Causal Relationship between Obesity and Vitamin D Status: Bi-Directional Mendelian Randomization Analysis of Multiple Cohorts

被引：733

作者：

Vimaleswaran, Karani S. ^{[1
,2
]}

Berry, Diane J. ^{[1
,2
]}

Lu, Chen ^{[3
]}

Tikkanen, Emmi ^{[4
,5
]}

Pilz, Stefan ^{[6
,7
]}

Hiraki, Linda T. ^{[8
]}

Cooper, Jason D. ^{[9
]}

Dastani, Zari ^{[10
]}

Li, Rui ^{[11
,12
,13
]}

Houston, Denise K. ^{[14
]}

Wood, Andrew R. ^{[15
]}

Michaelsson, Karl ^{[16
]}

Vandenput, Liesbeth ^{[17
]}

Zgaga, Lina ^{[18
,19
]}

Yerges-Armstrong, Laura M. ^{[20
]}

McCarthy, Mark I. ^{[21
,22
,23
]}

Dupuis, Josee ^{[3
,24
]}

Kaakinen, Marika ^{[25
,26
]}

Kleber, Marcus E. ^{[27
,28
]}

Jameson, Karen ^{[29
]}

Arden, Nigel ^{[30
,31
]}

Raitakari, Olli ^{[32
,33
,34
]}

Viikari, Jorma ^{[34
,35
]}

Lohman, Kurt K. ^{[36
]}

Ferrucci, Luigi ^{[37
]}

Melhus, Hakan ^{[38
]}

Ingelsson, Erik ^{[39
]}

Byberg, Liisa ^{[16
]}

Lind, Lars ^{[38
]}

Lorentzon, Mattias ^{[17
]}

Salomaa, Veikko ^{[5
]}

Campbell, Harry ^{[18
]}

Dunlop, Malcolm ^{[40
,41
]}

Mitchell, Braxton D. ^{[20
]}

Herzig, Karl-Heinz ^{[25
,26
,42
,43
]}

Pouta, Anneli ^{[44
]}

Hartikainen, Anna-Liisa ^{[45
]}

Streeten, Elizabeth A. ^{[20
]}

Theodoratou, Evropi ^{[18
]}

Jula, Antti ^{[5
]}

Wareham, Nicholas J. ^{[46
]}

Ohlsson, Claes ^{[17
]}

Frayling, Timothy M. ^{[15
]}

Kritchevsky, Stephen B. ^{[14
]}

Spector, Timothy D. ^{[47
]}

Richards, J. Brent ^{[11
,12
,13
,47
]}

Lehtimaki, Terho ^{[48
,49
]}

Ouwehand, Willem H. ^{[50
,51
,52
]}

Kraft, Peter ^{[8
]}

Cooper, Cyrus ^{[29
]}

机构：

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

[2] UCL Inst Child Hlth, MRC Ctr Epidemiol Child Hlth, London, England

[3] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA

[4] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland

[5] Natl Inst Hlth & Welf, Helsinki, Finland

[6] Med Univ Graz, Div Endocrinol & Metab, Dept Internal Med, Graz, Austria

[7] Vrije Univ Amsterdam Med Ctr, EMGO Inst Hlth & Care Res, Dept Epidemiol & Biostat, Amsterdam, Netherlands

[8] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, Boston, MA 02115 USA

[9] Univ Cambridge, Cambridge Inst Med Res, Dept Med Genet, Juvenile Diabet Res Fdn Wellcome Trust Diabet & I, Cambridge, England

[10] McGill Univ, Jewish Gen Hosp, Lady Davis Inst, Dept Epidemiol Biostat & Occupat Hlth, Montreal, PQ H3T 1E2, Canada

[11] McGill Univ, Jewish Gen Hosp, Lady Davis Inst, Dept Med, Montreal, PQ H3T 1E2, Canada

[12] McGill Univ, Jewish Gen Hosp, Lady Davis Inst, Dept Human Genet, Montreal, PQ H3T 1E2, Canada

[13] McGill Univ, Jewish Gen Hosp, Lady Davis Inst, Dept Epidemiol & Biostat, Montreal, PQ H3T 1E2, Canada

[14] Wake Forest Sch Med, Sect Gerontol & Geriatr Med, Dept Internal Med, Winston Salem, NC USA

