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Testosterone Replacement, Low T, HCG, & Beyond
Testosterone and Men's Health Articles
genetic impact on testosterone binding by SHBG
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<blockquote data-quote="Nelson Vergel" data-source="post: 26684" data-attributes="member: 3"><p>"By examining 14,429 men, we show that genetic variants in the sex hormone-binding globulin (<em>SHBG</em>) locus and on the X chromosome are associated with a substantial variation in serum testosterone concentrations and increased risk of low testosterone. The reported associations may now be used in order to better understand the functional background of recently identified disease associations related to low testosterone. Importantly, we identified the first known genetic variant, which affects SHBG's affinity for binding testosterone and the free testosterone fraction and could therefore influence the calculation of free testosterone. This finding suggests that individual-based SHBG-testosterone affinity constants are required depending on the genotype of this single-nucleotide polymorphism.'</p><p></p><p><strong>The rs6258 polymorphism affects SHBG binding affinity for testosterone and the measured free testosterone fraction</strong></p><p></p><p>As rs6258 is non-synonymous (P156L) and located in exon 4 of <em>SHBG,</em> we evaluated the serum SHBG steroid-binding capacity of the different rs6258 genotypes. As shown in <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3188559/#pgen.1002313.s005" target="_blank">Figure S5</a>, serum SHBG from CT but not CC subjects had a lower steroid-binding capacity than expected from values obtained by an SHBG immunoassay (p = 0.003). Therefore, we analyzed the SHBG affinity for testosterone using Scatchard plots of SHBG in serum of men with the rs6258 genotype (<a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3188559/figure/pgen-1002313-g003/" target="_blank">Figure 3A</a>), and revealed (<a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3188559/figure/pgen-1002313-g003/" target="_blank">Figure 3B</a>) a higher mean dissociation constant (Kd) indicative of a lower affinity in CT (Kd = 4.5 nM) and TT (Kd = 4.9 nM) individuals than in CC individuals (Kd = 2.8 nM). Recombinant SHBG corresponding to the T genotype demonstrated a higher dissociation constant (lower affinity) compared with recombinant SHBG corresponding to the C genotype (T genotype Kd 2.5 nM; C genotype Kd 1.2 nM, <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3188559/figure/pgen-1002313-g003/" target="_blank">Figure 3C</a>). In addition, the free testosterone fraction measured by an equilibrium dialysis method was 22% higher (p = 1.4×10−5) in serum from CT subjects than in serum from CC subjects (<a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3188559/figure/pgen-1002313-g003/" target="_blank">Figure 3D</a>)."</p><p></p><p></p><p>Jabbahop</p><p></p><p>I agree. In men with a certain mutation on the SHBG locus and on their X chromosome, calculating free T may not be accurate since they may show OK amounts of SHBG but poor binding of T to it. I guess the only way is to actually measure both free and total T.</p><p></p><p>Note:</p><p>DiscountedLabs.com TT and FT test actually measures both and it does not calculate free T by subtracting albumin and SHBG from total T.</p><p></p><p></p><p>Thanks for posting such an intriguing study!</p></blockquote><p></p>
[QUOTE="Nelson Vergel, post: 26684, member: 3"] "By examining 14,429 men, we show that genetic variants in the sex hormone-binding globulin ([I]SHBG[/I]) locus and on the X chromosome are associated with a substantial variation in serum testosterone concentrations and increased risk of low testosterone. The reported associations may now be used in order to better understand the functional background of recently identified disease associations related to low testosterone. Importantly, we identified the first known genetic variant, which affects SHBG's affinity for binding testosterone and the free testosterone fraction and could therefore influence the calculation of free testosterone. This finding suggests that individual-based SHBG-testosterone affinity constants are required depending on the genotype of this single-nucleotide polymorphism.' [B]The rs6258 polymorphism affects SHBG binding affinity for testosterone and the measured free testosterone fraction[/B] As rs6258 is non-synonymous (P156L) and located in exon 4 of [I]SHBG,[/I] we evaluated the serum SHBG steroid-binding capacity of the different rs6258 genotypes. As shown in [URL="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3188559/#pgen.1002313.s005"]Figure S5[/URL], serum SHBG from CT but not CC subjects had a lower steroid-binding capacity than expected from values obtained by an SHBG immunoassay (p = 0.003). Therefore, we analyzed the SHBG affinity for testosterone using Scatchard plots of SHBG in serum of men with the rs6258 genotype ([URL="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3188559/figure/pgen-1002313-g003/"]Figure 3A[/URL]), and revealed ([URL="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3188559/figure/pgen-1002313-g003/"]Figure 3B[/URL]) a higher mean dissociation constant (Kd) indicative of a lower affinity in CT (Kd = 4.5 nM) and TT (Kd = 4.9 nM) individuals than in CC individuals (Kd = 2.8 nM). Recombinant SHBG corresponding to the T genotype demonstrated a higher dissociation constant (lower affinity) compared with recombinant SHBG corresponding to the C genotype (T genotype Kd 2.5 nM; C genotype Kd 1.2 nM, [URL="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3188559/figure/pgen-1002313-g003/"]Figure 3C[/URL]). In addition, the free testosterone fraction measured by an equilibrium dialysis method was 22% higher (p = 1.4×10−5) in serum from CT subjects than in serum from CC subjects ([URL="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3188559/figure/pgen-1002313-g003/"]Figure 3D[/URL])." Jabbahop I agree. In men with a certain mutation on the SHBG locus and on their X chromosome, calculating free T may not be accurate since they may show OK amounts of SHBG but poor binding of T to it. I guess the only way is to actually measure both free and total T. Note: DiscountedLabs.com TT and FT test actually measures both and it does not calculate free T by subtracting albumin and SHBG from total T. Thanks for posting such an intriguing study! [/QUOTE]
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Testosterone Replacement, Low T, HCG, & Beyond
Testosterone and Men's Health Articles
genetic impact on testosterone binding by SHBG
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