NOD1 variation, immunoglobulin E and asthma.
Asthma is a familial inflammatory disease of the airways of the lung. Microbial exposures in childhood protect against asthma through unknown mechanisms. The innate immune system is able to identify microbial components through a variety of pattern-recognition receptors (PRRs). NOD1 is an intracellular PRR that initiates inflammation in response to bacterial diaminopimelic acid (iE-DAP). The NOD1 gene is on chromosome 7p14, in a region that has been genetically linked to asthma. We carried out a systematic search for polymorphism in the gene. We found an insertion-deletion polymorphism (ND(1)+32656) near the beginning of intron IX that accounted for approximately 7% of the variation in IgE in two panels of families (P<0.0005 in each). Allele*2 (the insertion) was associated with high IgE levels. The same allele was strongly associated with asthma in an independent study of 600 asthmatic children and 1194 super-normal controls [odds ratio (OR) 6.3; 95% confidence interval (CI) 1.4-28.3, dominant model]. Differential binding of the two ND(1)+32656 alleles was observed to a protein from nuclei of the Calu 3 epithelial cell line. In an accompanying study, the deletion allele (ND(1)+32656*1) was found to be associated with inflammatory bowel disease. The results indicate that intracellular recognition of specific bacterial products affects the presence of childhood asthma.
Hysi
Pirro
P
Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
Kabesch
Michael
M
Moffatt
Miriam F
MF
Schedel
Michaela
M
Carr
David
D
Zhang
Youming
Y
Boardman
Brenda
B
von Mutius
Erika
E
Weiland
Stephan K
SK
Leupold
Wolfgang
W
Fritzsch
Christian
C
Klopp
Norman
N
Musk
A William
AW
James
Alan
A
Nunez
Gabriel
G
Inohara
Naohiro
N
Cookson
William O C
WO
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000483:Alleles; D017398:Alternative Splicing; D001249:Asthma / Q000235:genetics*; D016022:Case-Control Studies; D002460:Cell Line; D002648:Child; D002897:Chromosomes, Human, Pair 7; D004848:Epithelium / Q000378:metabolism; D017353:Gene Deletion; D005821:Genetic Techniques; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007073:Immunoglobulin E / Q000737:chemistry / Q000235:genetics*; D007249:Inflammation; D015212:Inflammatory Bowel Diseases / Q000235:genetics*; D007438:Introns; D008957:Models, Genetic; D053474:Nod1 Signaling Adaptor Protein; D016017:Odds Ratio; D010641:Phenotype; D011110:Polymorphism, Genetic; D017434:Protein Structure, Tertiary; D014018:Tissue Distribution
D048868:Adaptor Proteins, Signal Transducing; C119067:NOD1 protein, human; D053474:Nod1 Signaling Adaptor Protein; D007073:Immunoglobulin E