The Role of Adiposity in Cardiometabolic Traits: A Mendelian Randomization Analysis

被引：150

作者：

Fall, Tove ^{[1
,2
]}

Hagg, Sara ^{[1
,2
]}

Maegi, Reedik ^{[3
,4
]}

Ploner, Alexander ^{[2
]}

Fischer, Krista ^{[4
]}

Horikoshi, Momoko ^{[3
,5
]}

Sarin, Antti-Pekka ^{[6
]}

Thorleifsson, Gudmar ^{[7
]}

Ladenvall, Claes ^{[8
,9
]}

Kals, Mart ^{[4
]}

Kuningas, Maris ^{[10
]}

Draisma, Harmen H. M. ^{[11
,12
]}

Ried, Janina S. ^{[13
]}

van Zuydam, Natalie R. ^{[14
]}

Huikari, Ville ^{[15
]}

Mangino, Massimo ^{[16
]}

Sonestedt, Emily ^{[17
]}

Benyamin, Beben ^{[18
,19
]}

Nelson, Christopher P. ^{[20
,21
]}

Rivera, Natalia V. ^{[22
,23
,24
]}

Kristiansson, Kati ^{[25
]}

Shen, Huei-yi ^{[6
,26
]}

Havulinna, Aki S. ^{[25
]}

Dehghan, Abbas ^{[10
,27
]}

Donnelly, Louise A. ^{[14
]}

Kaakinen, Marika ^{[15
,28
]}

Nuotio, Marja-Liisa ^{[25
]}

Robertson, Neil ^{[3
,5
]}

de Bruijn, Renee F. A. G. ^{[10
,29
]}

Ikram, M. Arfan ^{[10
,29
,30
]}

Amin, Najaf ^{[24
]}

Balmforth, Anthony J. ^{[31
]}

Braund, Peter S. ^{[20
]}

Doney, Alexander S. F. ^{[14
]}

Doering, Angela ^{[32
,33
]}

Elliott, Paul ^{[34
]}

Esko, Tonu ^{[4
]}

Franco, Oscar H. ^{[10
,27
]}

Gretarsdottir, Solveig ^{[7
]}

Hartikainen, Anna-Liisa ^{[35
]}

Heikkila, Kauko ^{[36
]}

Herzig, Karl-Heinz ^{[28
,37
,38
]}

Holm, Hilma ^{[7
]}

Hottenga, Jouke Jan ^{[11
,12
]}

Hypponen, Elina ^{[39
,40
]}

Illig, Thomas ^{[41
,42
]}

Isaacs, Aaron ^{[24
]}

Isomaa, Bo ^{[43
,44
]}

Karssen, Lennart C. ^{[24
]}

Kettunen, Johannes ^{[6
,25
]}

机构：

[1] Uppsala Univ, Dept Med Sci, Mol Epidemiol & Sci Life Lab, Uppsala, Sweden

[2] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden

[3] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England

[4] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia

[5] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England

[6] Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland

[7] deCODE Genet, Reykjavik, Iceland

[8] Lund Univ, Lund Univ Diabet Ctr, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden

[9] Skane Univ Hosp, Malmo, Sweden

[10] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands

[11] Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands

[12] EMGO Inst Hlth & Care Res, Amsterdam, Netherlands

[13] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany

[14] Univ Dundee, Ninewells Hosp & Med Sch, Med Res Inst, Dundee DD1 9SY, Scotland

[15] Univ Oulu, Inst Hlth Sci, Oulu, Finland

[16] Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England

[17] Lund Univ, Skane Univ Hosp, Dept Clin Sci, Diabet & Cardiovasc Dis Genet Epidemiol Res Unit, Malmo, Sweden

[18] Queensland Inst Med Res, Herston, Qld 4006, Australia

[19] Univ Queensland, Queensland Brain Inst, St Lucia, Qld, Australia

[20] Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England

[21] Glenfield Gen Hosp, Leicester Cardiovasc Biomed Res Unit, Natl Inst Hlth Res, Leicester LE3 9QP, Leics, England

[22] IRCSS Multimed, Milan, Italy

[23] CNR, Inst Genet & Biomed Res, I-20133 Milan, Italy

[24] Erasmus MC, Dept Genet Epidemiol, Rotterdam, Netherlands

[25] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland

[26] Natl Inst Hlth & Welf, Publ Hlth Genom Unit, Helsinki, Finland

[27] Netherlands Genom Initiat, Netherlands Consortium Hlth Ageing, Leiden, Netherlands

