Georgia M Dunston

Inter American University of Puerto Rico, Fajardo, Fajardo, Puerto Rico

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Publications (72)362.13 Total impact

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    ABSTRACT: Single nucleotide polymorphisms (SNPs) represent an important type of dynamic sites within the human genome. These common variants often locally correlate into more complex multi-SNP haploblocks that are maintained throughout generations in a stable population. The information encoded in the structure of common SNPs and SNP haploblock variation can be characterized through a normalized information content (NIC) metric. Such an intrinsic measure allows disparate regions of individual genomes and the genomes of various populations to be quantitatively compared in a meaningful way. Using our defined measures of genomic information, the interplay of maintained statistical variations due to the environmental baths within which stable populations exist can be interrogated. We develop the analogous "thermodynamics" characterizing the state variables for genomic populations that are stable under stochastic environmental stresses. Since living systems have not been found to develop in the absence of environmental influences, we focus on describing the analogous genomic free energy measures in this development. The intensive parameter describing how an environment drives genomic diversity is found to depend inversely upon the NIC of the genome of a stable population within that environment. Once this environmental potential has been determined from the whole genome of a population, additive state variables can be directly related to the probabilities of the occurrence of given viable SNP based units (alleles) within that genome. This formulation allows the determination of both population averaged state variables as well as the genomic energies of individual alleles and their combinations. The determination of individual allelic potentials then should allow the parameterization of specific environmental influences upon shared alleles across populations in varying environments.
    12/2013;
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    ABSTRACT: Characterization of genetic admixture of populations in the Americas and the Caribbean is of interest for anthropological, epidemiological, and historical reasons. Asthma has a higher prevalence and is more severe in populations with a high African component. Association of African ancestry with asthma has been demonstrated. We estimated admixture proportions of samples from six trihybrid populations of African descent and determined the relationship between African ancestry and asthma and total serum IgE levels (tIgE). We genotyped 237 ancestry informative markers in asthmatics and nonasthmatic controls from Barbados (190/277), Jamaica (177/529), Brazil (40/220), Colombia (508/625), African Americans from New York (207/171), and African Americans from Baltimore/Washington, D.C. (625/757). We estimated individual ancestries and evaluated genetic stratification using Structure and principal component analysis. Association of African ancestry and asthma and tIgE was evaluated by regression analysis. Mean ± SD African ancestry ranged from 0.76 ± 0.10 among Barbadians to 0.33 ± 0.13 in Colombians. The European component varied from 0.14 ± 0.05 among Jamaicans and Barbadians to 0.26 ± 0.08 among Colombians. African ancestry was associated with risk for asthma in Colombians (odds ratio (OR) = 4.5, P = 0.001) Brazilians (OR = 136.5, P = 0.003), and African Americans of New York (OR: 4.7; P = 0.040). African ancestry was also associated with higher tIgE levels among Colombians (β = 1.3, P = 0.04), Barbadians (β = 3.8, P = 0.03), and Brazilians (β = 1.6, P = 0.03). Our findings indicate that African ancestry can account for, at least in part, the association between asthma and its associated trait, tIgE levels.
    Genetic Epidemiology 04/2013; · 4.02 Impact Factor
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    ABSTRACT: Multiple Sclerosis (MS) is a complex disease where genetic and environmental factors have been implicated. The onset of symptoms occurs in individuals from twenty to fifty years of age, producing a progressive impairment of motor, sensory and cognitive functions. MS is more frequent in females than in males with a ratio of 4:1. The prevalence of the MS varies among ethnics groups such as Europeans, Africans and Caucasians. The estimated prevalence of MS in Puerto Rico is 42 for each 100,000 habitants, which is more than the prevalence reported for Central America and the Caribbean. In spite of this prevalence, the genetic component of MS has not been explored in order to know the alleles' expression of Puerto Rican MS patients and compare it with the allele expression in other ethnic groups. Thirty-five patients and 31 control subjects were genotyped. The allele frequencies expressed in this sample were similar to those expressed for Puerto Ricans in the National Marrow Donor Program Registry (n = 3,149). The most prevalent alleles for MS patients were HLA-DRB1*01 and *03. HLA-DQB1*04 was the most frequent in the control group and HLA-A*30, in MS patients. These findings are in agreement with published data. HLA-DQB1*04 was a marginal protector in this sample and this role has not been described before. The accuracy of the results is limited due to the sample size. After performing a statistical power analysis it showed that by increasing the sample the values would be significant.
