- Immunogenetics of the allergic response
- Genetic epidemiology of acute and chronic obstructive pulmonary disease
Linkage studies in asthma and allergic disease
Research was initially focused on the ascertainment of well-characterized families selected for asthma and allergic disease, the genotyping of polymorphic, microsatellite markers, and candidate gene and genome-wide linkage studies. One of our initial focuses was on a candidate gene region in chromosome 12q15-q24.1, where we reported the first evidence for linkage to asthma and tIgE concentrations in an Afro-Caribbean group of families from Barbados, the West Indies, and multiplex families from the isolated, Caucasian Amish in Pennsylvania (Barnes et al. 1996). Following dense mapping of microsatellite markers and an increased number of Barbados families, we observed the strongest evidence for linkage by multipoint relative analysis to markers in and near IFN? for asthma (P=0.002) and allergic rhinitis (P=0.006) (Barnes et al. 1999). By a multipoint linkage-disequilibrium–mapping approach based on the transmission disequilibrium testing (TDT) on case-parent trios, an unobserved QTL was identified at the same locus showing strong evidence of linkage and linkage disequilibrium (LD; P=0.0001) (Hsu et al. 2002).
As part of our involvement in the 10-year (1992-2002), NHLBI-funded Collaborative Study on the Genetics of Asthma (CSGA), evidence for linkage to the 12q locus was confirmed (CSGA 1997). The overall purpose of the CSGA was to perform studies in human pedigrees of Caucasian, African American, and Hispanic ethnicity, combining molecular genetic and clinical approaches with rigorous statistical genetic techniques designed to identify markers linked to a major gene(s) that contribute to the development of asthma. The CSGA was a multicenter study (Johns Hopkins University/Howard University, University of Maryland/University of New Mexico, University of Chicago, and University of Minnesota). In the initial five years, families were ascertained through two affected (asthmatic) siblings, who were required to meet the classic definitions of asthma and not represent equivocal phenotypes. As part of the second phase, efforts were focused on the recruitment of independent case-parent trios. The overall study design and protocol have been well-described (Lester et al. 2001).
Evidence for linkage to the C-C chemokine cluster locus on 17q11.2-q21.2 was also observed among the African American asthmatic families (but not among the Caucasian or Hispanic families) participating in the CSGA study (CSGA 1997). RANTES is localized in this region, and because of its potential role in allergic and infectious diseases, the Afro-Caribbean asthmatics from Barbados were screened for mutations in the proximal promoter region of the RANTES gene. A functional mutation was observed which was much more frequent among the Barbados subjects and other individuals of African descent compared to Caucasian subjects (P< 0.00001; Nickel 2000). Linkage to 17q was not observed, however, by two-point or multipoint analysis in the Barbados dataset. However, after 'conditioning' on evidence for linkage to 12q, linkage to 17q was observed, which was interpreted as evidence for gene-gene interaction in asthma (Barnes et al. 2001).
Further evidence of linkage to asthma and atopy in this and other loci has been demonstrated by Dr. Barnes' group in the isolated, Caucasian population from Tangier Island, Virginia, where the prevalence of asthma has been estimated at 14.2%, atopy (symptoms and specific IgE antibodies, 55%), and mean tIgE is164.5 ng/mL (Mathias et al. 2001, Grant et al. in prep.). Very recently, her group has observed that, after adjusting for 22 fatty acids and two fatty acid ratios, there is an increase in the evidence for linkage for tIgE to many 12q markers (P<0.001–0.03) and additional candidate loci for asthma, including markers on chromosomes 6p (P<0.05) and markers in the gene encoding the high affinity IgE receptor (FCER1B) on 11q (P=0.0006–0.004).
- Studies on the Immunogenetics of Cockroach Sensitization. These studies are focusing on the pathogenic basis for the interactive effect of current cockroach allergen exposure and susceptibility loci associated with asthma severity and allergic rhinitis in the absence of asthma, with a focus on African American, public housing residents in Baltimore city. These studies are supported in part by an NHLBI initiative designed to collaboratively investigate, with Howard University, factors associated with the disproportionate burden of asthma experienced by inner-city, African American children and adults.
