rs6162 — CYP17A1 His46=

CYP17A1 rs6162 — A Steroidogenesis Haplotype Tag Linked to DHEA-S Levels and Prostate Cancer Outcomes

CYP17A1¹¹ CYP17A1
cytochrome P450 17A1, encoding the bifunctional enzyme 17α-hydroxylase/17,20-lyase sits at one of the most critical branch points in human steroid biosynthesis. The enzyme converts pregnenolone and progesterone to 17-hydroxy intermediates (generating cortisol precursors) and catalyzes the subsequent lyase reaction that produces DHEA and androstenedione — the precursors to all androgens and estrogens. rs6162 is a synonymous coding variant at codon 46 of CYP17A1 (c.138C>T, His46=), meaning it does not change the encoded amino acid. Its biological significance is primarily as a haplotype-tagging SNP: it co-occurs in strong linkage disequilibrium with the 5'UTR variant rs743572 (T-34C)²² rs743572 (T-34C)
rs743572 lies 171 bp upstream of rs6162 and creates an Sp1 transcription factor binding site that alters CYP17A1 promoter activity, and the rs6162 A allele effectively tags the CYP17A1 haplotype associated with altered enzyme expression and steroid output.

The Mechanism

The rs6162 A allele (synonym: the CAT codon at position 46 vs. the reference CAC codon; both encode histidine) does not directly alter CYP17A1 protein function. Rather, it resides in strong LD with regulatory variants in the CYP17A1 locus — most notably rs743572 (T-34C), which creates an additional Sp1 binding site in the promoter region and is associated with increased transcription of the enzyme in some in vitro systems. Variants in this haplotype block influence how much CYP17A1 protein is produced, altering flux through the 17α-hydroxylase and 17,20-lyase reactions. The lyase step is rate-limiting for DHEA synthesis; increased CYP17A1 activity pushes more steroid substrate toward the Δ5 pathway³³ Δ5 pathway
the androgen biosynthesis pathway through DHEA and androstenedione, as opposed to the Δ4 glucocorticoid pathway and away from cortisol precursors. The downstream effects include elevated DHEA-S and, through peripheral conversion, raised androgen levels — an effect directly relevant to prostate cancer biology and androgen signaling in general.

The Evidence

The most rigorous study of rs6162 is Lévesque et al. 2013 in Clinical Cancer Research⁴⁴ Lévesque et al. 2013 in Clinical Cancer Research
Molecular markers in key steroidogenic pathways, circulating steroid levels, and prostate cancer progression. Clin Cancer Res 19:699–709, which genotyped 109 haplotype-tagging SNPs across CYP17A1, ESR1, CYP19A1, and HSD3B1 in 526 Caucasian men with organ-confined prostate cancer and validated findings in 601 Taiwanese men on androgen-deprivation therapy. After adjusting for known risk factors, CYP17A1 rs6162 was significantly associated with disease progression in both cohorts — hazard ratios of 2.29–4.10 in the Caucasian group (P=0.0014 to 2×10⁻⁷) and HR 3.74 (95% CI 1.71–8.19, P=0.009) in the Taiwanese group. Critically, the rs6162 polymorphism was also linked to plasma DHEA-S levels in Caucasian men (P=0.03), providing a plausible biochemical mechanism: the haplotype tagged by rs6162 influences adrenal androgen output, and elevated DHEA-S fuels intratumoral androgen synthesis even during castration.

Yamada et al. 2013 in Int J Clin Oncol⁵⁵ Yamada et al. 2013 in Int J Clin Oncol
CYP17A1 polymorphisms associated with risk of CRPC in Japanese men receiving ADT. Int J Clin Oncol 18:711–717 examined 214 Japanese men on hormone therapy and found that rs6162 (among three other CYP17A1 SNPs: rs743572, rs6163, rs1004467) was significantly associated with castration-resistant prostate cancer progression (P<0.05). This cross-ethnic replication — in a population with a 54% A allele frequency versus ~41% in Europeans — strengthens the evidence for a functional role of this haplotype.

Robles-Fernandez et al. 2017 in PLoS One⁶⁶ Robles-Fernandez et al. 2017 in PLoS One
Polymorphisms in sex hormone synthesis and metabolism genes and prostate cancer aggressiveness. PLoS One 12:e0185447 genotyped 311 Caucasian men and found the G allele of rs6162 was associated with PSA levels >10 ng/mL, while the AG+AA genotype group showed association with higher D'Amico risk stratification — suggesting the variant may influence both hormone levels and clinical tumor phenotype.

More recently, Hahn et al. 2025 in Prostate Cancer Prostatic Dis⁷⁷ Hahn et al. 2025 in Prostate Cancer Prostatic Dis
Body composition as a determinant of the therapeutic index with androgen signaling inhibition. Prostate Cancer Prostatic Dis 28:802–808 found CYP17A1 rs6162 among three androgen synthesis gene polymorphisms associated with baseline body composition differences (adiposity) in 186 metastatic CRPC patients on ADT — suggesting the variant's influence on steroid synthesis extends to body composition phenotypes during androgen suppression.

Practical Actions

For men with the A allele, the key implication is altered DHEA-S production and downstream androgen availability. Even in the context of ADT, residual adrenal DHEA-S can be peripherally converted to testosterone and DHT, fueling continued prostate cancer signaling. Measuring baseline DHEA-S provides a direct readout of adrenal androgen output relevant to this haplotype. Abiraterone acetate (a potent CYP17A1 inhibitor) is specifically designed to block this residual adrenal androgen production in CRPC; men with the rs6162 A allele who progress to CRPC may be particularly suited to this mechanism of action.

For the broader reproductive hormones category, altered DHEA-S levels affect both sexes: in women, elevated adrenal DHEA-S is a contributor to androgen excess in PCOS-like phenotypes; in men, it fuels testosterone synthesis throughout life.

Interactions

rs6162 forms a haplotype with rs743572 (T-34C, 5'UTR), rs6163, and rs1004467 within the CYP17A1 locus. The rs743572 variant is the most studied regulatory element in this block and has the broadest literature on breast cancer, endometriosis, and PCOS risk. Studies examining rs6162 frequently co-report rs743572 results; the two SNPs are functionally inseparable in many population analyses. The combined haplotype, more than any individual SNP, determines CYP17A1 expression level and steroid output phenotype.