    Boletín de la Asociación Médica de Puerto Rico 01/2013; 105(1):18-23.
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    Georgia M Dunston
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    ABSTRACT: The complete sequencing of the human genome introduced a new knowledge base for decoding information structured in DNA sequence variation. My research is predicated on the supposition that the genome is the most sophisticated knowledge system known, as evidenced by the exquisite information it encodes on biochemical pathways and molecular processes underlying the biology of health and disease. Also, as a living legacy of human origins, migrations, adaptations, and identity, the genome communicates through the complexity of sequence variation expressed in population diversity. As a biomedical research scientist and academician, a question I am often asked is: "How is it that a black woman like you went to the University of Michigan for a PhD in Human Genetics?" As the ASCB 2012 E. E. Just Lecturer, I am honored and privileged to respond to this question in this essay on the science of the human genome and my career perspectives.
    Molecular biology of the cell 11/2012; 23(21):4154-6. · 5.98 Impact Factor
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    ABSTRACT: Background:Prostate cancer (PCa) is a common malignancy and a leading cause of cancer death among men in the United States with African-American (AA) men having the highest incidence and mortality rates. Given recent results from admixture mapping and genome-wide association studies for PCa in AA men, it is clear that many risk alleles are enriched in men with West African genetic ancestry.Methods:A total of 77 ancestry informative markers (AIMs) within surrounding candidate gene regions were genotyped and haplotyped using Pyrosequencing in 358 unrelated men enrolled in a PCa genetic association study at the Howard University Hospital between 2000 and 2004. Sequence analysis of promoter region single-nucleotide polymorphisms (SNPs) to evaluate disruption of transcription factor-binding sites was conducted using in silico methods.Results:Eight AIMs were significantly associated with PCa risk after adjusting for age and West African ancestry. SNP rs1993973 (intervening sequences) had the strongest association with PCa using the log-additive genetic model (P=0.002). SNPs rs1561131 (genotypic, P=0.007), rs1963562 (dominant, P=0.01) and rs615382 (recessive, P=0.009) remained highly significant after adjusting for both age and ancestry. We also tested the independent effect of each significantly associated SNP and rs1561131 (P=0.04) and rs1963562 (P=0.04) remained significantly associated with PCa development. After multiple comparisons testing using the false discovery rate, rs1993973 remained significant. Analysis of the rs156113-, rs1963562-rs615382l and rs1993973-rs585224 haplotypes revealed that the least frequently found haplotypes in this population were significantly associated with a decreased risk of PCa (P=0.032 and 0.0017, respectively).Conclusions:The approach for SNP selection utilized herein showed that AIMs may not only leverage increased linkage disequilibrium in populations to identify risk and protective alleles, but may also be informative in dissecting the biology of PCa and other health disparities.Prostate Cancer and Prostatic Diseases advance online publication, 17 July 2012; doi:10.1038/pcan.2012.19.
