Identification of Four Novel Loci in Asthma in European American and African American Populations.
BACKGROUND
Despite significant advances in knowledge of the genetic architecture of asthma, specific contributors to the variability in the burden between populations remain uncovered.


OBJECTIVE
To identify additional genetic susceptibility factors of asthma in European American and African American populations.


METHODS
A phenotyping algorithm mining electronic medical records was developed and validated to recruit cases with asthma and control subjects from the Electronic Medical Records and Genomics network. Genome-wide association analyses were performed in pediatric and adult asthma cases and control subjects with European American and African American ancestry followed by metaanalysis. Nominally significant results were reanalyzed conditioning on allergy status.


RESULTS
The validation of the algorithm yielded an average of 95.8% positive predictive values for both cases and control subjects. The algorithm accrued 21,644 subjects (65.83% European American and 34.17% African American). We identified four novel population-specific associations with asthma after metaanalyses: loci 6p21.31, 9p21.2, and 10q21.3 in the European American population, and the PTGES gene in African Americans. TEK at 9p21.2, which encodes TIE2, has been shown to be involved in remodeling the airway wall in asthma, and the association remained significant after conditioning by allergy. PTGES, which encodes the prostaglandin E synthase, has also been linked to asthma, where deficient prostaglandin E2synthesis has been associated with airway remodeling.


CONCLUSIONS
This study adds to understanding of the genetic architecture of asthma in European Americans and African Americans and reinforces the need to study populations of diverse ethnic backgrounds to identify shared and unique genetic predictors of asthma.
1 Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Berta
B
Almoguera
1 Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Lyam
L
Vazquez
1 Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Frank
F
Mentch
1 Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
John
J
Connolly
2 Northwestern University Feinberg School of Medicine, Chicago, Illinois.
Jennifer A
JA
Pacheco
3 Geisinger Health System, Danville, Pennsylvania.
Agnes S
AS
Sundaresan
4 Marshfield Clinic Research Foundation, Marshfield, Wisconsin.
Peggy L
PL
Peissig
4 Marshfield Clinic Research Foundation, Marshfield, Wisconsin.
James G
JG
Linneman
5 Essentia Institute of Rural Health, Duluth, Minnesota.
Catherine A
CA
McCarty
6 University of Washington Medical Center, Seattle, Washington.
David
D
Crosslin
7 Group Health Research Institute, Seattle, Washington.
David S
DS
Carrell
8 Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Todd
T
Lingren
8 Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Bahram
B
Namjou-Khales
8 Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.|9 U.S. Department of Veterans Affairs Medical Center, Cincinnati, Ohio.
John B
JB
Harley
7 Group Health Research Institute, Seattle, Washington.
Eric
E
Larson
6 University of Washington Medical Center, Seattle, Washington.
Gail P
GP
Jarvik
4 Marshfield Clinic Research Foundation, Marshfield, Wisconsin.
Murray
M
Brilliant
3 Geisinger Health System, Danville, Pennsylvania.
Marc S
MS
Williams
10 Mayo Clinic, Rochester, Minnesota; and.
Iftikhar J
IJ
Kullo
1 Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Erik B
EB
Hysinger
1 Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.|11 Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Patrick M A
PM
Sleiman
1 Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.|11 Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Hakon
H
Hakonarson
D000293:Adolescent; D000328:Adult; D001741:Black or African American / Q000235:genetics*; D056151:Airway Remodeling / Q000235:genetics / Q000276:immunology; D000465:Algorithms; D001249:Asthma / Q000208:ethnology / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D057225:Data Mining / Q000379:methods; D057286:Electronic Health Records / Q000706:statistics & numerical data*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D015201:Meta-Analysis as Topic; D010641:Phenotype; D015995:Prevalence; D000071876:Prostaglandin-E Synthases / Q000235:genetics*; D014481:United States; D044465:White People / Q000235:genetics*
C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases
asthma; genetics; genome-wide association study