[28] Univ Oulu, Bioctr Oulu, Oulu, Finland

[29] Erasmus MC, Dept Neurol, Rotterdam, Netherlands

[30] Erasmus MC, Dept Radiol, Rotterdam, Netherlands

[31] Univ Leeds, Sch Med, Leeds Inst Genet Hlth & Therapeut, Div Epidemiol, Leeds LS2 9JT, W Yorkshire, England

[32] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 1, Neuherberg, Germany

[33] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany

[34] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, MRC HPA Ctr Environm & Hlth, London, England

[35] Univ Oulu, Dept Obstet & Gynaecol, Inst Clin Sci, Oulu, Finland

[36] Univ Helsinki, Dept Publ Hlth, Hjelt Inst, Helsinki, Finland

[37] Univ Oulu, Inst Biomed, Oulu, Finland

[38] Kuopio Univ Hosp, Dept Psychiat, SF-70210 Kuopio, Finland

[39] UCL, Inst Child Hlth, Ctr Paediat Epidemiol & Biostat, London, England

[40] UCL, Inst Child Hlth, Med Res Council Ctr Epidemiol Child Hlth, London, England

[41] Hannover Med Sch, Hannover Unified Biobank, Hannover, Germany

[42] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany

[43] Dept Social Serv & Hlth Care, Pietarsaari, Finland

[44] Folkhalsan Res Ctr, Helsinki, Finland

[45] Univ Ulm, Med Ctr, Dept Internal Med Cardiol 2, D-89069 Ulm, Germany

[46] Finnish Inst Occupat Hlth, Helsinki, Finland

[47] Steno Diabet Ctr, DK-2820 Gentofte, Denmark

[48] Univ Oulu, Dept Math Sci, Oulu, Finland

[49] Wellcome Trust Sanger Inst, Hinxton, England

[50] Natl Inst Hlth & Welf, Dept Children Young People & Families, Oulu, Finland

来源：

PLOS MEDICINE | 2013年 / 10卷 / 06期

基金：

英国医学研究理事会; 英国惠康基金; 瑞典研究理事会; 英国生物技术与生命科学研究理事会; 澳大利亚研究理事会; 芬兰科学院; 美国国家卫生研究院;

关键词：

BODY-MASS INDEX; LIFE-STYLE; FTO GENE; DIABETES PREVENTION; HEART-DISEASE; RISK; OBESITY; MORBIDITY; MORTALITY; VARIANT;

D O I：

10.1371/journal.pmed.1001474

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Background: The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach. Methods and Findings: We used the adiposity-associated variant rs9939609 at the FTO locus as an instrumental variable (IV) for body mass index (BMI) in a Mendelian randomization design. Thirty-six population-based studies of individuals of European descent contributed to the analyses. Age-and sex-adjusted regression models were fitted to test for association between (i) rs9939609 and BMI (n = 198,502), (ii) rs9939609 and 24 traits, and (iii) BMI and 24 traits. The causal effect of BMI on the outcome measures was quantified by IV estimators. The estimators were compared to the BMI-trait associations derived from the same individuals. In the IV analysis, we demonstrated novel evidence for a causal relationship between adiposity and incident heart failure (hazard ratio, 1.19 per BMI-unit increase; 95% CI, 1.03-1.39) and replicated earlier reports of a causal association with type 2 diabetes, metabolic syndrome, dyslipidemia, and hypertension (odds ratio for IV estimator, 1.1-1.4; all p<0.05). For quantitative traits, our results provide novel evidence for a causal effect of adiposity on the liver enzymes alanine aminotransferase and gamma-glutamyl transferase and confirm previous reports of a causal effect of adiposity on systolic and diastolic blood pressure, fasting insulin, 2-h post-load glucose from the oral glucose tolerance test, C-reactive protein, triglycerides, and high-density lipoprotein cholesterol levels (all p<0.05). The estimated causal effects were in agreement with traditional observational measures in all instances except for type 2 diabetes, where the causal estimate was larger than the observational estimate (p = 0.001). Conclusions: We provide novel evidence for a causal relationship between adiposity and heart failure as well as between adiposity and increased liver enzymes.

引用

页数：15

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