    Prostate cancer and prostatic diseases 07/2012; · 2.10 Impact Factor
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    ABSTRACT: The 21(st) century emergence of genomic medicine is shifting the paradigm in biomedical science from the population phenotype to the individual genotype. In characterizing the biology of disease and health disparities in population genetics, human populations are often defined by the most common alleles in the group. This definition poses difficulties when categorizing individuals in the population who do not have the most common allele(s). Various epidemiological studies have shown an association between common genomic variation, such as single nucleotide polymorphisms (SNPs), and common diseases. We hypothesize that information encoded in the structure of SNP haploblock variation in the human leukocyte antigen-disease related (HLA-DR) region of the genome illumines molecular pathways and cellular mechanisms involved in the regulation of host adaptation to the environment. In this paper we describe the development and application of the normalized information content (NIC) as a novel metric based on SNP haploblock variation. The NIC facilitates translation of biochemical DNA sequence variation into a biophysical quantity derived from Boltzmann's canonical ensemble in statistical physics and used widely in information theory. Our normalization of this information metric allows for comparisons of unlike, or even unrelated, regions of the genome. We report here NIC values calculated for HLA-DR SNP haploblocks constructed by Haploview, a product of the International Haplotype Map Project. These haploblocks were scanned for potential regulatory elements using ConSite and miRBase, publicly available bioinformatics tools. We found that all of the haploblocks with statistically low NIC values contained putative transcription factor binding sites and microRNA motifs, suggesting correlation with genomic regulation. Thus, we were able to relate a mathematical measure of information content in HLA-DR SNP haploblocks to biologically relevant functional knowledge embedded in the structure of DNA sequence variation. We submit that NIC may be useful in analyzing the regulation of molecular pathways involved in host adaptation to environmental pathogens and in decoding the functional significance of common variation in the human genome.
    Journal of computational biology and bioinformatics research. 02/2012; 4(2):15-22.
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    ABSTRACT: Although an increasing number of hypertension-associated genetic variants is being reported, replication of these findings in independent studies has been challenging. Several genes in a human chromosome 1q linkage region have been reported to be associated with hypertension. We examined polymorphisms in three of these genes (ATP1B1, RGS5 and SELE) in relation to hypertension and blood pressure in a cohort of African-Americans. We genotyped 87 single nucleotide polymorphisms (SNPs) from the ATP1B1, RGS5 and SELE genes in a well characterized cohort of 968 African-Americans and performed a case-control study to identify susceptibility alleles for hypertension and blood pressure regulation. Single SNP and haplotype association testing was done under an additive genetic model with adjustment for age, sex, BMI and ancestry-by-genotype (principal components). A total of 12 SNPs showed nominal association with hypertension and/or blood pressure. The strongest signal for hypertension was for rs2815272 in the RGS5 gene (P = 9.3 × 10). For SBP, rs3917420 in the SELE gene (P = 9.0 × 10) and rs4657251 in the RGS5 gene (P = 9.7 × 10) were the top hits. Effect size for each of these variants was approximately 2-3 mmHg. A five-SNP haplotype in the SELE gene also showed significant association with SBP after correction for multiple testing (P < 0.01). These findings provide additional support for the genetic role of ATP1B1, RGS5 and SELE in hypertension and blood pressure regulation.
    Journal of Hypertension 08/2011; 29(10):1906-12. · 4.22 Impact Factor
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    ABSTRACT: Asthma is a common disease with a complex risk architecture including both genetic and environmental factors. We performed a meta-analysis of North American genome-wide association studies of asthma in 5,416 individuals with asthma (cases) including individuals of European American, African American or African Caribbean, and Latino ancestry, with replication in an additional 12,649 individuals from the same ethnic groups. We identified five susceptibility loci. Four were at previously reported loci on 17q21, near IL1RL1, TSLP and IL33, but we report for the first time, to our knowledge, that these loci are associated with asthma risk in three ethnic groups. In addition, we identified a new asthma susceptibility locus at PYHIN1, with the association being specific to individuals of African descent (P = 3.9 × 10(-9)). These results suggest that some asthma susceptibility loci are robust to differences in ancestry when sufficiently large samples sizes are investigated, and that ancestry-specific associations also contribute to the complex genetic architecture of asthma.
    Nature Genetics 07/2011; 43(9):887-92. · 35.21 Impact Factor
  • Journal of Allergy and Clinical Immunology - J ALLERG CLIN IMMUNOL. 01/2011; 127(2).
