Abstract—The P2X receptor gene family encodes a series of proteins that function as ATP-gated nonselective ion channels. P2X receptor channels are involved in transducing aldosterone-mediated signaling in the distal renal tubule and are potential candidate genes for blood pressure regulation. We performed a family based quantitative genetic association study in 248 families ascertained through a proband with hypertension to investigate the relationship between common genetic variation in the P2X4, P2X6, and P2X7 genes and ambulatory blood pressure. We genotyped 28 single nucleotide polymorphisms, which together captured the common genetic variability in the 3 genes. We corrected our results for multiple comparisons specifying a false discovery rate of 5%. We found significant evidence of association between the single nucleotide polymorphism rs591874 in the first intron of the P2X7 gene and blood pressure. The strongest association was found for nighttime diastolic blood pressure (P=0.0032), although association was present for both systolic and diastolic blood pressures measured by an observer during the day and at night. Genotypes were associated with a 0.2 SD (2.5 mm Hg) difference in night diastolic blood pressure per allele and accounted for 1% of the total variability in this measurement. Other suggestive associations were found, but these were nonsignificant after correction for multiple testing. These genetic data suggest that drugs affecting P2X receptor signaling may have promise as clinical antihypertensive agents.