes in tumor margins with early pathological changes.
Carcinoma, Squamous Cell↗
Determinants of premenopausal bone mineral density: the interplay of genetic and lifestyle factors.
Bone mineral density (BMD) is a reflection of both genetic and lifestyle factors. The interplay of genetic (vitamin D receptor [VDR] gene polymorphisms) and lifestyle factors on BMD at the lumbar spine and proximal femur was examined in 470 healthy premenopausal women, aged 44-50 years, using a Hologic QDR 2000 densitometer. The objective of this study was to examine the genetic and lifestyle determinants of premenopausal BMD. Each participant was genotyped for BsmI polymorphism at the VDR gene locus. The presence of a restriction site within VDR, specified as bb (189, 40.2%) (n, %) was associated with reduced spinal BMD, whereas absence of this site in BB (97, 20.6%) conferred greater spinal BMD, as did the genotype Bb (184, 39.1%). Associations between smoking, alcohol use, oral contraceptives, education level, multivitamins, number of children, degree of obesity, body weight, physical activity, dietary calcium intake, and VDR genotype to BMDs were examined. VDR genotype, body weight, degree of obesity, physical activity, and dietary calcium intake were all significant determinants of BMD. The association of VDR genotype with BMD at the femoral neck appeared to be modified by calcium intake (BB and Bb: 0.797 +/- 0.11 g/cm2 vs. 0.844 +/- 0.11 g/cm2, interaction term, p = 0.06) for low (< 1036 mg/day) and high (> or = 1036 mg/day; upper quartile) calcium intakes, respectively. A similar trend was demonstrated for physical activity. These findings suggest that prophylactic interventions aimed at achieving and maintaining optimal BMD, such as greater calcium intake or physical activity, may be important in maximizing one's genetic potential for BMD.
Adult↗
The four founding lineage hypothesis for the New World: a critical reevaluation.
It has been proposed that all native American mitochondrial DNA variation in the New World can be attributed to divergence from four "founding lineages" which entered the New World in three waves of migration from across the Bering Strait (T.G. Schurr et al., 1990, Am. J. Hum. Genet. 46: 613-623; A. Torroni and D. C. Wallace, 1995, Am. J. Hum. Genet. 56: 1234-1236; A. Torroni et al., 1994, Am. J. Hum. Genet. 54: 303-318; A. Torroni et al., 1994, Proc. Natl. Acad. Sci. USA 91: 1158-1162; A. Torroni et al., 1994, Am. J. Phys. Anthropol. 93: 189-199; A. Torroni et al., 1993a, Am. J. Hum. Genet. 53: 563-590; A. Torroni et al., 1993b, Am. J. Hum. Genet. 53: 591-608; Wallace and A. Torroni, 1992, Hum. Biol. 64(3): 403-416). Torroni et al. (1993a) believe that only one haplotype from each of these four founding lineages arrived in the New World via migration, and all the additional variation arose in the New World. Any other types were attributed to Caucasian admixture. G. Bailliet et al. (1994, Am. J. Hum. Genet. 55: 27-33), N. O. Bianchi and F. Rothhammer (1995, Am. J. Hum. Genet. 56: 1236-1238), and D. A. Merriwether (1994, Experientia 50: 592-601; 1995, Am. J. Phys. Anthropol. 98(4): 411-430) suggest that multiple variants of each lineage entered the New World, and that additional unrelated lineages also entered. We present the distribution of multiple variants of the four founding lineages, plus two additional lineages which we call X6 and X7, throughout the New World, Siberia, and Asia. These distributions are strong evidence that at least nine different founding lineage haplotypes entered the New World. Further, we find these distributions among Native Americans best fit a single wave of migration into the New World.
Asia↗
Peripheral retinopathy in offspring of carriers of Norrie disease gene mutations. Possible transplacental effect of abnormal Norrin.