  • Journal of Allergy and Clinical Immunology - J ALLERG CLIN IMMUNOL. 01/2011; 127(2).
  • Human Immunology - HUM IMMUNOL. 01/2011; 72.
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    ABSTRACT: p53 is a transcription factor that regulates the cell cycle, DNA repair, and apoptosis. A variant at codon 72, rs1042522, results in altered activities for p53 and is, notably, differentially distributed among different ethnic populations. However, associations of this variant with cancer in men of African descent have not been explored. Herein, we tested the hypothesis that rs1042522 was associated with prostate cancer (PCa) risk. Genotypes were determined by PCR-RFLP methods in a study population of African descent consisting of 266 PCa patients and 196 male controls. Our results indicate that the p53 polymorphism may be associated with increased risk of PCa. Genotypes were significantly and marginally associated with PCa risk using the dominant and log-additive genetic models (OR=1.53, 95% CI: 1.02-2.29, P=0.04; OR=1.33, 95% CI: 0.99-1.78, P=0.06, respectively). After adjusting for age, the associations with PCa remained, but results were not statistically significant (OR=1.48, 95% CI: 0.95-2.31, P=0.08; OR=1.30, 95% CI: 0.95-1.80, P=0.10, respectively). The present study demonstrates that population-dependent differences in allele frequencies associated with health disparities provide a valuable framework for the interrogation of complex diseases in all populations.
    The Prostate 12/2010; 70(16):1739-45. · 3.84 Impact Factor
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    ABSTRACT: Admixture is a potential source of confounding in genetic association studies, so it becomes important to detect and estimate admixture in a sample of unrelated individuals. Populations of African descent in the US and the Caribbean share similar historical backgrounds but the distributions of African admixture may differ. We selected 416 ancestry informative markers (AIMs) to estimate and compare admixture proportions using STRUCTURE in 906 unrelated African Americans (AAs) and 294 Barbadians (ACs) from a study of asthma. This analysis showed AAs on average were 72.5% African, 19.6% European and 8% Asian, while ACs were 77.4% African, 15.9% European, and 6.7% Asian which were significantly different. A principal components analysis based on these AIMs yielded one primary eigenvector that explained 54.04% of the variation and captured a gradient from West African to European admixture. This principal component was highly correlated with African vs. European ancestry as estimated by STRUCTURE (r(2)=0.992, r(2)=0.912, respectively). To investigate other African contributions to African American and Barbadian admixture, we performed PCA on approximately 14,000 (14k) genome-wide SNPs in AAs, ACs, Yorubans, Luhya and Maasai African groups, and estimated genetic distances (F(ST)). We found AAs and ACs were closest genetically (F(ST)=0.008), and both were closer to the Yorubans than the other East African populations. In our sample of individuals of African descent, approximately 400 well-defined AIMs were just as good for detecting substructure as approximately 14,000 random SNPs drawn from a genome-wide panel of markers.
    Genetic Epidemiology 09/2010; 34(6):561-8. · 4.02 Impact Factor
  • Journal of Allergy and Clinical Immunology - J ALLERG CLIN IMMUNOL. 01/2010; 125(2).
