Presentation: Genetic association and eQTL analyses of genes associated with allergy in atopic/non-atopic asthma ( World Allergy Congress)

Wednesday, 14 October 2015: 11:30 - 11:45

Room R1 ABC (Floor 3) (Coex Convention Center)

Xingnan Li, PhD , Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC

Naftali Kaminski, MD , Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, CT

Sally Wenzel, MD , University of Pittsburgh, Division of Pulmonary, Allergy, and Critical Care Medicine, Pittsburgh, PA

Eugene Bleecker, MD , Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC

Deborah Meyers, MD , Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC

Background: Genome-wide association studies (GWASs) of allergic sensitization or self-reported allergic rhinitis (Ramasamy, JACI, 2011; Hinds, Nat Genet, 2013; Bonnelykke, Nat Genet, 2013) consistently identified nine genomic regions: IL1RL1-IL18R1, LPP, IL2-IL21, TLR1-TLR6, SLC25A46-TSLP, TSLP-WDR36, HLA-DQB1, C11orf30-LRRC32, and CLEC16A. Atopic and non-atopic asthma represent two distinctive subphenotypes, however, the genes involved in atopic/non-atopic asthma have not been studied.

Methods: Genetic association analysis of one single nucleotide polymorphism (SNP) from each candidate region was performed in non-Hispanic white asthmatic subjects from SARP, CSGA, ACRN, and TENOR cohorts (n = 1,209 and 154 for atopic and non-atopic asthma, respectively) using logistic regression model. Expression quantitative trait loci (eQTL) analysis, using linear regression model, of the candidate SNPs was performed in cells from human bronchial epithelial biopsy (BEC, n = 107) and bronchial alveolar lavage (BAL, n = 94) from the SARP cohort (GEO series accession number GSE67940).

Results: SNPs in seven genes (IL18R1, LPP, SLC25A46, WDR36, HLA-DQB1, C11orf30, and CLEC16A) were associated with general physician-diagnosed asthma in the GABRIEL study (P = 3.5x10^-12 - 4.4x10^-3) (Moffatt, NEJM, 2010). In our study, SNPs in five genes (IL18R1, LPP, IL21, TLR6, and C11orf30) were associated with atopic status in asthma subjects (P = 4.6x10^-3 - 0.05). SNPs in LPP and IL21 showed opposite risk alleles between asthma and autoimmune diseases. The gene expression pattern between BEC and BAL were distinct. In BAL, rs1464510, rs7696175, rs1043828, rs6906021, and rs7936562 were cis-correlated with mRNA expression levels of LPP, TLR6, TSLP, HLA-DQB1, and C11orf30, respectively (P = 1.1x10^-10 - 0.04).

Conclusions: Most of the genes associated with allergic sensitization or self-reported allergic rhinitis are also associated with general asthma, indicating shared genetic factors among allergic diseases. IL18R1, LPP, and C11orf30-LRRC32 are associated with atopic asthma and general asthma, however, the association effects (odds ratio) are stronger in atopic asthma. IL21 and TLR6 are associated with atopic status in asthma, but not associated with general asthma, indicating the importance to perform genetic analysis in more homogeneous asthma subphenotypes. Asthma and autoimmune diseases have shared immunopathogenesis pathways but in opposite directions. There is a tissue-specific gene expression regulation. SNPs in LPP, TLR6, and C11orf30 are associated with atopic asthma and cis-correlated with their gene expression in BAL, indicating they are likely to be functional SNPs.

(This abstract is funded by NIH HL87665 and Go Grant RC2HL101487)

1-3OAS Genetic association and eQTL analyses of genes associated with allergy in atopic/non-atopic asthma