Abstract--This study aims to test the implication of regions on chromosomes 9, 17, and 18 in essential hypertension (EH) by combining sibling-pair linkage analysis and case-control association studies. The selection of these chromosomal regions is based on previous evidence of their implication in EH or in related phenotypes by comparative genomics in several rat models and from genome-wide linkage studies in humans. For the affected sibling-pair linkage analysis, 27 microsatellite markers were genotyped in 56 pedigrees from Spain with hypertensive sibling pairs. Linkage analysis showed significant excess allele sharing at the D18S474 marker on 18q21.1, as shown by maximum likelihood of allele sharing methods (logarithm of odds=3.24; P=0.00011) and nonparametric linkage calculations (nonparametric linkage=3.32; P=0.00044). On the contrary, no significant results with any of the markers analyzed on chromosomes 9 and 17 were obtained. We further focused on the Ring finger and KH domain containing 2 (RKHD2) gene located 6 Kb distal from D18S474 and performed a case-control association study based on linkage disequilibrium in 112 hypertensive patients and 156 control subjects. We selected 2 RKHD2-tagged single nucleotide polymorphisms, rs1941958 and rs1893379, covering, in terms of linkage disequilibrium, the entire gene, and observed a significant overrepresentation of the rs1941958G-rs1893379T RKHD2 haplotype in the group of hypertensive patients in comparison with controls (2P=0.0004; odds ratio: 2.32). We also detected epistatic effects between the 2 RKHD2 single nucleotide polymorphisms (2P=0.002; odds ratio: 2.48). Our data confirm the implication of chromosome 18 in EH and support a contribution of RKHD2 to the genetic susceptibility of this complex phenotype.