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    ABSTRACT: Admixture mapping is a powerful approach for identifying genetic variants involved in human disease that exploits the unique genomic structure in recently admixed populations. To use existing published panels of ancestry-informative markers (AIMs) for admixture mapping, markers have to be genotyped de novo for each admixed study sample and samples representing the ancestral parental populations. The increased availability of dense marker data on commercial chips has made it feasible to develop panels wherein the markers need not be predetermined. We developed two panels of AIMs (approximately 2,000 markers each) based on the Affymetrix Genome-Wide Human SNP Array 6.0 for admixture mapping with African American samples. These two AIM panels had good map power that was higher than that of a denser panel of approximately 20,000 random markers as well as other published panels of AIMs. As a test case, we applied the panels in an admixture mapping study of hypertension in African Americans in the Washington, D.C. metropolitan area. Developing marker panels for admixture mapping from existing genome-wide genotype data offers two major advantages: (1) no de novo genotyping needs to be done, thereby saving costs, and (2) markers can be filtered for various quality measures and replacement markers (to minimize gaps) can be selected at no additional cost. Panels of carefully selected AIMs have two major advantages over panels of random markers: (1) the map power from sparser panels of AIMs is higher than that of approximately 10-fold denser panels of random markers, and (2) clusters can be labeled based on information from the parental populations. With current technology, chip-based genome-wide genotyping is less expensive than genotyping approximately 20,000 random markers. The major advantage of using random markers is the absence of ascertainment effects resulting from the process of selecting markers. The ability to develop marker panels informative for ancestry from SNP chip genotype data provides a fresh opportunity to conduct admixture mapping for disease genes in admixed populations when genome-wide association data exist or are planned.
    BMC Genomics 01/2010; 11:417. · 4.40 Impact Factor
  • Journal of Allergy and Clinical Immunology - J ALLERG CLIN IMMUNOL. 01/2010; 125(2).
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    ABSTRACT: Asthma is a complex disease characterized by striking ethnic disparities not explained entirely by environmental, social, cultural, or economic factors. Of the limited genetic studies performed on populations of African descent, notable differences in susceptibility allele frequencies have been observed. We sought to test the hypothesis that some genes might contribute to the profound disparities in asthma. We performed a genome-wide association study in 2 independent populations of African ancestry (935 African American asthmatic cases and control subjects from the Baltimore-Washington, DC, area and 929 African Caribbean asthmatic subjects and their family members from Barbados) to identify single-nucleotide polymorphisms (SNPs) associated with asthma. A meta-analysis combining these 2 African-ancestry populations yielded 3 SNPs with a combined P value of less than 10(-5) in genes of potential biologic relevance to asthma and allergic disease: rs10515807, mapping to the alpha-1B-adrenergic receptor (ADRA1B) gene on chromosome 5q33 (3.57 x 10(-6)); rs6052761, mapping to the prion-related protein (PRNP) gene on chromosome 20pter-p12 (2.27 x 10(-6)); and rs1435879, mapping to the dipeptidyl peptidase 10 (DPP10) gene on chromosome 2q12.3-q14.2. The generalizability of these findings was tested in family and case-control panels of United Kingdom and German origin, respectively, but none of the associations observed in the African groups were replicated in these European studies. Evidence for association was also examined in 4 additional case-control studies of African Americans; however, none of the SNPs implicated in the discovery population were replicated. This study illustrates the complexity of identifying true associations for a complex and heterogeneous disease, such as asthma, in admixed populations, especially populations of African descent.
    The Journal of allergy and clinical immunology 11/2009; 125(2):336-346.e4. · 12.05 Impact Factor
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    ABSTRACT: African American men have the highest rates of prostate cancer worldwide, and immunogenetic studies suggest that people of African descent have increased susceptibility to diseases of inflammation. Since genetic susceptibility is an etiological factor in prostate cancer, we hypothesize that sequence variants in the promoter region of the CD14 gene that regulate inflammation may modify individual susceptibility to this disease. The CD14 promoter was screened for single-nucleotide polymorphisms (SNPs) using dHPLC. One variant, -260 C>T (rs2569190), was genotyped via restriction digest in all study participants (264 cases and 188 controls). The association of disease status and the polymorphism was analyzed by unconditional logistic regression. Odds ratios with 95% confidence intervals were calculated, stratifying by ethnicity and adjusting for age. Two-sided P-values of < or =0.05 were considered as statistically significant. Eleven variants (four novel) were identified in the promoter region of CD14. A marginal association between the C genotypes (C/C + C/T) and prostate cancer was found (P = 0.07). When stratified by age, among men > or =55 years of age, the C genotypes were significantly associated with prostate cancer (P < 0.05). When stratified by self-reported ethnicity, African American males who had the C genotypes were at a higher risk for prostate cancer (P < 0.05). This is the first study to show an association between the C genotypes of the CD14 (-260) variant and prostate cancer which supports the hypothesis that genetic variation in the inflammatory process can contribute to prostate cancer susceptibility in African American men.
