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1. Variation in the SERPINA6/SERPINA1 locus alters morning plasma cortisol, hepatic corticosteroid binding globulin expression, gene expression in peripheral tissues, and risk of cardiovascular disease

Author

Crawford, A. A. (Andrew A.), Bankier, S. (Sean), Altmaier, E. (Elisabeth), Barnes, C. L. (Catriona L. K.), Clark, D. W. (David W.), Ermel, R. (Raili), Friedrich, N. (Nele), van der Harst, P. (Pim), Joshi, P. K. (Peter K.), Karhunen, V. (Ville), Lahti, J. (Jari), Mahajan, A. (Anubha), Mangino, M. (Massimo), Nethander, M. (Maria), Neumann, A. (Alexander), Pietzner, M. (Maik), Sukhavasi, K. (Katyayani), Wang, C. A. (Carol A.), Bakker, S. J. (Stephan J. L.), Bjorkegren, J. L. (Johan L. M.), Campbell, H. (Harry), Eriksson, J. (Johan), Gieger, C. (Christian), Hayward, C. (Caroline), Järvelin, M.-R. (Marjo-Riitta), McLachlan, S. (Stela), Morris, A. P. (Andrew P.), Ohlsson, C. (Claes), Pennell, C. E. (Craig E.), Price, J. (Jackie), Rudan, I. (Igor), Ruusalepp, A. (Arno), Spector, T. (Tim), Tiemeier, H. (Henning), Volzke, H. (Henry), Wilson, J. F. (James F.), Michoel, T. (Tom), Timpson, N. J. (Nicolas J.), Smith, G. D. (George Davey), Walker, B. R. (Brian R.), Crawford, A. A. (Andrew A.), Bankier, S. (Sean), Altmaier, E. (Elisabeth), Barnes, C. L. (Catriona L. K.), Clark, D. W. (David W.), Ermel, R. (Raili), Friedrich, N. (Nele), van der Harst, P. (Pim), Joshi, P. K. (Peter K.), Karhunen, V. (Ville), Lahti, J. (Jari), Mahajan, A. (Anubha), Mangino, M. (Massimo), Nethander, M. (Maria), Neumann, A. (Alexander), Pietzner, M. (Maik), Sukhavasi, K. (Katyayani), Wang, C. A. (Carol A.), Bakker, S. J. (Stephan J. L.), Bjorkegren, J. L. (Johan L. M.), Campbell, H. (Harry), Eriksson, J. (Johan), Gieger, C. (Christian), Hayward, C. (Caroline), Järvelin, M.-R. (Marjo-Riitta), McLachlan, S. (Stela), Morris, A. P. (Andrew P.), Ohlsson, C. (Claes), Pennell, C. E. (Craig E.), Price, J. (Jackie), Rudan, I. (Igor), Ruusalepp, A. (Arno), Spector, T. (Tim), Tiemeier, H. (Henning), Volzke, H. (Henry), Wilson, J. F. (James F.), Michoel, T. (Tom), Timpson, N. J. (Nicolas J.), Smith, G. D. (George Davey), and Walker, B. R. (Brian R.)

Abstract

The stress hormone cortisol modulates fuel metabolism, cardiovascular homoeostasis, mood, inflammation and cognition. The CORtisol NETwork (CORNET) consortium previously identified a single locus associated with morning plasma cortisol. Identifying additional genetic variants that explain more of the variance in cortisol could provide new insights into cortisol biology and provide statistical power to test the causative role of cortisol in common diseases. The CORNET consortium extended its genome-wide association meta-analysis for morning plasma cortisol from 12,597 to 25,314 subjects and from similar to 2.2 M to similar to 7 M SNPs, in 17 population-based cohorts of European ancestries. We confirmed the genetic association with SERPINA6/SERPINA1. This locus contains genes encoding corticosteroid binding globulin (CBG) and alpha 1-antitrypsin. Expression quantitative trait loci (eQTL) analyses undertaken in the STARNET cohort of 600 individuals showed that specific genetic variants within the SERPINA6/SERPINA1 locus influence expression of SERPINA6 rather than SERPINA1 in the liver. Moreover, trans-eQTL analysis demonstrated effects on adipose tissue gene expression, suggesting that variations in CBG levels have an effect on delivery of cortisol to peripheral tissues. Two-sample Mendelian randomisation analyses provided evidence that each genetically-determined standard deviation (SD) increase in morning plasma cortisol was associated with increased odds of chronic ischaemic heart disease (0.32, 95% CI 0.06–0.59) and myocardial infarction (0.21, 95% CI 0.00–0.43) in UK Biobank and similarly in CARDIoGRAMplusC4D. These findings reveal a causative pathway for CBG in determining cortisol action in peripheral tissues and thereby contributing to the aetiology of cardiovascular disease.

