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

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