- Asthma Positional Candidate Genes in the Complement Pathway in Mice and Humans. In collaboration with Dr. Marsha Wills-Karp at the Children's Hospital, University of Cincinnati, Medical Division of Immunobiology, we are investigating polymorphisms in the C5 gene and related candidates in the complement pathway to determine whether they are associated with the development of asthma or asthma related phenotypes in mice and humans. These candidate gene studies are being conducted in three family-based populations (2 Caucasian, 1 Afro-Caribbean).
- Asthma Studies in the HOPGENE Program for Genomic Applications. Since September, 2000, we have been heavily involved in the National Heart, Lung, and Blood Institute (NHLBI)-funded Programs for Genomic Applications (PGAs). The goals of the PGAs include developing information, tools, and resources to link genes to biological function on a genomic scale. The goal of the HOPGENE PGA is to define a subset of genes, derived from gene expression profiles, which are associated with pathogenic tissue remodeling in a number of cardiopulmonary diseases, including asthma. The Asthma Working Group is focused on the identification of disease-specific predictor genes variably expressed in both animal models of asthma and patients with asthma as well as genetic polymorphisms in priority genes associated with an increased risk and severity of disease. This work is greatly advantaged by multiple well characterized cohorts, including families from Barbados and Tangier Island, Virginia. The current focus is high-throughput (>1,000 SNPs), fine-mapping of the 12q locus and select asthma candidate genes in 6 additional chromosomal loci (5q, 6p, 9q, 11q, 17q, 19p). Along with other talented Hopkins experts in the Department of Genetic Epidemiology at the Johns Hopkins Bloomberg School of Public Health, we are aggressively exploring genetic modifiers, with a focus on innate immunity candidates, involved in asthma. This effort is tightly linked to key members of the Johns Hopkins Airways Disease Program, an integrated program which provides extensive experience in inpatient and outpatient management of asthma located at the Johns Hopkins Asthma & Allergy Center. Goals of this study include: (1) Identify genes that are differentially regulated in rodent airways after exposure to innate immune response inducers using high-throughput expression profiling; (2) Determine the impact that selective deficiencies in have on the ability of rodents to develop allergic hypersensitivity; (3) Identify 'downstream' effect innate immunity candidate genes from human expression profiling studies; and (4) Identify associations between asthma expression and genetic markers in candidate loci polymorphisms in ethnically diverse, family-based and case-control design studies Novel insights into the genetic basis of asthma susceptibility and disease severity will be forthcoming.
- Genetic Modifiers in Acute Lung Injury. A relatively new area of research by our group involves our role as both a genomics project and a genomics Core for the Specialized Centers of Clinically-Oriented Research (SCCOR) on 'Molecular Approaches to Ventilator-Associated Lung Injury' (Joe G.N. Garcia, PI). In these studies we are employing high-throughput genomic technologies to (i) examine the patterns of gene expression and (ii) candidate gene polymorphisms which explain susceptibility to acute lung injury (ALI) associated with sepsis and sepsis alone. These studies are being conducted in a large cohort of well-phenotyped patients with sepsis/ALI obtained from the collaborative Consortium to Evaluate Lung Edema Genetics (CELEG), which was spearheaded by Johns Hopkins University and Medical College of Wisconsin Investigators from the Hopkins SCCOR. We are focusing on allelic variants that are independent of ALI but generic for sepsis, as well as allelic variants associate with mortality due to ventilation. Because a growing number of studies have indicate that the distribution of allele frequencies associated with diseases of inflammation differs according to ethnicity, we are also testing the hypothesis that the frequency of susceptibility loci for ALI is higher in African Americans compared to Caucasians. These studies represent the most expansive genetic studies to date in the evaluation of ALI.
All of the above studies are greatly facilitated by resources available to us at the Johns Hopkins Asthma & Allergy Center at the Bayview Campus. In addition to our work conducted in 800 sq. ft. of wet laboratory space, much of our genotyping activities are conducted at the Genetic Research Core Facility (GRCF) (grcf.med.jhu.edu), a JHU service center, under the supervision and direction of Dr. Alan Scott at the new Canton Campus facility. Clinical laboratory activities (e.g., phenotyping) are conducted in-house and genetic data analysis is conducted by our staff and faculty in the Data Analysis Core as part of the Center for Translational Respiratory Medicine and in collaboration with the analytical team at the Genetic Epidemiology unit, the Bloomberg School of Public Health. In addition, two Registered Nurses conduct our studies off-campus at the Chronic Disease Research Centre in Barbados.
