Genetic factors are crucial in shaping various physiological processes within the human body, including regulating cortisol levels. Understanding the genetic determinants of cortisol regulation sheds light on individual differences in stress response and holds implications for wellness outcomes and susceptibility to stress-related conditions.
Interestingly, the chromosome 14 region with several genes encoding for SERPIN gene family members has emerged as a significant factor in determining blood cortisol levels in many studies, such as a GWAS meta-analysis published in 2021. Serpins (serine protease inhibitors or classified inhibitor family I4) are the largest and most broadly distributed superfamily of protease inhibitors. Serpin-like genes have been identified in animals, poxviruses, plants, bacteria, and archaea, and over 1,500 members of this family have been identified to date and they slow broad functional diversity.Â
SERPINA6
SERPINA6, located on chromosome 14, encodes for corticosteroid-binding globulin (CBG), the primary carrier protein for cortisol in plasma. CBG plays a crucial role in regulating the bioavailability and transport of cortisol.
Variations within the SERPINA6 gene have been associated with alterations in CBG concentrations and activity, impacting cortisol binding and release dynamics. Notably, common single nucleotide polymorphisms (SNPs) near the SERPINA6 promoter such as rs7146221, have been identified through genome-wide association studies (GWAS) as contributors to plasma cortisol levels.
These findings highlight the significance of SERPINA6 in modulating cortisol homeostasis and its potential implications in stress-related disorders and other cortisol-associated diseases.
SERPINA1
Situated adjacent to SERPINA6 on chromosome 14, SERPINA1 encodes for α1-antitrypsin, a protease inhibitor with diverse physiological functions, including inhibiting enzymes in inflammatory processes.Â
Of particular relevance to cortisol regulation, α1-antitrypsin also plays a role in modulating the activity of corticosteroid-binding globulin (CBG). By inhibiting the cleavage of the reactive center loop of CBG, α1-antitrypsin regulates the release of cortisol from its bound form.
Mutations or common genetic variations, such as rs1243171, within or close to SERPINA1 can affect its interaction with CBG, influencing cortisol availability and plasma levels. Through genetic studies, common variants and rare missense mutations within SERPINA1 have been identified as contributors to cortisol-related traits and diseases, underscoring the importance of this gene in cortisol metabolism and its potential implications for wellness and disease.
In conclusion, genetic factors, such as genetic variation affecting SERPINA1, 2, 6, and 10 genes, exert a significant influence on cortisol regulation, impacting individual responses to stress and vulnerability to stress-related disorders. These insights not only deepen our understanding of stress physiology but also hold promise for personalized interventions targeting stress-related conditions.