Does SULT2A1 rs2637125 GG lower circulating DHEA-S reserve?

Dehydroepiandrosterone (DHEA) and its sulfated storage form (DHEA-S) play vital roles in human steroidogenesis. While the biological pathway converting DHEA to DHEA-S is well-characterized, genetic assertions regarding specific variants require careful distinction.

Enzymatic pathway of DHEA sulfation

• SULT2A1 is the principal human cytosolic sulfotransferase responsible for converting DHEA into DHEA-S, primarily acting in the liver and adrenal cortex.
• The enzyme operates with a low-micromolar affinity (Michaelis constant, $K_m$, of 0.8 to 10 µM) and is subject to native substrate inhibition at DHEA concentrations exceeding 2 µM.
• This process is optimized by PAPS synthase 2 (PAPSS2), which physically couples with SULT2A1 to supply the essential sulfur donor. SULT2B1 serves as a secondary, tissue-restricted pathway but possesses lower catalytic efficiency.

Genetic influence of SULT2A1 rs2637125

• The claim that the homozygous common GG genotype of SULT2A1 rs2637125 is associated with a lower DHEA-S reserve is unsupported by scientific evidence.
• Large-scale genomic studies demonstrate that the minor allele (typically the A allele) is the variant associated with lower circulating DHEA-S levels. Consequently, individuals with the GG genotype exhibit higher baseline DHEA-S concentrations compared to minor allele carriers.
• Adult cohort analyses show rs2637125 does not alter absolute DHEA/DHEA-S diagnostic ratios, suggesting it acts as a regulatory genomic marker rather than directly modifying enzyme kinetics.

Bottom line

• SULT2A1 is the primary driver of DHEA to DHEA-S conversion, but the claim regarding rs2637125 is inverted; the GG genotype is associated with higher circulating DHEA-S reserves, while the minor allele is linked to lower levels.