rs523349 — SRD5A2 V89L

SRD5A2 V89L — Testosterone to DHT Conversion

The SRD5A2 gene encodes steroid 5-alpha-reductase type 2, the enzyme that converts testosterone to 5-alpha dihydrotestosterone (DHT)

— the most potent androgen in the body. This conversion is critical in the prostate, hair follicles, and skin. The V89L variant (rs523349) is a missense single nucleotide polymorphism resulting in a valine to leucine substitution at codon 89 that reduced SRD5A2 enzyme activity . The L allele (coded as C in 23andMe data) is extremely common, carried by

54.8% of Asians, 30.4% of whites, and 23.1% of African Americans .

The Mechanism

The valine-to-leucine substitution at position 89 sits in a functionally important region of the enzyme. Biochemical studies¹¹ Biochemical studies
Makridakis et al. demonstrated functional differences between variants show that the L variant produces about 30% less DHT from testosterone compared to the V variant. This reduced enzyme activity means that individuals with LL genotypes produce less DHT throughout their lifetime, while those with VV genotypes maintain higher DHT production. The heterozygous VL genotype shows intermediate activity.

Because DHT is the primary androgen driving prostate growth, hair follicle miniaturization in male pattern baldness, and sebum production, this variant has wide-ranging effects on androgen-mediated physiology.

The Evidence

The relationship between V89L and disease risk is complex and ethnicity-dependent:

Prostate cancer:

A 2010 meta-analysis of 25 studies (8,615 cases, 9,089 controls) found that V89L polymorphism could play a low-penetrant role in prostate cancer risk among Europeans , with an OR of 1.11 (95% CI 1.03-1.19) for carriers of at least one L allele.

However, a comprehensive meta-analysis found that prostate cancer was not associated with V89L overall (OR = 0.99, 95% CI: 0.94, 1.05) . The European-specific risk appears modest and was significantly associated with increased prostate cancer risk in men aged ≤65 (OR 1.70, 95% CI 1.09-2.66 for LL vs VV) .

Interestingly, one large French study found that the low-activity V89L variant is associated with an increased risk of aggressive prostate cancer , suggesting that chronically lower DHT levels may paradoxically increase risk of high-grade tumors. This finding helped explain controversies observed in finasteride chemoprevention trials.

Benign prostatic hyperplasia (BPH):

SRD5A2 rs523349 (V89L) polymorphism showed no significant role in BPH occurrence in total analysis, but its reducing and increasing effects on the disease risk were reflected in Caucasian and other-ethnicity subgroups, respectively . In Caucasians, the L variant appeared protective (OR 0.47, 95% CI 0.24-0.93), while in Asian populations it increased risk (OR 2.74, 95% CI 1.27-5.92).

Male pattern baldness: Studies have been inconsistent.

Genetic association studies of 5 alpha reductase genes SRD5A1 and SRD5A2 in 828 families failed to show an association between these genes and male androgenetic alopecia , despite the clear role of DHT in hair loss and the efficacy of 5-alpha-reductase inhibitors as treatment.

Metabolic effects:

Metabolic syndrome develops more frequently in testicular cancer survivors homozygous or heterozygous variant for SNP rs523349 in SRD5A2 , with patients with lower testosterone levels (<15 nmol/l) and a variant genotype showing a high prevalence of metabolic syndrome (66.7%) .

Practical Implications

The main clinical relevance of this variant lies in pharmacogenomics and understanding individual androgen physiology:

Finasteride response: Finasteride works by inhibiting 5-alpha-reductase type 2.

Substantial pharmacogenetic variation was observed among the mutants, with finasteride inhibition varying 60-fold depending on the variant. Studies suggest²² Studies suggest
Genetic variation affects drug binding affinity that individuals with different SRD5A2 genotypes may respond differently to finasteride treatment for BPH or male pattern baldness, though clinical dosing guidelines do not yet account for genotype.

Prostate health monitoring: Men of European descent who carry the L allele, particularly those over 40, may benefit from more vigilant prostate cancer screening, given the modest increase in risk and association with aggressive disease. However, the effect size is small enough that this should not override standard screening guidelines.

Understanding DHT-mediated effects: If you have LL genotype, you produce less DHT throughout your life. This may contribute to less severe male pattern baldness, reduced prostate enlargement with age, but potentially different metabolic patterns. The VV genotype maintains higher DHT production, which may manifest as more robust androgen effects.

Interactions

The SRD5A2 V89L variant interacts with rs9282858 (A49T), another variant in the same gene.

The effects of compound heterozygotes and haplotypes composed of homozygotes for the common V89L variant plus one rare heterozygous mutation were determined , showing that the V89L–A49T haplotype demonstrated the highest affinity for finasteride compared with other haplotypes . Individuals with both variants may have substantially different enzyme kinetics and drug response.

The HSD3B2 gene (encoding 3-beta-hydroxysteroid dehydrogenase) also influences androgen metabolism.

Most of the prostate cancer risk associated with the intron 3 HSD3B2 short allele was confined to the SRD5A2 89L variant subgroup , indicating that combined genotype analysis may better predict risk than either variant alone.