[15] Univ Exeter, Peninsula Coll Med & Dent, Exeter, Devon, England

[16] Uppsala Univ, Dept Surg Sci, Uppsala, Sweden

[17] Univ Gothenburg, Inst Med, Dept Internal Med, Ctr Bone & Arthrit Res, Gothenburg, Sweden

[18] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland

[19] Univ Zagreb, Sch Med, Andrija Stampar Sch Publ Hlth, Zagreb 41001, Croatia

[20] Univ Maryland, Sch Med, Div Endocrinol, Baltimore, MD 21201 USA

[21] Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England

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

[23] Churchill Hosp, Oxford NIHR Biomed Res Ctr, Oxford OX3 7LJ, England

[24] NHLBI, Framingham, MA USA

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

[26] Univ Oulu, Bioctr Oulu, Oulu, Finland

[27] LURIC Study Non Profit LLC, Freiburg, Germany

[28] Heidelberg Univ, Mannheim Inst Publ Hlth, Mannheim Med Fac, Social & Prevent Med, Mannheim, Germany

[29] Univ Southampton, MRC Lifecourse Epidemiol Unit, Southampton, Hants, England

[30] Botnar Res Ctr, NIHR Musculoskeletal BRU, Oxford, England

[31] Univ Southampton, MRC Lifecourse Epidemiol Unit, Southampton, Hants, England

[32] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland

[33] Univ Turku, Dept Clin Physiol & Nucl Med, Turku, Finland

[34] Turku Univ Hosp, FIN-20520 Turku, Finland

[35] Univ Turku, Dept Med, Turku, Finland

[36] Wake Sch Med, Div Publ Hlth Sci, Dept Biostat Sci, Winston Salem, NC USA

[37] Harbor Hosp, Clin Res Branch, Baltimore, MD USA

[38] Uppsala Univ, Dept Med Sci, Uppsala, Sweden

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

[40] Univ Edinburgh, Inst Genet & Mol Med, Colon Canc Genet Grp & Acad Coloproctol, Edinburgh EH8 9YL, Midlothian, Scotland

[41] Western Gen Hosp Edinburgh, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland

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

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

[44] Univ Oulu, Dept Publ Hlth Sci & Gen Practice, Oulu, Finland

[45] Univ Oulu, Dept Obstet & Gynaecol & Publ Hlth & Gen Practice, Oulu, Finland

[46] Addenbrookes Hosp, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England

[47] Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England

[48] Tampere Univ Hosp, Dept Clin Chem, Fimlab Labs, FIN-33521 Tampere, Finland

[49] Univ Tampere, FIN-33101 Tampere, Finland

[50] Univ Cambridge, Dept Haematol, Cambridge CB2 1TN, England

来源：

PLOS MEDICINE | 2013年 / 10卷 / 02期

基金：

英国医学研究理事会;

关键词：

BODY-MASS INDEX; INSTRUMENTAL VARIABLES; 25-HYDROXYVITAMIN D; GENETIC-VARIANTS; D INSUFFICIENCY; D DEFICIENCY; PREVALENCE; RISK; ASSOCIATION; WEIGHT;

D O I：

10.1371/journal.pmed.1001383

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Background: Obesity is associated with vitamin D deficiency, and both are areas of active public health concern. We explored the causality and direction of the relationship between body mass index (BMI) and 25-hydroxyvitamin D [25(OH) D] using genetic markers as instrumental variables (IVs) in bi-directional Mendelian randomization (MR) analysis. Methods and Findings: We used information from 21 adult cohorts (up to 42,024 participants) with 12 BMI-related SNPs (combined in an allelic score) to produce an instrument for BMI and four SNPs associated with 25(OH) D (combined in two allelic scores, separately for genes encoding its synthesis or metabolism) as an instrument for vitamin D. Regression estimates for the IVs (allele scores) were generated within-study and pooled by meta-analysis to generate summary effects. Associations between vitamin D scores and BMI were confirmed in the Genetic Investigation of Anthropometric Traits (GIANT) consortium (n = 123,864). Each 1 kg/m(2) higher BMI was associated with 1.15% lower 25(OH) D (p = 6.52x10(-27)). The BMI allele score was associated both with BMI (p = 6.30x10(-62)) and 25(OH) D (20.06% [95% CI -0.10 to -0.02], p = 0.004) in the cohorts that underwent meta-analysis. The two vitamin D allele scores were strongly associated with 25(OH) D (p <= 8.07x10(-57) for both scores) but not with BMI (synthesis score, p = 0.88; metabolism score, p = 0.08) in the meta-analysis. A 10% higher genetically instrumented BMI was associated with 4.2% lower 25(OH) D concentrations (IV ratio: -4.2 [95% CI -7.1 to -1.3], p = 0.005). No association was seen for genetically instrumented 25(OH) D with BMI, a finding that was confirmed using data from the GIANT consortium (p >= 0.57 for both vitamin D scores). Conclusions: On the basis of a bi-directional genetic approach that limits confounding, our study suggests that a higher BMI leads to lower 25(OH) D, while any effects of lower 25(OH) D increasing BMI are likely to be small. Population level interventions to reduce BMI are expected to decrease the prevalence of vitamin D deficiency.

