Variation in plasma levels of cortisol, an essential hormone in the stress response, is associated in population-based studies with cardio-metabolic, inflammatory and neuro-cognitive traits and diseases. Heritability of plasma cortisol is estimated at 30–60% but no common genetic contribution has been identified. The CORtisol NETwork (CORNET) consortium undertook genome wide association meta-analysis for plasma cortisol in 12,597 Caucasian participants, replicated in 2,795 participants. The results indicate that <1% of variance in plasma cortisol is accounted for by genetic variation in a single region of chromosome 14. This locus spans SERPINA6, encoding corticosteroid binding globulin (CBG, the major cortisol-binding protein in plasma), and SERPINA1, encoding α1-antitrypsin (which inhibits cleavage of the reactive centre loop that releases cortisol from CBG). Three partially independent signals were identified within the region, represented by common SNPs; detailed biochemical investigation in a nested sub-cohort showed all these SNPs were associated with variation in total cortisol binding activity in plasma, but some variants influenced total CBG concentrations while the top hit (rs12589136) influenced the immunoreactivity of the reactive centre loop of CBG. Exome chip and 1000 Genomes imputation analysis of this locus in the CROATIA-Korcula cohort identified missense mutations in SERPINA6 and SERPINA1 that did not account for the effects of common variants. These findings reveal a novel common genetic source of variation in binding of cortisol by CBG, and reinforce the key role of CBG in determining plasma cortisol levels. In turn this genetic variation may contribute to cortisol-associated degenerative diseases.
Evidence for immune/neuroimmune disturbances as a possible root cause of a range of disorders, including neurodevelopmental disorders, is growing. Although prenatal alcohol exposure (PAE) impacts immune function, few studies to date have examined immune function in relation to long-term negative health outcomes following PAE, and most have focused on males. To fill this gap, we utilized a rat model to examine the effects of PAE on immune/neuroimmune function during early-life [birth (postnatal day 1; P1), P8, and weaning (P22)] in PAE and control females. Due to the extensive interplay between the immune and endocrine systems, we also measured levels of corticosterone and corticosterone binding globulin (CBG). While corticosterone levels were not different among groups, CBG levels were lower in PAE offspring from P1–P8, suggesting a lower corticosterone reservoir that may underlie susceptibility to inflammation. Spleen weights were increased in PAE rats on P22, a marker of altered immune function. Moreover, we detected a unique cytokine profile in PAE compared to control offspring on P8 – higher levels in the PFC and hippocampus, and lower levels in the hypothalamus and spleen. The finding of a specific immune signature in PAE offspring during a sensitive developmental period has important implications for understanding the basis of long-term immune alterations and health outcomes in children with Fetal Alcohol Spectrum Disorder (FASD). Our findings also highlight the future possibility that immune-based intervention strategies could be considered as an adjunctive novel therapeutic approach for individuals with FASD.
Our data provide insight into how specific residues affect CBG secretion or function and illustrate the need to consider the various naturally occurring human CBG mutations in clinical evaluations of diseases associated with abnormalities in cortisol levels or activity.
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