Published
2021

2. Risk thresholds for alcohol consumption:combined analysis of individual-participant data for 599 912 current drinkers in 83 prospective studies

Author

Wood, A. M. (Angela M.), Kaptoge, S. (Stephen), Butterworth, A. S. (Adam S.), Willeit, P. (Peter), Warnakula, S. (Samantha), Bolton, T. (Thomas), Paige, E. (Ellie), Paul, D. S. (Dirk S.), Sweeting, M. (Michael), Burgess, S. (Stephen), Bell, S. (Steven), Astle, W. (William), Stevens, D. (David), Koulman, A. (Albert), Selmer, R. M. (Randi M.), Verschuren, W. M. (W. M. Monique), Sato, S. (Shinichi), Njolstad, I. (Inger), Woodward, M. (Mark), Salomaa, V. (Veikko), Nordestgaard, B. G. (Borge G.), Yeap, B. B. (Bu B.), Fletcher, A. (Astrid), Melander, O. (Olle), Kuller, L. H. (Lewis H.), Balkau, B. (Beverley), Marmot, M. (Michael), Koenig, W. (Wolfgang), Casiglia, E. (Edoardo), Cooper, C. (Cyrus), Arndt, V. (Volker), Franco, O. H. (Oscar H.), Wennberg, P. (Patrik), Gallacher, J. (John), de la Camara, A. G. (Agustin Gomez), Volzke, H. (Henry), Dahm, C. C. (Christina C.), Dale, C. E. (Caroline E.), Bergmann, M. M. (Manuela M.), Crespo, C. J. (Carlos J.), van der Schouw, Y. T. (Yvonne T.), Kaaks, R. (Rudolf), Simons, L. A. (Leon A.), Lagiou, P. (Pagona), Schoufour, J. D. (Josje D.), Boer, J. M. (Jolanda M. A.), Key, T. J. (Timothy J.), Rodriguez, B. (Beatriz), Moreno-Iribas, C. (Conchi), Davidson, K. W. (Karina W.), Taylor, J. O. (James O.), Sacerdote, C. (Carlotta), Wallace, R. B. (Robert B.), Quiros, J. R. (J. Ramon), Tumino, R. (Rosario), Blazer, D. G. (Dan G., II), Linneberg, A. (Allan), Daimon, M. (Makoto), Panico, S. (Salvatore), Howard, B. (Barbara), Skeie, G. (Guri), Strandberg, T. (Timo), Weiderpass, E. (Elisabete), Nietert, P. J. (Paul J.), Psaty, B. M. (Bruce M.), Kromhout, D. (Daan), Salamanca-Fernandez, E. (Elena), Kiechl, S. (Stefan), Krumholz, H. M. (Harlan M.), Grioni, S. (Sara), Palli, D. (Domenico), Huerta, J. M. (Jose M.), Price, J. (Jackie), Sundstrom, J. (Johan), Arriola, L. (Larraitz), Arima, H. (Hisatomi), Travis, R. C. (Ruth C.), Panagiotakos, D. B. (Demosthenes B.), Karakatsani, A. (Anna), Trichopoulou, A. (Antonia), Kuhn, T. (Tilman), Grobbee, D. E. (Diederick E.), Barrett-Connor, E. (Elizabeth), van Schoor, N. (Natasja), Boeing, H. (Heiner), Overvad, K. (Kim), Kauhanen, J. (Jussi), Wareham, N. (Nick), Langenberg, C. (Claudia), Forouhi, N. (Nita), Wennberg, M. (Maria), Despres, J.-P. (Jean-Pierre), Cushman, M. (Mary), Cooper, J. A. (Jackie A.), Rodriguez, C. J. (Carlos J.), Sakurai, M. (Masaru), Shaw, J. E. (Jonathan E.), Knuiman, M. (Matthew), Voortman, T. (Trudy), Meisinger, C. (Christa), Tjonneland, A. (Anne), Brenner, H. (Hermann), Palmieri, L. (Luigi), Dallongeville, J. (Jean), Brunner, E. J. (Eric J.), Assmann, G. (Gerd), Trevisan, M. (Maurizio), Gillum, R. F. (Richard F.), Ford, I. (Ian), Sattar, N. (Naveed), Lazo, M. (Mariana), Thompson, S. G. (Simon G.), Ferrari, P. (Pietro), Leon, D. A. (David A.), Smith, G. D. (George Davey), Peto, R. (Richard), Jackson, R. (Rod), Banks, E. (Emily), Di Angelantonio, E. (Emanuele), Danesh, J. (John), Wood, A. M. (Angela M.), Kaptoge, S. (Stephen), Butterworth, A. S. (Adam S.), Willeit, P. (Peter), Warnakula, S. (Samantha), Bolton, T. (Thomas), Paige, E. (Ellie), Paul, D. S. (Dirk