引用

页数：13

共 51 条

[41] Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index [J].

Speliotes, Elizabeth K. ;

Willer, Cristen J. ;

Berndt, Sonja I. ;

Monda, Keri L. ;

Thorleifsson, Gudmar ;

Jackson, Anne U. ;

Allen, Hana Lango ;

Lindgren, Cecilia M. ;

Luan, Jian'an ;

Maegi, Reedik ;

Randall, Joshua C. ;

Vedantam, Sailaja ;

Winkler, Thomas W. ;

Qi, Lu ;

Workalemahu, Tsegaselassie ;

Heid, Iris M. ;

Steinthorsdottir, Valgerdur ;

Stringham, Heather M. ;

Weedon, Michael N. ;

Wheeler, Eleanor ;

Wood, Andrew R. ;

Ferreira, Teresa ;

Weyant, Robert J. ;

Segre, Ayellet V. ;

Estrada, Karol ;

Liang, Liming ;

Nemesh, James ;

Park, Ju-Hyun ;

Gustafsson, Stefan ;

Kilpelaenen, Tuomas O. ;

Yang, Jian ;

Bouatia-Naji, Nabila ;

Esko, Tonu ;

Feitosa, Mary F. ;

Kutalik, Zoltan ;

Mangino, Massimo ;

Raychaudhuri, Soumya ;

Scherag, Andre ;

Smith, Albert Vernon ;

Welch, Ryan ;

Zhao, Jing Hua ;

Aben, Katja K. ;

Absher, Devin M. ;

Amin, Najaf ;

Dixon, Anna L. ;

Fisher, Eva ;

Glazer, Nicole L. ;

Goddard, Michael E. ;

Heard-Costa, Nancy L. ;

Hoesel, Volker .

NATURE GENETICS, 2010, 42 (11) :937-U53

[42] Instrumental variables regression with weak instruments [J].

Staiger, D ;

Stock, JH .

ECONOMETRICA, 1997, 65 (03) :557-586

[43] Re: Estimation of bias in nongenetic observational studies using "Mendelian triangulation" by bautista et al. [J].

Thomas, Duncan C. ;

Lawlor, Debbie A. ;

Thompson, John R. .

ANNALS OF EPIDEMIOLOGY, 2007, 17 (07) :511-513

[44] Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity [J].

Thorleifsson, Gudmar ;

Walters, G. Bragi ;

Gudbjartsson, Daniel F. ;

Steinthorsdottir, Valgerdur ;

Sulem, Patrick ;

Helgadottir, Anna ;

Styrkarsdottir, Unnur ;

Gretarsdottir, Solveig ;

Thorlacius, Steinunn ;

Jonsdottir, Ingileif ;

Jonsdottir, Thorbjorg ;

Olafsdottir, Elinborg J. ;

Olafsdottir, Gudridur H. ;

Jonsson, Thorvaldur ;

Jonsson, Frosti ;

Borch-Johnsen, Knut ;

Hansen, Torben ;

Andersen, Gitte ;

Jorgensen, Torben ;

Lauritzen, Torsten ;

Aben, Katja K. ;

Verbeek, Andre L. M. ;

Roeleveld, Nel ;

Kampman, Ellen ;

Yanek, Lisa R. ;

Becker, Lewis C. ;

Tryggvadottir, Laufey ;

Rafnar, Thorunn ;

Becker, Diane M. ;

Gulcher, Jeffrey ;

Kiemeney, Lambertus A. ;

Pedersen, Oluf ;

Kong, Augustine ;

Thorsteinsdottir, Unnur ;

Stefansson, Kari .