BACKGROUND: The Norrie disease (ND) gene (Xp11.3) (McKusick 310600) consists of one untranslated exon and two exons partially translated as the Norrie disease protein (Norrin). Norrin has sequence homology and computer-predicted tertiary structure of a growth factor containing a cystine knot motif, which affects endothelial cell migration and proliferation. Norrie disease (congenital retinal detachment), X-linked primary retinal dysplasia (congenital retinal fold), and X-linked exudative vitreoretinopathy (congenital macular ectopia) are allelic disorders. METHODS: Blood was drawn for genetic studies from members of two families to test for ND gene mutations. Sixteen unaffected family members were examined ophthalmologically. If any retinal abnormality were identified, fundus photography and fluorescein angiography was performed. RESULTS: Family A had ND (R109stp), and family B had X-linked exudative vitreoretinopathy (R121L). The retinas of 11 offspring of carrier females were examined: three of seven carrier females, three of three otherwise healthy females, and one of one otherwise healthy male had peripheral inner retinal vascular abnormalities. The retinas of five offspring of affected males were examined: none of three carrier females and none of two otherwise healthy males had this peripheral retinal finding. CONCLUSIONS: Peripheral inner retinal vascular abnormalities similar to regressed retinopathy of prematurity were identified in seven offspring of carriers of ND gene mutations in two families. These ophthalmologic findings, especially in four genetically healthy offspring, strongly support the hypothesis that abnormal Norrin may have an adverse transplacental (environmental) effect on normal inner retinal vasculogenesis.
Adult↗
Associations between dietary factors and serum lipids by apolipoprotein E polymorphism.
A geographically based observational study of 852 nondiabetic Hispanic and non-Hispanic white persons in southern Colorado aged 20-74 y was conducted to determine whether diet-lipid associations were modified by the apolipoprotein E (apoE, protein; APOE, gene) polymorphism. Subjects were seen for up to three visits from 1984 to 1992. A 24-h diet recall was collected and fasting serum lipid concentrations were measured at all visits. In longitudinal-regression analyses, dietary factors were significantly associated with serum lipid concentrations in the directions expected based on the large amount of literature on this topic. The positive relation between dietary cholesterol and serum total and low-density-lipoprotein cholesterol was strongest in Hispanic subjects with the APOE*2 allele (E2/ 2,3/2 genotypes) and non-Hispanic white subjects with the APOE*3 allele (E3/3 genotype), and there was no association in subjects with the APOE*4 allele (E4/3, 4/4 genotypes) in either ethnic group. No other statistically significant differences in the relations between dietary factors and serum lipid concentrations by APOE polymorphism were identified. These findings suggest that the APOE polymorphism plays only a minor role in modifying the association between dietary factors and serum lipids.
Adult↗
Genotype-environment interaction: apolipoprotein E (ApoE) gene effects and age as an index of time and spatial context in the human.
We analyzed the age-dependence of the estimates of the parameters of the genetic architecture of plasma ApoE levels associated with ApoE gene variation. Our study sample included 1988 individuals in multigeneration pedigrees from the Rochester, MN, population. We used a 30-yr sliding window across the age range (5-90 yr) to estimate the age dependency of parameters. Additive ApoE allelic variance of transformed plasma ApoE values for both genders, heritabilities for males and phenotypic and residual variance for females peaked in the 20-40-yr age windows and decreased significantly with age (P < 0.05). Phenotypic and residual variance for males and dominance variance for both genders did not vary significantly with age. All parameter estimates were significantly different from zero across all age windows for both genders. Most studies of ApoE have focused on its functions in the pathophysiology of coronary artery disease (CAD) in middle-aged and older individuals. Our findings suggest the greatest role of this gene is in determining phenotype differences among younger and middle-aged individuals. These observed genotypic effects on the plasma ApoE levels may contribute to age-dependent differences in physiological health, growth, and risk of disease.
Adolescent↗
Dispersion of human Y chromosome haplotypes based on five microsatellites in global populations.
We have analyzed five microsatellite loci from the nonrecombining portion of the human Y chromosome in 15 diverse human populations to evaluate their usefulness in the reconstruction of human evolution and early male migrations. The results show that, in general, most populations have the same set of the most frequent alleles at these loci. Hypothetical ancestral haplotypes, reconstructed on the basis of these alleles and their close derivatives, are shared by multiple populations across racial and geographical boundaries. A network of the observed haplotypes is characterized by a lack of clustering of geographically proximal populations. In spite of this, few distinct clusters of closely related populations emerged in the network, which are associated with population-specific alleles. A tree based on allele frequencies also shows similar results. Lack of haplotypic structure associated with the presumed ancestral haplotypes consisting of individuals from almost all populations indicate a recent common ancestry and/or extensive male migration during human evolutionary history. The convergent nature of microsatellite mutation confounds population relationships. Optimum resolution of Y chromosome evolution will require the use of additional microsatellite loci and diallelic genetic markers with lower mutation rates.
