IL1RN encodes interleukin-1 receptor antagonist (IL-1Ra), a soluble anti-inflammatory protein that competitively antagonizes interleukin-1 family cytokines (IL-1α and IL-1β) by binding their receptors, thereby protecting against immune dysregulation and uncontrolled systemic inflammation 1. IL-1Ra functions as a negative regulator of IL-1-mediated signaling, limiting inflammatory responses triggered by pathogenic stimuli 2. Genetically, IL1RN polymorphisms modulate disease susceptibility across multiple conditions. Maternal IL1RN*2 variants increase preterm delivery risk, particularly when preterm premature rupture of membranes occurs 1. Lower IL1RN mRNA expression associated with specific polymorphisms predisposes to idiopathic pulmonary fibrosis susceptibility 3. In coronary artery disease, the IL1RN+8006T/C polymorphism exhibits protective effects 4. Gene-environment interactions occur: rare IL1RN genotypes protect against asthma without environmental tobacco smoke exposure but increase early-onset asthma risk with childhood ETS exposure 2. IL1RN variants modulate COVID-19 severity; specific haplotypes reduce inflammatory markers and mortality 5. Additionally, IL1RN VNTR polymorphisms associate with male infertility 6 and chr2 obstructive pulmonary disease risk in East Asian populations 7. These findings demonstrate IL1RN's critical role in regulating inflammatory homeostasis across diverse physiological and pathological contexts.