A study of genetic variability at the CYP11B2/B1 locus and its importance in human hypertension

The studies reported in this thesis aimed to identify the pattern of variation across the CYP11B1/CYP11B2 locus in order to determine the genetic variation responsible for the observed impaired 11ß-hydroxylation and its link with aldosterone levels and hypertension. In Chapter 3, an attempt was made to identify polymorphisms in CYP11B1 that associate with hypertension and a raised aldesterone-to-renin ratio (ARR) and therefore might contribute to the genetic component of these phenotypes. The study in Chapter 4 aimed to analyze the pattern of variation across the CYP11B2/B1 locus in detail. In Chapter 5, the frequency and phenotypic associations of the newly identified CYP11B1 5’UTR polymorphisms -1889 G/T and -1859 A/G were investigated in a hypertensive population. The frequencies were found to be -1889 G-0.53, T- 0.47; -1859 A-0.5, G-0.5. Interestingly, the -1889 G/T and -1859 A/G polymorphisms were found to be associated with impaired 11ß-hydroxylase efficiency in a hypertensive population. The THS/total F ratio (index of 11ß-hydroxylase activity) was significantly higher in -1889 TT homozygotes than in GG homozygotes (p=0.025). A similar pattern was seen with the -1859 SNP, with GG homozygotes tending to have a higher ratio than AA homozygotes (p=0.056). These steroid data were supported by the results from Chapter 6 that examined the effects of these polymorphisms in vitro using luciferase reporter gene constructs transfected into Y1 mouse adrenal cells. In summary, these studies have confirmed that the CYP11B2 and CYP11B1 genes contain a high frequency of genetic variation. Many of the variants identified in CYP11B1 have been shown to alter activity significantly. There is strong evidence to suggest that the impaired 11ß-hydroxylase efficiency previously associated with the -344 C/T and IC variants in CYP11B2 is due to linkage with the -1889 G/T and -1859 A/G polymorphisms upstream of CYP11B1