Allergic rhinitis (AR) is a multifactorial disease characterized by an inflammatory immune reaction in the nasal mucosa against one or more innocuous airborne allergens, such as pollen in seasonal AR or dust mites in perennial AR. Its prevalence has been estimated to be over 500 million individuals worldwide [PMID 18331513], while in the United States, AR affects up to 30% of adults and 40% of children annually [PMID 18662584]. Given the estimated 33% to 91% heritability of AR [PMID 21682736], genetic association studies have been performed in attempt to elucidate the genetic factors involved in the disease.
In 2011, a genome-wide association study for atopy and AR was performed on a group of ethnic Chinese from Singapore. This study included 456 AR cases and 486 non-allergic non-rhinitis controls and was replicated with an independent cohort of 676 AR cases and 511 controls. No loci achieved genome-wide significance, potentially due to the limited sample sizes, however the authors suggest that two variants, rs8111930 and rs505010, show suggestive association given their presence in both the discovery and replication cohorts. The authors hypothesize these variants may be relevant to the disease given that the first variant, located within an intron in MRPL4, may relate to regulation of nasal allergic reactions, while the second may be involved with B cell activation or maturation [PMID 21625490].
In 2012, another study was published that focused on MRPL4 polymorphisms, in addition to polymorphisms in NF-κB, TNF-α, and ICAM-1. The cohort in this study was Han Chinese from Beijing, and included 414 patients with AR and 293 controls. The authors found that TNF-α variant rs1799964 and MRPL4 variant rs1166861 were significantly associated with AR, adding credence to some role of MRPL4 in AR [PMID 23472126].
In a 2011 genome-wide meta-analysis of AR association, which included 3,933 self-reported cases of AR and 8,965 controls, the authors described one locus achieving genome-wide significance for AR (p-value < 5x10-8). The variant, rs2155219, had already been associated with atopic dermatitis and eczema and lies near chromosome 11 open reading frame 30 (C11orf30) and leucine-rich repeat containing 32 (LRRC32). The first gene has a suggested relevance to epithelial cancer, while the second may related to regulatory T-cell receptors. In the same study, the authors also report two genome-wide significant variants associated with grass sensitization: rs7775288 and rs17513503 [PMID 22036096].
In a follow-up to this meta-analysis, authors of the 2011 GWAS study of ethnic Chinese sought to determine if the significant and suggestive results reported in the meta-analysis were similarly significant in an ethnic Chinese cohort. In agreement, the authors found that the same variant, rs2155219, was the only variant out of thirteen genotyped that was significantly associated with AR. Of note, however, is that the authors also investigated house dust mite sensitization, for which they found two significant variants: rs7617456 and rs1898671 [PMID 23228246]. While these results appear encouraging, it has been suggested that there may be little reproducibility in AR SNP associations, according to a study published in 2013. In this study, the authors compared 253 Swedish AR cases and 709 controls with 948 Singapore Chinese cases and 580 controls and found none of the associations were common to both cohorts. They also did not find convincing evidence that any of the 49 previously-associated SNPs gathered from other studies were strongly associated with AR in their cohorts [PMID 23382861].
In an analysis of personalized genotyping data, scientists from commercial genotyping company 23andme revealed sixteen loci achieving genome-wide significance in a 2013 study [PMID 23817569]. The authors investigated allergies to cat, dust-mite, and pollen in 46,646 individuals and found that eight loci had been previously associated with asthma. Also included in the study were 7,216 subjects from the Avon Longitudinal Study of Parents and Children. An analysis of the variants yielded interesting correspondence to HLA and TLR genes, as well to as genes implicated in T cell differentiation, celiac disease, diabetes, inflammation, and more. Variants achieving genome-wide significance were as follows:
In another 2013 meta-analysis of allergic sensitization, researchers identified 10 loci using a two-stage GWAS study design [PMID 23817571]. The first study of 5789 cases and 10056 controls was followed by a similarly sized second study of 6114 cases and 9920 controls. In concordance with previous studies, SNPs found to be significant were located near HLA and TLR genes, as well as near C11orf30, STAT6, MYC and interleukin genes. A list of the researchers' significant findings, including the effect alleles are listed below:
In 2014, a study using a larger cohort and a more clinically well-defined AR phenotype suggested that there may in fact higher reproducibility than suggested by the earlier 2013 study. The authors compared the three, low concordance meta-analyses presented above ([PMID 22036096], [PMID 23817569], and [PMID 23817571]) to data from a longitudinal cohort of 2153 children. Out of the 39 SNPs examined, the authors found 12 previously associated with AR to be significant [PMID 25066275]. The list of 11 unique variants includes the following:
In an effort to not only determine genes correlated with AR, but also a potential biological pathway, one 2014 study performed a GWAS and pathway analysis that yielded ethnicity-specific findings. From a cohort of 5633 subjects, five genome-wide significant variants were found, four of which were significant among Latinos (rs11680788, rs6583203, rs17133587, and rs12973620) and one across ethnic groups (rs7780001). The authors then found AR-associated eSNPS, which are SNPs associated with gene expression and AR. Performing a pathway analysis using this paired association and expression data pointed to a mitochondrial pathway as implicated in the disease [PMID 25085501].