Recent genome-wide association studies (GWAS) implicate the CYP17A1 locus in human blood pressure regulation. This gene is important in steroidogenesis, regulating both glucocorticoid and androgen synthesis through catalysis of 17α-hydroxylation and 17,20 lyase reactions. We hypothesised that functional CYP17A1 polymorphisms linked to those identified by GWAS influence blood pressure levels. We therefore screened the entire CYP17A1 locus by direct sequencing, identifying possible functional variants through in vitro analysis and correlating genotype with intermediate corticosteroid phenotype in a hypertensive cohort.
Examination of polymorphic variation to establish patterns of linkage disequilibrium across the CYP17A1 locus was conducted in a normotensive cohort. Variants located in the 5′ regulatory region were prioritised for further investigation. Bioinformatic analysis coupled with in vitro reporter gene assays confirmed that single base changes at three polymorphic sites each altered transcriptional activity. Association between genotype and intermediate corticosteroid phenotype was explored using 24-h urinary metabolite excretion data from a cohort of 232 hypertensive subjects. When stratified by genotype and gender, increased cortisol excretion rates were found to associate with the minor allele at rs248658 in males (P=0.05) and at rs2150927 in females (P=0.04). Furthermore, ratios of selected corticosteroid intermediary metabolites (e.g. THDOC:THS) were significantly reduced in the presence of the rs2150927 minor allele, in a manner indicative of increased 17α-hydroxylase efficiency (P=0.02). Aldosterone excretion was also significantly elevated in individuals with CC genotype at rs138009835 (P=0.05); we propose an indirect genotype-dependent effect.
This study identifies that polymorphisms linked to those implicated in previous GWAS significantly alter CYP17A1 transcription. Furthermore, these variants associate with corticosteroid intermediate phenotypes in a hypertensive population, implying functional effect and a mechanism for the development of hypertension. Further studies will determine whether observed changes in transcriptional activity are the direct result of altered transcription factor binding at polymorphic sites.