S.), Sweeting, M. (Michael), Burgess, S. (Stephen), Bell, S. (Steven), Astle, W. (William), Stevens, D. (David), Koulman, A. (Albert), Selmer, R. M. (Randi M.), Verschuren, W. M. (W. M. Monique), Sato, S. (Shinichi), Njolstad, I. (Inger), Woodward, M. (Mark), Salomaa, V. (Veikko), Nordestgaard, B. G. (Borge G.), Yeap, B. B. (Bu B.), Fletcher, A. (Astrid), Melander, O. (Olle), Kuller, L. H. (Lewis H.), Balkau, B. (Beverley), Marmot, M. (Michael), Koenig, W. (Wolfgang), Casiglia, E. (Edoardo), Cooper, C. (Cyrus), Arndt, V. (Volker), Franco, O. H. (Oscar H.), Wennberg, P. (Patrik), Gallacher, J. (John), de la Camara, A. G. (Agustin Gomez), Volzke, H. (Henry), Dahm, C. C. (Christina C.), Dale, C. E. (Caroline E.), Bergmann, M. M. (Manuela M.), Crespo, C. J. (Carlos J.), van der Schouw, Y. T. (Yvonne T.), Kaaks, R. (Rudolf), Simons, L. A. (Leon A.), Lagiou, P. (Pagona), Schoufour, J. D. (Josje D.), Boer, J. M. (Jolanda M. A.), Key, T. J. (Timothy J.), Rodriguez, B. (Beatriz), Moreno-Iribas, C. (Conchi), Davidson, K. W. (Karina W.), Taylor, J. O. (James O.), Sacerdote, C. (Carlotta), Wallace, R. B. (Robert B.), Quiros, J. R. (J. Ramon), Tumino, R. (Rosario), Blazer, D. G. (Dan G., II), Linneberg, A. (Allan), Daimon, M. (Makoto), Panico, S. (Salvatore), Howard, B. (Barbara), Skeie, G. (Guri), Strandberg, T. (Timo), Weiderpass, E. (Elisabete), Nietert, P. J. (Paul J.), Psaty, B. M. (Bruce M.), Kromhout, D. (Daan), Salamanca-Fernandez, E. (Elena), Kiechl, S. (Stefan), Krumholz, H. M. (Harlan M.), Grioni, S. (Sara), Palli, D. (Domenico), Huerta, J. M. (Jose M.), Price, J. (Jackie), Sundstrom, J. (Johan), Arriola, L. (Larraitz), Arima, H. (Hisatomi), Travis, R. C. (Ruth C.), Panagiotakos, D. B. (Demosthenes B.), Karakatsani, A. (Anna), Trichopoulou, A. (Antonia), Kuhn, T. (Tilman), Grobbee, D. E. (Diederick E.), Barrett-Connor, E. (Elizabeth), van Schoor, N. (Natasja), Boeing, H. (Heiner), Overvad, K. (Kim), Kauhanen, J. (Jussi), Wareham, N. (Nick), Langenberg, C. (Claudia), Forouhi, N. (Nita), Wennberg, M. (Maria), Despres, J.-P. (Jean-Pierre), Cushman, M. (Mary), Cooper, J. A. (Jackie A.), Rodriguez, C. J. (Carlos J.), Sakurai, M. (Masaru), Shaw, J. E. (Jonathan E.), Knuiman, M. (Matthew), Voortman, T. (Trudy), Meisinger, C. (Christa), Tjonneland, A. (Anne), Brenner, H. (Hermann), Palmieri, L. (Luigi), Dallongeville, J. (Jean), Brunner, E. J. (Eric J.), Assmann, G. (Gerd), Trevisan, M. (Maurizio), Gillum, R. F. (Richard F.), Ford, I. (Ian), Sattar, N. (Naveed), Lazo, M. (Mariana), Thompson, S. G. (Simon G.), Ferrari, P. (Pietro), Leon, D. A. (David A.), Smith, G. D. (George Davey), Peto, R. (Richard), Jackson, R. (Rod), Banks, E. (Emily), Di Angelantonio, E. (Emanuele), and Danesh, J. (John)

Abstract

Background: Low-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease. Methods: We did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose–response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12·5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5·6 years [5th–95th percentile 1·04–13·5]) from 71 011 participants from 37 studies. Findings: In the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5·4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality ris

Published
2018

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