Understanding the Influence of Genetic Differences on SHBG Hormone Levels in Men

Understanding the Influence of Genetic Differences on SHBG Hormone Levels in Men​

The Connection Between Genetics and Hormone Binding

Our bodies are finely tuned systems where even the smallest changes can have significant impacts. This is especially true with hormones, the chemical messengers that govern many of our bodily functions. One such messenger, testosterone, plays a crucial role in male health. Sex hormone-binding globulin (SHBG) is a protein that regulates it in part. The amount of free testosterone, the hormone's active form that the body can use, is under the control of SHBG. However, variations in the SHBG gene can affect how well it binds to testosterone. If SHBG doesn’t bind properly, it might lead to inaccuracies in how much testosterone doctors think is in the body, potentially affecting diagnosis and treatment.

Exploring Genetic Variations

A recent study by a group of researchers aimed to learn more about how variations in the SHBG gene affect the levels of SHBG and testosterone in the bloodstream. Conducted as a population-based study, it involved 999 healthy men between the ages of 25 and 45. By focusing on siblings, researchers hoped to minimize genetic variability outside of the SHBG gene.

How the Study Was Conducted

Researchers used advanced genetic testing methods to identify variations, known as single nucleotide polymorphisms (SNPs), in the SHBG gene. These SNPs could potentially alter the protein’s ability to bind with testosterone. Blood tests were then used to measure levels of SHBG and testosterone directly. Furthermore, the free testosterone—that which is not bound and is biologically active—was both calculated using standard methods and directly measured in a subset of participants.

Findings from the Genetic Investigation

The study found a range of SNPs that influenced SHBG and testosterone levels. Some variations led to lower levels of SHBG, while others resulted in higher levels. These changes in SHBG levels also corresponded with alterations in total testosterone levels. Interestingly, while the calculated levels of free testosterone showed some variation, direct measurements did not consistently show significant changes, except in specific genetic cases.

Implications of the Study

This research highlights the complexity of hormone regulation and the potential need to consider genetic differences when evaluating hormone levels in men. Understanding these genetic influences could improve the accuracy of hormone assessments and lead to more personalized approaches in treating hormone-related conditions.

In conclusion, the study underscores the importance of considering genetic variations in medical assessments and paves the way for more research into how these genetic factors affect our health.

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References:

• Joeri Walravens, Bas Sleumer, Michel J Vos, et al. "SHBG gene polymorphisms and their influence on serum SHBG, total and free testosterone concentrations in men." Journal of Clinical Endocrinology and Metabolism, doi: 10.1210/clinem/dgae280, 2024.

 

SHBG Gene Polymorphisms and Testosterone Concentrations in Men
1 source
This source presents a journal article from "The Journal of Clinical Endocrinology & Metabolism," published by Oxford Academic. The article investigates the impact of genetic variations, specifically single-nucleotide polymorphisms (SNPs) in the SHBG gene, on serum concentrations of Sex Hormone-Binding Globulin (SHBG), total testosterone, and free testosterone in men. It explores how these genetic differences influence hormone levels and the accuracy of both calculated and directly measured free testosterone, employing liquid chromatography-tandem mass spectrometry (LC-MS/MS) for precise measurements. The study concludes that while SNPs affect SHBG and total testosterone, their impact on measured free testosterone and the reliability of free testosterone calculations is minimal in healthy men.

Briefing Document: SHBG Gene Polymorphisms and Their Influence on Serum SHBG, Total and Free Testosterone Concentrations in Men​

Source: Excerpts from "SHBG Gene Polymorphisms and Their Influence on Serum SHBG, Total and Free Testosterone Concentrations in Men | The Journal of Clinical Endocrinology & Metabolism | Oxford Academic" by Walravens et al. (2025).

Date of Publication: April 23, 2024 (March 2025, Volume 110, Issue 3, Pages e641–e649)

Authors: Joeri Walravens, Bas Sleumer, Michel J Vos, Gido Snaterse, Nick Narinx, Leen Antonio, Tim Reyns, Tom Fiers, Ido P Kema, Jean-Marc Kaufman, Nico C van de Merbel, Bruno Lapauw.

I. Executive Summary

This study investigates the impact of single-nucleotide polymorphisms (SNPs) in or near the Sex Hormone-Binding Globulin (SHBG) gene on serum concentrations of SHBG, total testosterone (T), and both calculated and directly measured free T in a cohort of 999 healthy men. The primary findings indicate that while these SNPs are relatively common and can significantly affect SHBG and total T levels, their impact on directly measured free T is largely negligible. This suggests that clinical decisions based solely on total T may be susceptible to misdiagnosis in SNP carriers, whereas free T measurements and calculations appear to be more robust. The study also highlights the utility of liquid chromatography-tandem mass spectrometry (LC-MS/MS) for detecting mutant SHBG isoforms and reveals that a specific mutant (P156L SHBG from rs6258) is present in lower concentrations than expected in carriers.

