Chronic obstructive pulmonary disease (COPD) is due to interactions between cigarette smoke exposure and other risk factors. Genetic variations of human beta-defensin-1 (hBD-1), an endogenous antimicrobial peptide in the airway, were investigated in 60 patients and 213 healthy volunteers by single-strand conformation and restriction fragment length polymorphism analysis and DNA sequencing. Four nucleotide variations in the 5' and 3' untranslated regions and two nonsynonymous substitutions in the coding region were identified. Of these, a newly found Ile38 variant was observed in 15.0% of patients but only in 2.8% of healthy individuals and was significantly associated with the disease (OR = 6.1, 95% confidence intervals 2.0-18.3, P=0.0012). More than 80% of those with Ile38 experienced sputum production for more than 3 months during the follow-up period. Genetic variations in hBD-1 may define a high-risk subgroup of COPD where the component of chronic bronchitis is predominant. (C) 2002 Elsevier Science (USA).