期刊
PLOS GENETICS
卷 10, 期 7, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1004474
关键词
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资金
- Chief Scientist Office of the Scottish Government [CZB-4-733]
- British Heart Foundation [RG11/4/28734]
- Medical Research Council (UK)
- Republic of Croatia Ministry of Science, Education and Sports research grants [108-1080315-0302]
- European Commission [LSHG-CT-2006-018947, QLK4-CT-2002-02528]
- Chief Scientist Office of the Scottish Government
- Royal Society
- MRC Human Genetics Unit
- Arthritis Research UK
- European Union [LSHG-CT-2006-018947]
- Research Institute for Diseases in the Elderly [014-93-015]
- Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research [050-060-810]
- Erasmus MC
- Erasmus University, Rotterdam
- Netherlands Organization for the Health Research and Development
- Ministry of Education, Culture and Science
- Ministry for Health, Welfare and Sports
- European Commission (Directorate-General XII)
- Municipality of Rotterdam
- Netherlands Organization for the Health Research and Development [2009-017.106.370]
- Netherlands Consortium for Healthy Ageing
- Academy of Finland
- Finnish Diabetes Research Society
- Folkhalsan Research Foundation
- Novo Nordisk Foundation
- Finska Lakaresallskapet, Signe and Ane Gyllenberg Foundation
- University of Helsinki
- European Science Foundation (EUROSTRESS)
- Ministry of Education
- Ahokas Foundation
- Emil Aaltonen Foundation
- Juho Vainio Foundation
- Wellcome Trust [WT089062, 092731, WT098017, WT064890, WT090532]
- Academy of Finland [104781, 120315, 129418]
- Academy of Finland Center of Excellence in Complex Disease Genetics and Public Health Challenges Research Program (SALVE)
- University Hospital Oulu, Biocenter, University of Oulu, Finland [75617]
- European Commission [EUROBLCS] [QLG1-CT-2000-01643]
- National Heart, Lung and Blood Institute through the SNP Typing for Association [5R01HL087679-02]
- Multiple Phenotypes from Existing Epidemiologic Data (STAMPEED) program [1RL1MH083268-01]
- National Institute of Health/The National Institute of Mental Health [5R01MH63706:02]
- European Network of Genomic and Genetic Epidemiology (ENGAGE) project [HEALTH-F4-2007-201413]
- Medical Research Council, UK [PrevMetSyn/Public Health Challenges Research Program (SALVE)] [G0500539, G0600705]
- UK Medical Research Council
- University of Bristol
- Italian Ministry of Health
- U.S. National Institute on Aging
- Uppsala University
- Uppsala University Hospital
- Swedish Research Council
- Swedish Heart-Lung Foundation
- Dutch Kidney Foundation [E.033]
- Groningen University Medical Center (Beleidsruimte)
- Bristol Myers Squibb
- Dade Behring
- Ausam
- Roche
- Abbott
- The Netherlands Organization of Scientific Research
- Dutch Heart Foundation
- De Cock Foundation
- UK Medical Research Council [G0500877]
- National Health and Medical Research Council of Australia [353514, 572613, 403981]
- Canadian Institutes of Health Research [MOP82893]
- University of Western Australia (UWA)
- Raine Medical Research Foundation
- Telethon Institute for Child Health Research
- UWA Faculty of Medicine, Dentistry and Health Sciences
- Women and Infants Research Foundation
- Curtin University
- Swedish Foundation for Strategic Research
- ALF/LUA research grant in Gothenburg
- Lundberg Foundation
- Torsten and Ragnar Soderber's Foundation
- Petrus and Augusta Hedlunds Foundation
- Academy of Finland (AKA) [129418, 129418] Funding Source: Academy of Finland (AKA)
- British Heart Foundation [RG/11/4/28734] Funding Source: researchfish
- Chief Scientist Office [CZB/4/710] Funding Source: researchfish
- Medical Research Council [G9815508, G0500877, MC_UU_12013/3, MC_PC_15018, G0600705, MC_PC_U127561128, MC_UU_12013/4, MC_UU_12013/1] Funding Source: researchfish
- Novo Nordisk Fonden [NNF13OC0005785, NNF14OC0010513] Funding Source: researchfish
- MRC [MC_UU_12013/3, MC_UU_12013/4, G0500877, G0600705, MC_UU_12013/1, MC_PC_U127561128] Funding Source: UKRI
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 alpha 1-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.
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