A locus for essential hypertension has been found recently on chromosome 17 in the general vicinity of the inducible nitric oxide synthase (iNOS) gene (NOS2A at 17cen-q11.2). We therefore tested NOS2A markers for association and linkage with hypertension in affected Australian Anglo-Caucasians. Patients for the association study (n=112) were from our cohort of hypertensives (systolic/diastolic=175+/-25 SD/112+/-19 mm Hg) who were the offspring of 2 hypertensive parents; control subjects (n=164) were normotensives whose parents were both normotensive. The linkage study involved 156 hypertensive sib-pairs. Genotypes for an 8-allele pentameric repeat located 2.6 kb upstream of NOS2A and of a biallelic tetranucleotide repeat 0.7 kb upstream were determined by polymerase chain reaction and automated gene scan analysis. In the association study, the frequency of the minor allele of the biallelic marker was 0.18 in the hypertensives and 0.14 in the normotensives (chi21 df=1.1, P=0.3). Allele frequencies for the multiallelic marker were also similar in each group (chi2 7 df=9.8, P=0.2). Furthermore, no genotypic differences in blood pressure were apparent. In the sib-pair study, SPLINK APM, and MAPMAKERS/SIBS did not indicate excess allele sharing. We also examined genotype as a function of age. In the younger (< 60 years) hypertensives as well as younger or older normotensives, genotype and allele frequency of the biallelic marker was similar (0.12 to 0.14). However, in hypertensives >/=60 years of age, frequency of the minor allele was 0.28 (chi2=7.4, P=0.006). Homozygotes for this allele were rare. Frequency of heterozygotes was 0.19 for normotensives but 0.39 for the older hypertensives (chi2=8.0, P=0.018) and was 0.40 for hypertensive sibs >/=60 years of age with a diastolic pressure >/=100 mm Hg. Furthermore, homozygotes for the major allele were 7 years younger than heterozygotes (P=0.05 by ANOVA). In conclusion, the present study shows (1) no evidence for a role of NOS2A in hypertension and (2) a genotypic difference in frequency of a NOS2A promoter variant in older hypertensives, seen in 2 different cohorts. A possible interpretation of the latter observation is that NOS2A genotype could affect longevity, at least in patients at high risk by having moderate to severe hypertension.