NATURE GENETICS, 2009, 41 (01) :18-24

[45] Progress in the genetics of common obesity and type 2 diabetes [J].

Vimaleswaran, Karani S. ;

Loos, Ruth J. F. .

EXPERT REVIEWS IN MOLECULAR MEDICINE, 2010, 12

[46] Common genetic determinants of vitamin D insufficiency: a genome-wide association study [J].

Wang, Thomas J. ;

Zhang, Feng ;

Richards, J. Brent ;

Kestenbaum, Bryan ;

van Meurs, Joyce B. ;

Berry, Diane ;

Kiel, Douglas P. ;

Streeten, Elizabeth A. ;

Ohlsson, Claes ;

Koller, Daniel L. ;

Peltonen, Leena ;

Cooper, Jason D. ;

O'Reilly, Paul F. ;

Houston, Denise K. ;

Glazer, Nicole L. ;

Vandenput, Liesbeth ;

Peacock, Munro ;

Shi, Julia ;

Rivadeneira, Fernando ;

McCarthy, Mark I. ;

Anneli, Pouta ;

de Boer, Ian H. ;

Mangino, Massimo ;

Kato, Bernet ;

Smyth, Deborah J. ;

Booth, Sarah L. ;

Jacques, Paul F. ;

Burke, Greg L. ;

Goodarzi, Mark ;

Cheung, Ching-Lung ;

Wolf, Myles ;

Rice, Kenneth ;

Goltzman, David ;

Hidiroglou, Nick ;

Ladouceur, Martin ;

Wareham, Nicholas J. ;

Hocking, Lynne J. ;

Hart, Deborah ;

Arden, Nigel K. ;

Cooper, Cyrus ;

Malik, Suneil ;

Fraser, William D. ;

Hartikainen, Anna-Liisa ;

Zhai, Guangju ;

Macdonald, Helen M. ;

Forouhi, Nita G. ;

Loos, Ruth J. F. ;

Reid, David M. ;

Hakim, Alan ;

Dennison, Elaine .

LANCET, 2010, 376 (9736) :180-188

[47] Multivariate random-effects meta-analysis [J].

White, Ian R. .

STATA JOURNAL, 2009, 9 (01) :40-56

[48] Decreased bioavailability of vitamin D in obesity [J].

Wortsman, J ;

Matsuoka, LY ;

Chen, TC ;

Lu, ZR ;

Holick, MF .

AMERICAN JOURNAL OF CLINICAL NUTRITION, 2000, 72 (03) :690-693

[49] A Comparison of Approaches to Account for Uncertainty in Analysis of Imputed Genotypes [J].

Zheng, Jin ;

Li, Yun ;

Abecasis, Goncalo R. ;

Scheet, Paul .

GENETIC EPIDEMIOLOGY, 2011, 35 (02) :102-110

[50] Association between Body-Mass Index and Risk of Death in More Than 1 Million Asians [J].

Zheng, Wei ;

McLerran, Dale F. ;

Rolland, Betsy ;

Zhang, Xianglan ;

Inoue, Manami ;

Matsuo, Keitaro ;

He, Jiang ;

Gupta, Prakash Chandra ;

Ramadas, Kunnambath ;

Tsugane, Shoichiro ;

Irie, Fujiko ;

Tamakoshi, Akiko ;

Gao, Yu-Tang ;

Wang, Renwei ;

Shu, Xiao-Ou ;

Tsuji, Ichiro ;

Kuriyama, Shinichi ;

Tanaka, Hideo ;

Satoh, Hiroshi ;

Chen, Chien-Jen ;

Yuan, Jian-Min ;

Yoo, Keun-Young ;

Ahsan, Habibul ;

Pan, Wen-Harn ;

Gu, Dongfeng ;

Pednekar, Mangesh Suryakant ;

Sauvaget, Catherine ;

Sasazuki, Shizuka ;

Sairenchi, Toshimi ;

Yang, Gong ;

Xiang, Yong-Bing ;

Nagai, Masato ;

Suzuki, Takeshi ;

Nishino, Yoshikazu ;

You, San-Lin ;

Koh, Woon-Puay ;

Park, Sue K. ;

Chen, Yu ;

Shen, Chen-Yang ;

Thornquist, Mark ;

Feng, Ziding ;

Kang, Daehee ;

Boffetta, Paolo ;

Potter, John D. .

NEW ENGLAND JOURNAL OF MEDICINE, 2011, 364 (08) :719-729

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