BACKGROUNDAdducin is a membrane skeleton protein consisting of α- and β- or α- and γ-subunits. Mutations in α- and β-adducin are associated with hypertension. In the European Project on Genes in Hypertension, we investigated whether polymorphisms in the genes encoding α-adducin (Gly460Trp), β-adducin (C1797T) and γ-adducin (A386G), alone or in combination, affected pulse pressure (PP), an index of vascular stiffness. METHODSWe measured peripheral and central PP by conventional sphygmomanometry and applanation tonometry, respectively. We randomly recruited 642 subjects (162 nuclear families and 70 unrelated individuals) from three European populations. In multivariate analyses, we used generalized estimating equations and the quantitative transmission disequilibrium test. RESULTSPeripheral and central PP averaged 46.1 and 32.6 mmHg, respectively. Among carriers of the α-adducin Trp allele, peripheral and central PP were 5.8 and 4.7 mmHg higher in γ-adducin GG homozygotes than in their AA counterparts, due to an increase in systolic pressure. γ-Adducin GG homozygosity was associated with lower urinary Na/K ratio among α-adducin Trp allele carriers and with higher urinary aldosterone excretion among α-adducin GlyGly homozygotes. Sensitivity analyses in founders and offspring separately, and tests based on the transmission of the γ-adducin G allele across families, confirmed the interaction between the α- and γ-adducin genes. CONCLUSIONSIn α-adducin Trp allele carriers, peripheral and central PP increased with the γ-adducin G allele. This epistatic interaction is physiologically consistent with the heterodimeric structure of the protein and its influence on transmembranous sodium transport.