II. Key Themes and Findings

A. Prevalence and Characteristics of SHBG SNPs:

• Commonality: SNPs that can affect sex steroid or SHBG concentrations are "relatively common in a healthy male population."
• Allelic Frequencies: The allelic frequencies of the analyzed SNPs (rs6258, rs6259, rs1799941, rs12150660, rs727428, rs5934505) ranged from 0.5% to 58.2%.
• Structural vs. Noncoding Mutations: Structural mutations like rs6258 (allelic prevalence 0.5%) and rs6259 (allelic prevalence 11.5%) were less common than noncoding mutations. The low prevalence of rs6258 is noted as unclear, potentially due to exclusion of individuals with SNP-related diseases.
• Hardy-Weinberg Equilibrium: No SNPs deviated significantly from Hardy-Weinberg equilibrium, indicating a healthy, unselected study population.
• Linkage Disequilibrium: Significant linkage was observed between rs12150660 and rs1799941 (R2 = 0.90), leading to the exclusion of rs12150660 from further analysis, implying that rs1799941 results should be interpreted as a combined effect of both.

B. Impact of SNPs on SHBG and Total Testosterone Concentrations:

• SHBG Concentrations:Lowered by rs6258: Rs6258 heterozygosity was associated with "lower SHBG concentrations (−24.7%; P < .05)" in the general population.
• Increased by other SNPs: Rs6259 heterozygosity, rs727428 homozygosity, and rs1799941 hetero- or homozygosity were associated with "higher SHBG concentrations (+10.8 to 23.1%; all P < .05)."
• Total Testosterone (T) Concentrations:Increased by several SNPs: Rs727428 homozygosity, and carriers of rs5934505, rs1799941, and rs6259 were associated with "higher concentrations of total T (+3.9 to 21.4%; all P < .05)."
• Implication for Diagnosis: The authors note that "The higher total T concentrations without concomitant higher free T, which we observed for several SNPs, also suggest that clinical decisions based on total T concentrations alone may lead to a potentially incorrect diagnosis of hypogonadism in carriers of these SNPs."

C. Impact of SNPs on Free Testosterone (T) Concentrations and Calculator Performance:

• No Clear Effects on Measured Free T: The study found "No clear effects on measured free T were found," with the exception of a trend toward higher values in rs6259 homozygotes.
• Minimal Effect on Calculator Performance: "No effects of SNPs were observed on the difference between calculated and measured free T, indicating a minimal effect of SNPs on calculator performance." This reinforces the reliability of current free T calculation methods (e.g., Vermeulen calculator) despite genetic variations in SHBG.
• Rs6259 and Calculated Free T: A significant trend toward higher calculated free T was found for rs6259 homozygotes in the larger study population (+18.7%; P < .05), but this genotype is rare (1.4% prevalence), limiting its practical impact.
• Rs6258 and Percentage Free T: Rs6258 heterozygosity was associated with a "higher percentage calculated free T (2.23%)," and a similar statistically significant trend for measured free T percentage, suggesting altered binding affinity.

D. SHBG Measurement Methodologies and Structural Mutants:

• Immunoassay vs. LC-MS/MS: LC-MS/MS-derived SHBG concentrations were generally "15% to 20% lower than those found with the immunoassays." This difference is attributed to potential variations in antibody binding in immunoassays compared to the antibody-free LC-MS/MS method.
• Detection of Mutant SHBG: The LC-MS/MS method was capable of detecting the P156L SHBG mutant (resulting from rs6258).
• Lower Than Expected P156L SHBG Concentration: In rs6258 heterozygotes, the percentage of P156L SHBG was "remarkably lower than expected, as theoretically the percentage of P156L expression would be 50% of all SHBG." The observed range was 14.1% to 19.2%.
• Possible Explanations for Low P156L Concentration: This "concentration gap" could be due to "a poorer production or excretion of the mutant protein, a faster degradation, or a combination of both." The authors suggest that P156 is a "pivotal structural disruptor" and its substitution by leucine likely impacts protein folding and stability, aligning with previous in silico analyses showing reduced stability for rs6258.

III. Clinical Implications

• Reliability of Free T Measurements/Calculations: The study concludes that "free T measurements and calculations appear less affected by variations induced by SNPs compared to total T measurements." This supports the continued use of free T estimates, especially in cases where SHBG concentrations might be altered (e.g., obesity, HIV disease), as recommended by clinical guidelines.
• Caution with Total T: Clinical decisions based solely on total T concentrations "may be more vulnerable to the effects of SNPs," potentially leading to incorrect diagnoses of hypogonadism in carriers of certain SNPs.
• No Extra Measures for SNP Carriers (Free T): For clinical decision-making using free T calculations, the study suggests "no extra measures should be taken when using the calculations in SNP carriers."

IV. Study Strengths and Limitations

• Strengths:Large, well-characterized population of 999 healthy men.
• Inclusion of direct free T measurement using equilibrium dialysis LC-MS/MS (a reference method).
• Use of a novel LC-MS/MS method for SHBG measurement, allowing specific detection of mutant isoforms and evaluation of immunoassay performance.
• Limitations:Low numbers of individuals with rarer genotypes (e.g., rs6258 heterozygosity, rs6259 homozygosity) limited statistical power for these groups.
• Simplification of genetic variation to average effects per SNP; synergistic or antagonistic effects of multiple SNPs were not fully explored.
• Difficulty in selecting a "true control reference" due to the high prevalence of multiple SNPs.
• Findings are specific to healthy men and cannot be directly extrapolated to women or men with altered free T regulation due to disease.

V. Future Research

• Further research is needed to "elucidate the exact molecular mechanisms responsible for these low concentrations of mutant SHBG," particularly the P156L variant.
• Investigation into the association between SHBG SNPs and disease, particularly for rarer variants, remains largely unexplored.