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Genome wide association identifies common variants at the SERPINA6/SERPINA1 locus influencing plasma cortisol and corticosteroid binding globulin.

PLoS genetics (2014-07-11)
Jennifer L Bolton, Caroline Hayward, Nese Direk, John G Lewis, Geoffrey L Hammond, Lesley A Hill, Anna Anderson, Jennifer Huffman, James F Wilson, Harry Campbell, Igor Rudan, Alan Wright, Nicholas Hastie, Sarah H Wild, Fleur P Velders, Albert Hofman, Andre G Uitterlinden, Jari Lahti, Katri Räikkönen, Eero Kajantie, Elisabeth Widen, Aarno Palotie, Johan G Eriksson, Marika Kaakinen, Marjo-Riitta Järvelin, Nicholas J Timpson, George Davey Smith, Susan M Ring, David M Evans, Beate St Pourcain, Toshiko Tanaka, Yuri Milaneschi, Stefania Bandinelli, Luigi Ferrucci, Pim van der Harst, Judith G M Rosmalen, Stephen J L Bakker, Niek Verweij, Robin P F Dullaart, Anubha Mahajan, Cecilia M Lindgren, Andrew Morris, Lars Lind, Erik Ingelsson, Laura N Anderson, Craig E Pennell, Stephen J Lye, Stephen G Matthews, Joel Eriksson, Dan Mellstrom, Claes Ohlsson, Jackie F Price, Mark W J Strachan, Rebecca M Reynolds, Henning Tiemeier, Brian R Walker
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Hydrocortisone, BioReagent, suitable for cell culture
Sigma-Aldrich
Hydrocortisone, ≥98% (HPLC)
Sigma-Aldrich
Hydrocortisone, γ-irradiated, powder, BioXtra, suitable for cell culture
Supelco
Hydrocortisone, Pharmaceutical Secondary Standard; Certified Reference Material
USP
Hydrocortisone, United States Pharmacopeia (USP) Reference Standard
Sigma-Aldrich
Hydrocortisone, meets USP testing specifications
Hydrocortisone for peak identification, European Pharmacopoeia (EP) Reference Standard
Hydrocortisone, European Pharmacopoeia (EP) Reference Standard
Hydrocortisone, British Pharmacopoeia (BP) Assay Standard
Supelco
Hydrocortisone, VETRANAL®, analytical standard