FSHB rs10835638 T allele is associated with lower circulating FSH levels in women.

The relationship between the FSHB rs10835638 variant and follicle-stimulating hormone (FSH) production is well-established in genomic research. However, the evidence indicates that the direction of the effect for the T allele is the opposite of what was claimed.

Clinical and genomic evidence

Large-scale genome-wide association studies (GWAS) and clinical cohorts have consistently identified the rs10835638 T allele (specifically the c.-211G>T variant) as a potent FSH-lowering variant. In female populations, carrying the T allele is robustly associated with decreased serum FSH levels across various stages of the reproductive lifespan.

• Effect Direction: Quantitative data from biobank studies (such as the UK Biobank) show that the T allele correlates with lower circulating FSH concentrations rather than higher levels.
• Reproductive Impact: Because it reduces FSH levels, this variant is associated with clinically significant reproductive phenotypes, including longer menstrual cycles and a later age at natural menopause.
• Disease Associations: Due to its FSH-lowering properties, the T allele has been identified as a protective factor against conditions driven by high estrogen or FSH-driven follicular recruitment, such as endometriosis and polycystic ovary syndrome (PCOS).

Mechanistic explanations

The rs10835638 polymorphism is located within the promoter region of the FSHB gene, which encodes the specific β-subunit of the follicle-stimulating hormone.

• Transcriptional Activity: The T allele functions as a regulatory variant that reduces the transcriptional activity of the FSHB promoter. In vitro reporter assays demonstrate that the G-to-T substitution decreases the promoter's ability to drive gene expression.
• Protein Synthesis: The reduction in FSHB mRNA expression leads directly to a decrease in the synthesis and secretion of the FSH protein by the anterior pituitary gland.
• LH Interactions: Interestingly, while it lowers FSH, the T allele has been associated with compensatory or independent increases in luteinizing hormone (LH) levels in some contexts, but its primary effect on the FSHB gene remains inhibitory.

Bottom line

The FSHB rs10835638 T allele is associated with lower circulating FSH levels in women, not higher. By reducing the transcriptional output of the FSHB gene, this variant leads to decreased hormone production, which clinically manifests as delayed reproductive aging and altered risk for gynecological conditions.