    The Prostate 10/2009; 70(3):262-9. · 3.84 Impact Factor
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    ABSTRACT: The C825T single nucleotide polymorphism (SNP) in the guanine nucleotide-binding protein, beta polypeptide 3 ( GNB3) gene gives rise to a splice variant, GNB3s that has enhanced G protein activation and signal transduction activity. This variant has been reported to be associated with cardiovascular disease, diabetes and obesity. We studied this SNP in 95 healthy 18 to 30 year-old African American university students to determine its association with aerobic capacity and cardiorespiratory fitness as measured by peak oxygen consumption (VO (2)peak). We also tested the effect of heart rate variability (HRV) as an independent predictor of VO (2)peak. We tested the association of the SNP and HRV with VO (2)peak in a multivariate regression analysis with appropriate adjustments of covariates, under dominant and recessive models. We found a significant independent association of the 825T allele with VO (2)peak under the dominant model (beta-coef.=-0.101, P=0.0442). We also observed that HRV marginally influenced VO (2)peak. This finding suggests that GNB3 C825T polymorphism is associated with VO (2)peak which is influenced by autonomic modulation of heart rate in African Americans.
    International Journal of Sports Medicine 04/2009; 30(5):315-9. · 2.27 Impact Factor
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    ABSTRACT: The RNASEL and HPC2/ELAC2 genes have been implicated in hereditary prostate cancer. Further assessment of the role of these genes in sporadic prostate cancer in African American men (AAM) is warranted. Genotyping of HPC2/ELAC2 variants (S217L, A541T), along with RNASEL variants (R462Q and E541D) was completed in 155 African American sporadic and 88 familial prostate cancer cases, and 296 healthy male controls. Logistic regression analysis was performed and odds ratios (OR) were calculated, while correcting for both age and population stratification using admixture informative markers. The HPC2/ELAC2 217L allele was significantly associated with risk of prostate cancer when taking all cases into account (OR = 1.6; 1.0-2.6; P = 0.03). The RNASEL 541D allele was associated with a decrease in risk of prostate cancer in sporadic cases (OR = 0.4; 0.2-0.8; P = 0.01). We did not detect an association between prostate cancer risk and the RNASEL R462Q variant. Results from haplotype analyses of the two RNASEL variants revealed highly significant differences in haplotype allele frequencies between cases and controls suggesting a synergistic effect at the RNASEL locus. One haplotype in particular (462R-541D) is far more frequent in our control population and shows a strong protective effect against prostate cancer (OR = 0.47, P = 8.1 x 10(-9)). These results suggest that HPC2/ELAC2 and RNASEL may play a role, however minor, in prostate cancer risk among AAM.
    The Prostate 10/2008; 68(16):1790-7. · 3.84 Impact Factor

Publication Stats

2k Citations
362.13 Total Impact Points

Institutions

  • 2013
    • Inter American University of Puerto Rico
      Fajardo, Fajardo, Puerto Rico
  • 2007–2013
    • Johns Hopkins University
      • Department of Medicine
      Baltimore, MD, United States
    • Calgary Laboratory Services
      Calgary, Alberta, Canada
  • 1999–2012
    • Howard University
      • • College of Medicine
      • • Department of Microbiology
      Washington, West Virginia, United States
  • 2010
    • University of the District of Columbia
      Washington, Washington, D.C., United States
    • Johns Hopkins Bloomberg School of Public Health
      • Department of Epidemiology
      Baltimore, Maryland, United States
  • 2009
    • National Human Genome Research Institute
      Maryland, United States
  • 2000–2009
    • Howard University Hospital
      Washington, Washington, D.C., United States
  • 2001
    • Karmanos Cancer Institute
      Detroit, Michigan, United States