Functional variants of 17q12-21 are associated with allergic asthma but not allergic rhinitis.
BACKGROUND
Allergic rhinitis (AR) and asthma are common allergic conditions with a shared genetic component to their cause. The 17q12-21 locus includes several genes that have been linked to asthma susceptibility, but the role of this locus in AR is unclear. Asthma and AR in adults of Chinese ethnicity in Singapore are predominately caused by sensitization against house dust mites with a nearly complete penetrance of the allergen, which presents a unique opportunity for accurately identifying genetic associations with allergic diseases.


OBJECTIVE
We sought to define the functional role of 17q12-21 in patients with AR and allergic asthma.


METHODS
We asked whether single nucleotide polymorphisms (SNPs) in the 17q12-21 locus were associated with AR or asthma in a cohort of 3460 ethnic Chinese subjects residing in Singapore (1435 in the discovery phase and 2025 in the validation phase). Full-blood mRNA gene expression data, plasma IgE levels, and immune cell frequencies in peripheral blood were tested against the tag SNP genotypes. Luciferase assays were used to measure the effect of putative promoter SNPs on expression of the asthma-associated orosomucoid-like 3 gene (ORMDL3).


RESULTS
Within 17q12-21, only the tag SNP rs8076131 was significantly associated with asthma (P = 8.53 × 10(-10); odds ratio, 0.6715), and AR status was independent of SNPs in this region. C-A alleles at rs8076131 resulted in significantly increased ORMDL3 expression in HEK293 cells in vitro relative to T-G alleles. Moreover, subjects with the risk genotype AA exhibited significantly higher total IgE levels and higher blood eosinophil counts than those with the lower-risk genotypes.


CONCLUSIONS
The 17q12-21 locus has a strong genetic association with allergic asthma but not with AR. The polymorphic effect of this locus is attributed to the linkage set tagged by rs8076131, which affects the expression of ORMDL3, protein phosphatase 1, regulatory inhibitor subunit 1B (PPP1R1B), zona pellucida binding protein 2 (ZPBP2), and gasdermin B (GSDMB) and is correlated with high IgE levels and eosinophil counts in subjects bearing the risk genotype.
Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore; Department of Biological Sciences, National University of Singapore, Singapore.
Anand Kumar
AK
Andiappan
Department of Biological Sciences, National University of Singapore, Singapore.
Yang Yie
YY
Sio
Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore.
Bernett
B
Lee
Department of Biological Sciences, National University of Singapore, Singapore.
Bani Kaur
BK
Suri
Department of Biological Sciences, National University of Singapore, Singapore.
Sri Anusha
SA
Matta
Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore.
Josephine
J
Lum
Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore.
Shihui
S
Foo
Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore.
Geraldine
G
Koh
Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Singapore.
Jianjun
J
Liu
Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore.
Francesca
F
Zolezzi
Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore.
Michael
M
Poidinger
Department of Otolaryngology, National University of Singapore, National University Health System, Singapore. Electronic address: entwdy@nus.edu.sg.
De Yun
de Y
Wang
Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore. Electronic address: olaf_rotzschke@immunol.a-star.edu.sg.
Olaf
O
Rotzschke
Department of Biological Sciences, National University of Singapore, Singapore. Electronic address: dbscft@nus.edu.sg.
Fook Tim
FT
Chew
D000293:Adolescent; D000328:Adult; D000483:Alleles; D001249:Asthma / Q000097:blood / Q000235:genetics* / Q000276:immunology; D016022:Case-Control Studies; D002648:Child; D002886:Chromosomes, Human, Pair 17; D004804:Eosinophils; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood / Q000276:immunology; D007958:Leukocyte Count; D015810:Linkage Disequilibrium; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D040641:Quantitative Trait Loci; D065631:Rhinitis, Allergic / Q000097:blood / Q000235:genetics* / Q000276:immunology; D055815:Young Adult
D008565:Membrane Proteins; C464399:ORMDL3 protein, human; D007073:Immunoglobulin E
17q21; IgE; ORMDL3; Singapore Chinese; allergic asthma; allergic rhinitis; eosinophil counts