Alleles↗
Distribution and evolution of CTG repeats at the myotonin protein kinase gene in human populations.
We have analyzed the CTG repeat length and the neighboring Alu insertion/deletion (+/-) polymorphism in DNA samples from 16 ethnically and geographically diverse human populations to understand the evolutionary dynamics of the myotonic dystrophy-associated CTG repeat. Our results show that the CTG repeat length is variable in human populations. Although the (CTG)5 repeat is the most common allele in the majority of populations, this allele is absent among Costa Ricans and New Guinea highlanders. We have detected a (CTG)4 repeat allele, the smallest CTG known allele, in an American Samoan individual. (CTG) > or = 19 alleles are the most frequent in Europeans followed by the populations of Asian origin and are absent or rare in Africans. To understand the evolution of CTG repeats, we have used haplotype data from the CTG repeat and Alu(+/-) locus. Our results are consistent with previous studies, which show that among individuals of Caucasian and Japanese origin, the association of the Alu(+) allele with CTG repeats of 5 and > or = 19 is complete, whereas the Alu(-) allele is associated with (CTG)11-16 repeats. However, these associations are not exclusive in non-Caucasian populations. Most significantly, we have detected the (CTG)5 repeat allele on an Alu(-) background in several populations including Native Africans. As no (CTG)5 repeat allele on an Alu(-) background was observed thus far, it was proposed that the Alu(-) allele arose on a (CTG)11-13 background. Our data now suggest that the most parsimonious evolutionary model is (1) (CTG)5-Alu(+) is the ancestral haplotype; (2) (CTG)5-Alu(-) arose from a (CTG)5-Alu(+) chromosome later in evolution; and (3) expansion of CTG alleles occurred from (CTG)5 alleles on both Alu(+) and Alu(-) backgrounds.
Biological Evolution↗
X-linked exudative vitreoretinopathy caused by an arginine to leucine substitution (R121L) in the Norrie disease protein.
We report the cosegregation of an arginine to leucine substitution at position 121 of the Norrie disease protein in a large kindred where exudative vitreoretinopathy segregates as an X-linked recessive trait. The clinical phenotype and rate of disease progression were extremely variable, with progression to total retinal detachment from less than age 2 years to more than 21 years. To date, all mutations in X-linked vitreoretinopathy have been missense mutations, presumably not affecting the three-dimensional structure of the NDP gene product, and clustered around residues 121-126 of the Norrie protein. This contrasts with the diversity of mutations seen in the more severe, allelic Norrie disease.
Arginine↗
Segregation distortion of the CTG repeats at the myotonic dystrophy locus.
Myotonic dystrophy (DM), an autosomal dominant neuromuscular disease, is caused by a CTG-repeat expansion, with affected individuals having > or = 50 repeats of this trinucleotide, at the DMPK locus of human chromosome 19q13.3. Severely affected individuals die early in life; the milder form of this disease reduces reproductive ability. Alleles in the normal range of CTG repeats are not as unstable as the (CTG)(> or = 50) alleles. In the DM families, anticipation and parental bias of allelic expansions have been noted. However, data on mechanism of maintenance of DM in populations are conflicting. We present a maximum-likelihood model for examining segregation distortion of CTG-repeat alleles in normal families. Analyzing 726 meiotic events in 95 nuclear families from the CEPH panel pedigrees, we find evidence of preferential transmission of larger alleles (of size < or = 29 repeats) from females (the probability of transmission of larger alleles is .565 +/- 0.03, different from .5 at P approximately equal .028). There is no evidence of segregation distortion during male meiosis. We propose a hypothesis that preferential transmission of larger CTG-repeat alleles during female meiosis can compensate for mutational contraction of repeats within the normal allelic size range, and reduced viability and fertility of affected individuals. Thus, the pool of premutant alleles at the DM locus can be maintained in populations, which can subsequently mutate to the full mutation status to give rise to DM.
Alleles↗