BackgroundCRTh2 is G protein coupled receptor for prostaglandin D2 (PGD)₂expressed by immune cells that drive type 2 inflammation such as CD4⁺T cells (Th2), eosinophils and group 2 innate lymphoid cells (ILC2) as well as structural cells including smooth muscle and epithelium. CRTh2-expressing cells are increased in the blood and airways of asthmatics and severe asthma is characterized by increased activity of the PGD₂-CRTh2 pathway. TheCRTh2single nucleotide polymorphism (SNP) rs533116 G > A is associated with development of asthma and increased Th2 cell differentiation.ObjectiveTo examine whether CRTh2 rs533116G > A associates with asthma severity. Since severe asthma is more common in females than males, we performed a sex-stratified analysis.MethodsClinical data from asthmatics (n= 170) were obtained from clinic visits and chart review. Asthma severity was assessed according to ERS/ATS guidelines. Peripheral blood cells were characterized by flow cytometry and qRT-PCR. Genotyping was performed by TaqMan assay.ResultsOlder females (≥45 years) homozygous for minor A allele of rs533116 were more likely to have severe asthma, lower FEV₁, a higher prescribed dose of inhaled corticosteroid and more type 2 inflammation than females carrying GA or GG genotypes. Comparing females and males with the AA genotype also revealed that women had more type 2 inflammation.Conclusions and significanceThe polymorphism CRTh2 rs533116 G > A associates with severe asthma and type 2 inflammation in older females. This study reveals a gene-sex-aging interaction influencing the effect of CRTh2 on asthma severity.