Cornelis Marilyn C, Byrne Enda M, Esko Tõnu, Nalls Michael A, Ganna Andrea, Paynter Nina, Monda Keri L, Amin Najaf, Fischer Krista, Renstrom Frida, Ngwa Julius S, Huikari Ville, Cavadino Alana, Nolte Ilja M, Teumer Alexander, Yu Kai, Marques-Vidal Pedro, Rawal Rajesh, Manichaikul Ani, Wojczynski Mary K, Vink Jacqueline M, Zhao Jing Hua, Burlutsky George, Lahti Jari, Mikkilä Vera, Lemaitre Rozenn N, Eriksson Joel, Musani Solomon K, Tanaka Toshiko, Geller Frank, Luan Jian'an, Hui Jennie, Mägi Reedik, Dimitriou Maria, Garcia Melissa E, Ho Weang-Kee, Wright Margaret J, Rose Lynda M, Magnusson Patrik Ke, Pedersen Nancy L, Couper David, Oostra Ben A, Hofman Albert, Ikram Mohammad Arfan, Tiemeier Henning W, Uitterlinden Andre G, van Rooij Frank Ja, Barroso Inês, Johansson Ingegerd, Xue Luting, Kaakinen Marika, Milani Lili, Power Chris, Snieder Harold, Stolk Ronald P, Baumeister Sebastian E, Biffar Reiner, Gu Fangyi, Bastardot François, Kutalik Zoltán, Jacobs David R, Forouhi Nita G, Mihailov Evelin, Lind Lars, Lindgren Cecilia, Michaëlsson Karl, Morris Andrew, Jensen Majken, Khaw Kay-Tee, Luben Robert N, Wang Jie Jin, Männistö Satu, Perälä Mia-Maria, Kähönen Mika, Lehtimäki Terho, Viikari Jorma, Mozaffarian Dariush, Mukamal Kenneth, Psaty Bruce M, Döring Angela, Heath Andrew C, Montgomery Grant W, Dahmen Norbert, Carithers Teresa, Tucker Katherine L, Ferrucci Luigi, Boyd Heather A, Melbye Mads, Treur Jorien L, Mellström Dan, Hottenga Jouke Jan, Prokopenko Inga, Tönjes Anke, Deloukas Panos, Kanoni Stavroula, Lorentzon Mattias, Houston Denise K, Liu Yongmei, Danesh John, Rasheed Asif, Mason Marc A, Zonderman Alan B, Franke Lude, Kristal Bruce S, Karjalainen Juha, Reed Danielle R, Westra Harm-Jan, Evans Michele K, Saleheen Danish, Harris Tamara B, Dedoussis George, Curhan Gary, Stumvoll Michael, Beilby John, Pasquale Louis R, Feenstra Bjarke, Bandinelli Stefania, Ordovas Jose M, Chan Andrew T, Peters Ulrike, Ohlsson Claes, Gieger Christian, Martin Nicholas G, Waldenberger Melanie, Siscovick David S, Raitakari Olli, Eriksson Johan G, Mitchell Paul, Hunter David J, Kraft Peter, Rimm Eric B, Boomsma Dorret I, Borecki Ingrid B, Loos Ruth Jf, Wareham Nicholas J, Vollenweider Peter, Caporaso Neil, Grabe Hans Jörgen, Neuhouser Marian L, Wolffenbuttel Bruce Hr, Hu Frank B, Hyppönen Elina, Järvelin Marjo-Riitta, Cupples L Adrienne, Franks Paul W, Ridker Paul M, van Duijn Cornelia M, Heiss Gerardo, Metspalu Andres, North Kari E, Ingelsson Erik, Nettleton Jennifer A, van Dam Rob M, Chasman Daniel I
Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.
Mol Psychiatry. 2015 May;20(5):647-656. doi: 10.1038/mp.2014.107. Epub 2014 Oct 7.
Coffee, a major dietary source of caffeine, is among the most widely consumed beverages in the world and has received considerable attention regarding health risks and benefits. We conducted a genome-wide (GW) meta-analysis of predominately regular-type coffee consumption (cups per day) among up to 91,462 coffee consumers of European ancestry with top single-nucleotide polymorphisms (SNPs) followed-up in ~30 062 and 7964 coffee consumers of European and African-American ancestry, respectively. Studies from both stages were combined in a trans-ethnic meta-analysis. Confirmed loci were examined for putative functional and biological relevance. Eight loci, including six novel loci, met GW significance (log10Bayes factor (BF)>5.64) with per-allele effect sizes of 0.03-0.14 cups per day. Six are located in or near genes potentially involved in pharmacokinetics (ABCG2, AHR, POR and CYP1A2) and pharmacodynamics (BDNF and SLC6A4) of caffeine. Two map to GCKR and MLXIPL genes related to metabolic traits but lacking known roles in coffee consumption. Enhancer and promoter histone marks populate the regions of many confirmed loci and several potential regulatory SNPs are highly correlated with the lead SNP of each. SNP alleles near GCKR, MLXIPL, BDNF and CYP1A2 that were associated with higher coffee consumption have previously been associated with smoking initiation, higher adiposity and fasting insulin and glucose but lower blood pressure and favorable lipid, inflammatory and liver enzyme profiles (P<5 × 10(-8)).Our genetic findings among European and African-American adults reinforce the role of caffeine in mediating habitual coffee consumption and may point to molecular mechanisms underlying inter-individual variability in pharmacological and health effects of coffee.
咖啡是咖啡因的主要饮食来源，是世界上消费最为广泛的饮品之一，其对健康的风险和益处备受关注。我们对多达91462名欧洲血统的咖啡消费者进行了全基因组（GW）荟萃分析，主要分析的是常规类型咖啡的消费量（每天杯数），并对顶级单核苷酸多态性（SNP）进行了后续研究，分别在约30062名欧洲血统和7964名非裔美国血统的咖啡消费者中进行。两个阶段的研究合并进行了跨种族荟萃分析。对已确认的基因座进行了推定的功能和生物学相关性检查。八个基因座，包括六个新基因座，达到了全基因组显著性（对数10贝叶斯因子（BF）>5.64），每个等位基因的效应大小为每天0.03 - 0.14杯。其中六个位于可能参与咖啡因药代动力学（ABCG2、AHR、POR和CYP1A2）和药效学（BDNF和SLC6A4）的基因内或附近。另外两个映射到与代谢特征相关但在咖啡消费中尚无已知作用的GCKR和MLXIPL基因。增强子和启动子组蛋白标记存在于许多已确认基因座的区域，并且几个潜在的调控SNP与每个主SNP高度相关。与较高咖啡消费量相关的GCKR、MLXIPL、BDNF和CYP1A2附近的SNP等位基因此前与开始吸烟、较高肥胖率、空腹胰岛素和血糖有关，但与较低血压以及有利的血脂、炎症和肝酶谱有关（P<5×10⁻⁸）。我们在欧洲和非裔美国成年人中的基因研究结果强化了咖啡因在介导习惯性咖啡消费中的作用，并可能指出咖啡药理和健康效应个体间差异的潜在分子机制。
