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PLoS Genet. 2014 Jul 10;10(7):e1004474. doi: 10.1371/journal.pgen.1004474. eCollection 2014 Jul.

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

Author information

1
University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
2
MRC Human Genetics Unit, Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
3
Department of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands.
4
Canterbury Health Laboratories, Christchurch, New Zealand.
5
Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, Canada.
6
Centre for Population Health Sciences, Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
7
Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland.
8
National Institute for Health and Welfare, Helsinki, Finland.
9
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
10
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland; Department of Medical Genetics, University of Helsinki and University Central Hospital, Helsinki, Finland.
11
National Institute for Health and Welfare, Helsinki, Finland; Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland; Helsinki University Central Hospital, Unit of General Practice, Helsinki, Finland; Folkhalsan Research Centre, Helsinki, Finland; Vasa Central Hospital, Vasa, Finland.
12
Institute of Health Sciences and Biocenter Oulu, University of Oulu, Oulu, Finland.
13
Institute of Health Sciences and Biocenter Oulu, University of Oulu, Oulu, Finland; Department of Children and Young People and Families, National Institute for Health and Welfare, Oulu, Finland; Department of Epidemiology and Biostatistics, MRC-HPA Centre for Environment and Health, Imperial College London, London, United Kingdom; Unit of Primary Care, Oulu University Hospital, Oulu, Finland.
14
MRC Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
15
School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
16
Longitudinal Studies Section, Clinical Research Branch, National Institute on Aging, Baltimore, Maryland, United States of America.
17
Longitudinal Studies Section, Clinical Research Branch, National Institute on Aging, Baltimore, Maryland, United States of America; Department of Psychiatry, VU University Medical Center/GGZ inGeest, Amsterdam, The Netherlands.
18
Geriatric Unit, ASF, Florence, Italy.
19
University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen, The Netherlands; University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands; Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, The Netherlands.
20
University of Groningen, University Medical Center Groningen, Interdisciplinary Center for Psychiatric Epidemiology, Groningen, The Netherlands.
21
University of Groningen, University Medical Center Groningen, Department of Internal Medicine, Groningen, The Netherlands.
22
University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen, The Netherlands.
23
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
24
Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
25
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
26
School of Women's and Infant's Health, The University of Western Australia, Crawley, Australia.
27
Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
28
Center for Bone and Arthritis Research, Institute of Medicin, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

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.

PMID:
25010111
PMCID:
PMC4091794
DOI:
10.1371/journal.pgen.1004474
[Indexed for MEDLINE]
Free PMC Article

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