A genome-wide meta-analysis of genetic variants associated with allergic rhinitis and grass sensitization and their interaction with birth order.
BACKGROUND
Hay fever or seasonal allergic rhinitis (AR) is a chronic disorder associated with IgE sensitization to grass. The underlying genetic variants have not been studied comprehensively. There is overwhelming evidence that those who have older siblings have less AR, although the mechanism for this remains unclear.


OBJECTIVE
We sought to identify common genetic variant associations with prevalent AR and grass sensitization using existing genome-wide association study (GWAS) data and to determine whether genetic variants modify the protective effect of older siblings.


METHODS
Approximately 2.2 million genotyped or imputed single nucleotide polymorphisms were investigated in 4 large European adult cohorts for AR (3,933 self-reported cases vs 8,965 control subjects) and grass sensitization (2,315 cases vs 10,032 control subjects).


RESULTS
Three loci reached genome-wide significance for either phenotype. The HLA variant rs7775228, which cis-regulates HLA-DRB4, was strongly associated with grass sensitization and weakly with AR (P(grass) = 1.6 × 10(-9); P(AR) = 8.0 × 10(-3)). Variants in a locus near chromosome 11 open reading frame 30 (C11orf30) and leucine-rich repeat containing 32 (LRRC32), which was previously associated with atopic dermatitis and eczema, were also strongly associated with both phenotypes (rs2155219; P(grass) = 9.4 × 10(-9); P(AR) = 3.8 × 10(-8)). The third genome-wide significant variant was rs17513503 (P(grass) = 1.2 × 10(-8); PAR = 7.4 × 10(-7)) which was located near transmembrane protein 232 (TMEM232) and solute carrier family 25, member 46 (SLC25A46). Twelve further loci with suggestive associations were also identified. Using a candidate gene approach, where we considered variants within 164 genes previously thought to be important, we found variants in 3 further genes that may be of interest: thymic stromal lymphopoietin (TSLP), Toll-like receptor 6 (TLR6) and nucleotide-binding oligomerization domain containing 1 (NOD1/CARD4). We found no evidence for variants that modified the effect of birth order on either phenotype.


CONCLUSIONS
This relatively large meta-analysis of GWASs identified few loci associated with AR and grass sensitization. No birth order interaction was identified in the current analyses.
Respiratory Epidemiology and Public Health, Imperial College, London, United Kingdom.
Adaikalavan
A
Ramasamy
Ivan
I
Curjuric
Lachlan J
LJ
Coin
Ashish
A
Kumar
Wendy L
WL
McArdle
Medea
M
Imboden
Benedicte
B
Leynaert
Manolis
M
Kogevinas
Peter
P
Schmid-Grendelmeier
Juha
J
Pekkanen
Matthias
M
Wjst
Andreas J
AJ
Bircher
Ulla
U
Sovio
Thierry
T
Rochat
Anna-Liisa
AL
Hartikainen
David J
DJ
Balding
Marjo-Riitta
MR
Jarvelin
Nicole
N
Probst-Hensch
David P
DP
Strachan
Deborah L
DL
Jarvis
D000328:Adult; D001722:Birth Order; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D006109:Poaceae / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D006255:Rhinitis, Allergic, Seasonal / Q000235:genetics*