Kathleen C. Barnes, Ph.D
Associate Professor of Medicine, Divisions of Allergy & Clinical Immunology (Primary) and Pulmonary & Critical Care Medicine, Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University
Eva Ehrlich, MS
Chris Cheadle Ph.D.
Li Gao M.D., Ph.D
Instructor in Medicine:
Dmitry Grigoryev M.D., Ph.D.
JinShui Fan M.D., Ph.D.
No Positions available at this time.
- Barnes, KC, Neely, JD, Duffy, DL, Freidhoff, LR, Breazeale, DR, Schou, C, Naidu, RP, Levett, PN, Renault, B, Kucherlapati, R, Iozzino, S, Ehrlich, E, Beaty, TH, Marsh, DG 1996. Linkage of Asthma and Total Serum IgE Concentration to Markers on Chromosome 12q: Evidence from Afro-Caribbean and Caucasian Populations. Genomics
- CSGA (Collaborative Studies on the Genetics of Asthma). 1997. A genome-wide search for asthma susceptibility loci in ethnically diverse populations. Nat Genet 15:389-392.
- Barnes, KC , DG Marsh. 1998. The genetics and complexity of allergy and asthma. Immunol Today 19(7): 325-332.
- Barnes, KC, Freidhoff, LR, Chiu, Y-F, Juo, S-H, Duffy, DL, Hizawa, H, Naidu, RP, Nickel, R, Ehrlich, E, Schou, C, Beaty, TH, and Marsh, DG 1999. Dense mapping of chromosome 12q14.3-q24.1 and linkage to asthma and atopy. J Allergy Clin Immunol. 104(1, Pt. 2): 485-491.
- Nickel, R, Willadsen, SA, Freidhoff, LR, Huang, SK, Raana, NP, Caraballo, L, Ehrlich, E, Ober, C, Beaty, T, and Barnes, KC 1999. Determination of Duffy-phenotypes in three populations of African descent using PCR and sequence specific oligonucleotides. Human Immunol 60:738-742.
- Nickel, R, Casolaro, V, Wahn, U, Beyer, K, Barnes, KC, Plunkett, B, Freidhoff, LR, Sengler, C, Plitt, J, Schleimer, RP, Caraballo, L, Naidu, RN, Beaty, T, Huang, S-K 2000. Atopic dermatitis is associated with a functional mutation in the promoter of the CC chemokine RANTES. J Immunol Feb 1;164(3):1612-1616.
- Mathias, RA, CA Bickel, TH Beaty, GM Petersen, JB Hetmanski, K-Y Liang, and KC Barnes. 2000. A Genealogical analysis of the Tangier Island, Virginia, Population. J Phys Anthro. 112:29-38.
- Lonjou, C, Barnes, K, Chen, H, Cookson, WO, Deichmann, KA, Hall, IP, Holloway, JW, Laitinen, T, Palmer, LJ, Wjst, M, Morton, NE 2000. A first trial of retrospective collaboration for positional cloning in complex inheritance: assay of the cytokine region on chromosome 5 by the consortium on asthma genetics. Proc Natl Acad Sci USA 97(20):10942-7.
- Barnes, K.C., Mathias, RA, Nickel, R, Freidhoff, LR, Stockton, ML, Xue, X, Naidu, RP., Levett, PN, Casolaro, V, Beaty, TH 2001. Testing for gene-gene interaction controlling total IgE in families from Barbados: Evidence of sensitivity regarding linkage heterogeneity among families. Genomics. 71(2):246-251.
- Liang, K-Y, F-C Hsu, TH Beaty, KC Barnes. 2001. A multipoint linkage disequilibrium mapping approach based on the case-parent trio design. Am. J. Hum. Genet. 68:937-950.
- F.C. Hsu, K.Y. Liang, T.H. Beaty, and K.C. Barnes. 2002. Unified sampling approach for multipoint linkage disequilibrium mapping of qualitative and quantitative traits. Genetic Epidemiology. 22(4):298 312.
Last Updated 08/2009