Is SULT2A1 rs2637125 associated with differences in DHEA-S levels and adrenal androgen sulfation?

The SULT2A1 gene encodes the primary enzyme responsible for the sulfation of dehydroepiandrosterone (DHEA) into its storage form, DHEA-S. Genetic variation at the rs2637125 locus has been widely investigated for its influence on systemic androgen profiles.

Genetic association with circulating DHEA-S

• Large-scale genome-wide association studies (GWAS) firmly establish the SULT2A1 rs2637125 polymorphism as a major quantitative trait locus strongly associated with circulating DHEA-S concentrations.
• This genetic association exhibits age- and sex-dependent phenotypic penetrance; for example, the rare allele is associated with lower plasma DHEA-S levels in pubertal boys aged 12–16 years, while no significant differences are observed in younger children or girls.

Functional impact on adrenal androgen sulfation

• The functional consequence of the rs2637125 variant on direct adrenal androgen sulfation capacity remains inconsistent. Because this polymorphism is located in a regulatory flanking region and not a coding sequence, it does not alter the amino acid sequence of the SULT2A1 enzyme.
• To assess sulfation efficiency, researchers look at the DHEA/DHEA-S ratio. Some clinical evaluations show that individuals with the AA genotype exhibit an elevated DHEA/DHEA-S ratio, reflecting reduced sulfation efficiency.
• Conversely, other large population cohorts show no significant differences in the DHEA/DHEA-S ratio, total DHEA, or DHEA-S levels across genotypes, and direct molecular evidence linking the variant to altered SULT2A1 expression or enzymatic kinetics is still lacking.

Bottom line

• The SULT2A1 rs2637125 polymorphism is a robustly established genetic marker for circulating DHEA-S levels, but its direct role in altering individual adrenal androgen sulfation capacity is currently only plausible due to conflicting clinical evidence.