Endothelin-1 (EDN1) has been reported to be implicated in the pathophysiology of asthma. Literature results on the genetic association of EDN1 in asthma are inconsistent. Eleven single nucleotide polymorphisms in EDN1 were genotyped in 342 and 100 families from UK and Norway, respectively. Asthma, bronchial hyperreactivity (BHR) and atopic asthma phenotypes were analyzed for the family-based association. Five single nucleotide polymorphisms (SNPs) were associated with asthma (0.0017<or=P<or=0.0291), five with BHR (0.0026<or=P<or=0.0315) and three with atopic asthma (0.0016<or=P<or=0.041) in the UK population. Three SNPs were associated with asthma (0.0041<or=P<or=0.019), seven with BHR (0.0018<or=P<or=0.041) and two with atopic asthma (0.0123<or=P<or=0.0153) in the Norwegian population. A polymorphism (rs1800541) in the promoter region of EDN1 was replicated in the two populations. A nonsynonymous coding polymorphism (rs5370) resulting in a change of amino acid Asn to Lys at position 198 was also replicated. The results of haplotype-based association analyses strongly supported the ones of single SNP associations. This study demonstrates the significant evidence of association between polymorphisms in EDN1 and asthma.