Does the rs727428 C/T genotype increase SHBG levels?

The rs727428 single nucleotide polymorphism (SNP), located downstream of the sex hormone-binding globulin (SHBG) gene, is a major genetic regulator of circulating SHBG levels.

Clinical evidence

• Contrary to the claim that the rs727428 C/T genotype increases SHBG, large-scale genome-wide association studies (GWAS) show that the minor T allele is robustly associated with a dose-dependent decrease in circulating SHBG.
• Individuals with the heterozygous C/T genotype exhibit a modest 10% to 15% reduction in circulating SHBG levels compared to those with the wild-type CC genotype.
• The reduction is even more pronounced in individuals homozygous for the T/T genotype, who experience an approximate 25% to 30% decrease in serum SHBG concentrations.

Mechanistic pathways

• The rs727428 variant acts as a regulatory genetic modifier that modulates and decreases the expression of the SHBG gene.
• Because SHBG is the primary carrier protein that binds and inactivates sex steroids in the bloodstream, a reduction in circulating SHBG directly leads to a higher fraction of free, biologically active testosterone.
• For a 61-year-old male, carrying the C/T genotype shifts the hormone balance by decreasing SHBG levels, thereby increasing the circulation of bioavailable testosterone.

Bottom line

• The claim is unsupported; the rs727428 C/T genotype is associated with a modest 10% to 15% decrease—not an increase—in circulating SHBG levels, which ultimately increases bioavailable free testosterone.