The locus comprising the genes that catalyse the final steps of cortisol and aldosterone synthesis (CYP11B1 and CYP11B2 respectively) is a plausible candidate risk region for hypertension and other cardiovascular diseases. Nevertheless, there remains uncertainty as to the strength of the relationship between polymorphisms at this locus and increased blood pressure. In this study, association with hypertension at the CYP11B1/CYP11B2 locus in a Caucasian casecontrol population was tested and replicated in an independent Caucasian population. In the discovery phase, 8 SNPs were genotyped and 29 SNPs imputed in 1643 hypertensive cases and 1697 controls (BRIGHT Study). The SNPs significantly associated with hypertension (rs6410, rs4471016 (−1859A/G), rs43131369 (−1889G/T), rs6471581, rs4546, intron conversion and rs1799998 (−344T/C)) were tested for replication in 1612 hypertensive cases (NORDIL Study) and 1317 controls (MDC Study). Only the intron conversion showed significant association with hypertension in the single SNP analysis. Subjects with the conversion allele in intron 2 of CYP11B2 had a higher risk of hypertension (OR=1.19 (1.101.29), P=1.06×10−5). In the three-marker sliding window haplotype analysis, three haplotypes showed significant association with hypertension in a combined meta-analysis of the two studies:
|Gene||Sets of three SNPs in sliding windows||Haplotype||OR (95% CI)||P|
|CYP11B1||rs6410, rs4471016, 4313136||T/A/G||3.14 (2.274.32)||2.99×10−12|
|CYP11B1/CYP11B2||rs4471016, rs4313136, rs6414||A/G/G||2.64 (1.873.74)||3.90×10−8|
|CYP11B2||rs6414, rs4546, intron conversion||A/T/Conv||4.64 (2.638.18)||1.11×10−7|
Thus, for the first time, the regions most strongly associated with hypertension in Caucasians one between intron 2 and intron 3 of CYP11B2 and another between the promoter and exon 1 of CYP11B1 have been replicated. The variability in the strength of these associations suggests the locus is involved in hypertension in a complex manner. Additional functional studies are required to elucidate the mechanism by which these genetic variations lead to alterations in aldosterone and cortisol production and subsequent hypertension.