Genome Wide Association Identifies Common Variants at the SERPINA6/SERPINA1 Locus Influencing Plasma Cortisol and Corticosteroid Binding Globulin

被引:108
作者
Bolton, Jennifer L. [1 ]
Hayward, Caroline [2 ]
Direk, Nese [3 ]
Lewis, John G. [4 ]
Hammond, Geoffrey L. [5 ]
Hill, Lesley A. [5 ]
Anderson, Anna [1 ]
Huffman, Jennifer [2 ]
Wilson, James F. [6 ]
Campbell, Harry [6 ]
Rudan, Igor [6 ]
Wright, Alan [2 ]
Hastie, Nicholas [2 ]
Wild, Sarah H. [6 ]
Velders, Fleur P. [3 ]
Hofman, Albert [3 ]
Uitterlinden, Andre G. [3 ]
Lahti, Jari [7 ]
Raikkonen, Katri [7 ]
Kajantie, Eero [8 ]
Widen, Elisabeth [9 ]
Palotie, Aarno [9 ,10 ,11 ]
Eriksson, Johan G. [8 ,12 ,13 ,14 ,15 ]
Kaakinen, Marika [16 ,17 ]
Jarvelin, Marjo-Riitta [16 ,17 ,18 ,19 ,20 ]
Timpson, Nicholas J. [21 ]
Smith, George Davey [21 ]
Ring, Susan M. [22 ]
Evans, David M. [21 ]
St Pourcain, Beate [22 ]
Tanaka, Toshiko [23 ]
Milaneschi, Yuri [23 ,24 ]
Bandinelli, Stefania [25 ]
Ferrucci, Luigi [23 ]
van der Harst, Pim [26 ,27 ,28 ]
Rosmalen, Judith G. M. [29 ]
Bakker, Stephen J. L. [30 ]
Verweij, Niek [26 ]
Dullaart, Robin P. F. [30 ]
Mahajan, Anubha [31 ]
Lindgren, Cecilia M. [31 ]
Morris, Andrew [31 ]
Lind, Lars [32 ]
Ingelsson, Erik [32 ]
Anderson, Laura N. [33 ]
Pennell, Craig E. [34 ]
Lye, Stephen J. [33 ]
Matthews, Stephen G. [35 ]
Eriksson, Joel [36 ]
Mellstrom, Dan [36 ]
机构
[1] Univ Edinburgh, Queens Med Res Inst, Univ BHF Ctr Cardiovasc Sci, Edinburgh, Midlothian, Scotland
[2] Univ Edinburgh, Inst Genet & Mol Med, MRC, Human Genet Unit, Edinburgh, Midlothian, Scotland
[3] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands
[4] Canterbury Hlth Labs, Christchurch, New Zealand
[5] Univ British Columbia, Inst Life Sci, Dept Cellular & Physiol Sci, Vancouver, BC V5Z 1M9, Canada
[6] Univ Edinburgh, Ctr Populat Hlth Sci, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland
[7] Univ Helsinki, Inst Behav Sci, Helsinki, Finland
[8] Natl Inst Hlth & Welf, Helsinki, Finland
[9] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland
[10] Univ Helsinki, Dept Med Genet, Helsinki, Finland
[11] Univ Cent Hosp, Helsinki, Finland
[12] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland
[13] Helsinki Univ Cent Hosp, Unit Gen Practice, Helsinki, Finland
[14] Folkhalsan Res Ctr, Helsinki, Finland
[15] Vasa Cent Hosp, Vaasa, Finland
[16] Univ Oulu, Inst Hlth Sci, Oulu, Finland
[17] Univ Oulu, Bioctr Oulu, Oulu, Finland
[18] Natl Inst Hlth & Welf, Dept Children & Young People & Families, Oulu, Finland
[19] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, MRC HPA Ctr Environm & Hlth, London, England
[20] Oulu Univ Hosp, Unit Primary Care, Oulu, Finland
[21] Univ Bristol, Sch Social & Community Med, MRC Ctr Causal Analyses Translat Epidemiol, Bristol, Avon, England
[22] Univ Bristol, Sch Social & Community Med, Bristol, Avon, England
[23] NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD USA
[24] Vrije Univ Amsterdam, Dept Psychiat, Med Ctr, GGZ InGeest, Amsterdam, Netherlands
[25] ASF, Geriatr Unit, Florence, Italy
