Polymorphisms in HTR4 were associated with FEV1/FVC at genome-wide significance in the joint meta-analysis of CHARGE and SpiroMeta results. HTR4 encodes a G-coupled transmembrane receptor that regulates cAMP production in response to 5-hydroxytryptamine (serotonin). Elevated levels of free serotonin have been found in the plasma of symptomatic asthmatics31, and serotonin signaling pathways involving HTR4 have been implicated in cholinergic and immune-mediated airway reactivity32,33. Upon activation by serotonin, HTR4 in human airway epithelial cells regulates the release of a pro-inflammatory cytokine, a signature characteristic of asthma34.
