Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness.
Asthma is a common respiratory disorder characterized by recurrent episodes of coughing, wheezing and breathlessness. Although environmental factors such as allergen exposure are risk factors in the development of asthma, both twin and family studies point to a strong genetic component. To date, linkage studies have identified more than a dozen genomic regions linked to asthma. In this study, we performed a genome-wide scan on 460 Caucasian families and identified a locus on chromosome 20p13 that was linked to asthma (log(10) of the likelihood ratio (LOD), 2.94) and bronchial hyperresponsiveness (LOD, 3.93). A survey of 135 polymorphisms in 23 genes identified the ADAM33 gene as being significantly associated with asthma using case-control, transmission disequilibrium and haplotype analyses (P = 0.04 0.000003). ADAM proteins are membrane-anchored metalloproteases with diverse functions, which include the shedding of cell-surface proteins such as cytokines and cytokine receptors. The identification and characterization of ADAM33, a putative asthma susceptibility gene identified by positional cloning in an outbred population, should provide insights into the pathogenesis and natural history of this common disease.
Genome Therapeutics Corporation, 100 Beaver St, Waltham, Massachusetts 02453, USA.
Paul
P
Van Eerdewegh
Randall D
RD
Little
Josée
J
Dupuis
Richard G
RG
Del Mastro
Kathy
K
Falls
Jason
J
Simon
Dana
D
Torrey
Sunil
S
Pandit
Joyce
J
McKenny
Karen
K
Braunschweiger
Alison
A
Walsh
Ziying
Z
Liu
Brooke
B
Hayward
Colleen
C
Folz
Susan P
SP
Manning
Alicia
A
Bawa
Lisa
L
Saracino
Michelle
M
Thackston
Youssef
Y
Benchekroun
Neva
N
Capparell
Mei
M
Wang
Ron
R
Adair
Yun
Y
Feng
JoAnn
J
Dubois
Michael G
MG
FitzGerald
Hui
H
Huang
René
R
Gibson
Kristina M
KM
Allen
Alex
A
Pedan
Melvyn R
MR
Danzig
Shelby P
SP
Umland
Robert W
RW
Egan
Francis M
FM
Cuss
Steuart
S
Rorke
Joanne B
JB
Clough
John W
JW
Holloway
Stephen T
ST
Holgate
Tim P
TP
Keith
D051722:ADAM Proteins; D001249:Asthma / Q000235:genetics*; D016535:Bronchial Hyperreactivity / Q000235:genetics*; D016022:Case-Control Studies; D002874:Chromosome Mapping; D002890:Chromosomes, Human, Pair 20 / Q000235:genetics*; D005091:Exons; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D015894:Genome, Human; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007438:Introns; D015810:Linkage Disequilibrium / Q000235:genetics; D008126:Lod Score; D008666:Metalloendopeptidases / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D006113:United Kingdom; D014481:United States; D044465:White People / Q000235:genetics
D051722:ADAM Proteins; C450441:ADAM33 protein, human; D008666:Metalloendopeptidases