[26] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands
[27] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands
[28] Durrer Ctr Cardiogenet Res, ICIN Netherlands Heart Inst, Utrecht, Netherlands
[29] Univ Groningen, Univ Med Ctr Groningen, Groningen, Netherlands
[30] Univ Groningen, Univ Med Ctr Groningen, Dept Internal Med, Groningen, Netherlands
[31] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England
[32] Uppsala Univ, Dept Med Sci, Uppsala, Sweden
[33] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada
[34] Univ Western Australia, Sch Womens & Infants Hlth, Crawley, Australia
[35] Univ Toronto, Dept Physiol, Toronto, ON, Canada
[36] Univ Gothenburg, Sahlgrenska Acad, Inst Medicin, Ctr Bone & Arthrit Res, Gothenburg, Sweden
基金
芬兰科学院; 加拿大健康研究院; 英国医学研究理事会; 瑞典研究理事会; 英国惠康基金;
关键词
INSULIN-RESISTANCE SYNDROME; LOW-BIRTH-WEIGHT; BLOOD-PRESSURE; STRESS; MEN; GLUCOCORTICOIDS; POLYMORPHISMS; DISEASE; RISK; CBG;
D O I
10.1371/journal.pgen.1004474
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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.
引用
收藏
页数:11
相关论文
共 52 条
[1]   GenABEL: an R library for genome-wide association analysis [J].
Aulchenko, Yurii S. ;
Ripke, Stephan ;
Isaacs, Aaron ;
Van Duijn, Cornelia M. .
BIOINFORMATICS, 2007, 23 (10) :1294-1296
[2]   Cortisol circadian rhythms and stress responses in infants at risk of allergic disease [J].
Ball, Thomas M. .
NEUROIMMUNOMODULATION, 2006, 13 (5-6) :294-300
[3]   Corticosteroid binding globulin gene polymorphism influences cortisol driven fat distribution in obese women [J].
Barat, P ;
Duclos, M ;
Gatta, B ;
Roger, P ;
Mormede, P ;
Moisan, MP .
OBESITY RESEARCH, 2005, 13 (09) :1485-1490
[4]  
BARAT P, 2012, J PHYSL BIOCH
[5]   Heritability of daytime cortisol levels in children [J].
Bartels, M ;
de Geus, EJC ;
Kirschbaum, C ;
Sluyter, F ;
Boomsma, DI .
BEHAVIOR GENETICS, 2003, 33 (04) :421-433
[6]   Hypothalamic arousal, insulin resistance and Type 2 diabetes mellitus [J].
Björntorp, P ;
Holm, G ;
Rosmond, R .
DIABETIC MEDICINE, 1999, 16 (05) :373-383
[7]   Cortisol Binding Globulin: More Than Just a Carrier? [J].
Cizza, Giovanni ;
Rother, Kristina I. .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2012, 97 (01) :77-80
[8]   CLINICAL USE OF UNBOUND PLASMA-CORTISOL AS CALCULATED FROM TOTAL CORTISOL AND CORTICOSTEROID-BINDING GLOBULIN [J].
COOLENS, JL ;
VANBAELEN, H ;
HEYNS, W .
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY, 1987, 26 (02) :197-202
[9]   Improved whole-chromosome phasing for disease and population genetic studies [J].
Delaneau, Olivier ;
Zagury, Jean-Francois ;
Marchini, Jonathan .
NATURE METHODS, 2013, 10 (01) :5-6
[10]   A common polymorphism in the mineralocorticoid receptor modulates stress responsiveness [J].
DeRijk, Roel H. ;
Wust, Stefan ;
Meijer, Onno C. ;
Zennaro, Maria-Christina ;
Federenko, Ilona S. ;
Hellhammer, Dirk H. ;
Giacchetti, Gilberta ;
Vreugdenhil, Erno ;
Zitman, Frans G. ;
de Kloet, E. Ronald .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2006, 91 (12) :5083-5089