Mendelian Randomization Studies Do Not Support a Causal Role for Reduced Circulating Adiponectin Levels in Insulin Resistance and Type 2 Diabetes

被引：115

作者：

Yaghootkar, Hanieh ^{[1
]}

Lamina, Claudia ^{[2
]}

Scott, Robert A. ^{[3
]}

Dastani, Zari ^{[4
]}

Hivert, Marie-France ^{[5
,6
]}

Warren, Liling L. ^{[7
]}

Stancakova, Alena ^{[8
]}

Buxbaum, Sarah G. ^{[9
]}

Lyytikaeinen, Leo-Pekka ^{[10
,11
]}

Henneman, Peter ^{[12
]}

Wu, Ying ^{[13
]}

Cheung, Chloe Y. Y. ^{[14
]}

Pankow, James S. ^{[15
]}

Jackson, Anne U. ^{[16
,17
]}

Gustafsson, Stefan ^{[18
]}

Zhao, Jing Hua ^{[3
]}

Ballantyne, Christie M. ^{[19
,20
]}

Xie, Weijia ^{[1
]}

Bergman, Richard N. ^{[21
]}

Boehnke, Michael ^{[16
,17
]}

el Bouazzaoui, Fatiha ^{[12
]}

Collins, Francis S. ^{[22
]}

Dunn, Sandra H. ^{[23
]}

Dupuis, Josee ^{[24
]}

Forouhi, Nita G. ^{[3
]}

Gillson, Christopher ^{[3
]}

Hattersley, Andrew T. ^{[1
]}

Hong, Jaeyoung ^{[24
]}

Kaehoenen, Mika ^{[25
,26
]}

Kuusisto, Johanna ^{[8
]}

Kedenko, Lyudmyla ^{[27
]}

Kronenberg, Florian ^{[2
]}

Doria, Alessandro ^{[28
]}

Assimes, Themistocles L. ^{[29
,30
]}

Ferrannini, Ele ^{[32
]}

Hansen, Torben ^{[33
]}

Hao, Ke ^{[8
]}

Haering, Hans ^{[31
,34
,35
,36
]}

Knowles, Joshua W. ^{[29
,30
]}

Lindgren, Cecilia M. ^{[32
]}

Nolan, John J. ^{[33
]}

Paananen, Jussi ^{[8
]}

Pedersen, Oluf ^{[31
]}

Quertermous, Thomas ^{[29
,30
]}

Smith, Ulf ^{[37
]}

Lehtimaeki, Terho ^{[10
,11
]}

Liu, Ching-Ti ^{[24
]}

Loos, Ruth J. F. ^{[3
,38
]}

McCarthy, Mark I. ^{[32
,39
,40
]}

Morris, Andrew D. ^{[41
]}

机构：

[1] Univ Exeter, Sch Med, Exeter, Devon, England

[2] Med Univ Innsbruck, Dept Med Genet Mol & Clin Pharmacol, Div Genet Epidemiol, A-6020 Innsbruck, Austria

[3] Inst Met Sci, MRC Epidemiol Unit, Cambridge, England

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

[5] Univ Sherbrooke, Dept Med, Sherbrooke, PQ J1K 2R1, Canada

[6] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA

[7] GlaxoSmithKline, Res Triangle Pk, NC USA

[8] Univ Eastern Finland, Kuopio, Finland

[9] Jackson State Univ, Sch Hlth Sci, Jackson, MS USA

[10] Fimlab Labs, Dept Clin Chem, Tampere, Finland

[11] Univ Tampere, Sch Med, Dept Clin Chem, FIN-33101 Tampere, Finland

[12] Leiden Univ Med Ctr, Dept Human Genet, NL-2300 RA Leiden, Netherlands

[13] Univ N Carolina, Dept Genet, Chapel Hill, NC USA

[14] Univ Hong Kong, Li Ka Shing Fac Med, Dept Med, Hong Kong, Peoples R China

[15] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA

[16] Univ Michigan, Dept Biostat & Ctr Stat Genet, Ann Arbor, MI 48109 USA

[17] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA

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

[19] Baylor Coll Med, Houston, TX USA

[20] Methodist DeBakey Heart & Vasc Ctr, Houston, TX USA

[21] Cedars Sinai Med Ctr, Diabetes & Obes Res Inst, Los Angeles, CA 90048 USA

[22] Natl Human Genome Res Inst, Natl Inst Hlth, Genome Technol Branch, Bethesda, MD USA

[23] Univ Pittsburgh, Sch Nursing, Pittsburgh, PA 15261 USA

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

[25] Tampere Univ Hosp, Dept Clin Psychol, Tampere, Finland

[26] Univ Tampere, Sch Med, FIN-33101 Tampere, Finland

[27] Paracelsus Private Med Univ Salzburg, St Johann Spital, Dept Internal Med 1, Salzburg, Austria

[28] Joslin Diabet Ctr, Sect Genet & Epidemiol, Boston, MA 02215 USA

[29] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA

[30] Stanford Univ, Sch Med, Cardiovasc Inst, Stanford, CA 94305 USA

[31] Univ Copenhagen, Fac Hlth Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark

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

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

[34] Hagedorn Res Inst, Copenhagen, Denmark

[35] Univ Copenhagen, Fac Hlth Sci, Inst Biomed Sci, Copenhagen, Denmark

[36] Univ Aarhus, Fac Hlth Sci, Aarhus, Denmark

[37] Sahlgrens Acad, Lundberg Lab Diabet Res, Dept Mol & Clin Med, Gothenburg, Sweden

[38] Inst Child Hlth & Dev, Charles Bronfman Inst Personalized Med, Mt Sinai Sch Med, Dept Prevent Med, New York, NY USA

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

[40] Churchill Hosp, Oxford Natl Inst Hlth Res Biomed Res Ctr, Oxford OX3 7LJ, England

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

[42] Boston Univ, Sch Med, Boston, MA 02118 USA

[43] Framingham Heart Dis Epidemiol Study, Framingham, MA USA

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

[45] Natl Inst Hlth & Welf, Diabetes Prevent Unit, Helsinki, Finland

[46] King Abdulaziz Univ, Jeddah 21413, Saudi Arabia

[47] Hosp Univ La Paz, Red RECAVA Grp RD06 0014 0015, Madrid, Spain

[48] Danube Univ Krems, Ctr Vasc Prevent, Krems, Austria

[49] Turku Univ Hosp, Dept Med, FIN-20520 Turku, Finland

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

来源：

DIABETES | 2013年 / 62卷 / 10期

关键词：

MOLECULAR-WEIGHT ADIPONECTIN; GREATER-THAN-G; PLASMA ADIPONECTIN; ASSOCIATION ANALYSES; GENETIC-VARIANTS; SUPPRESSION TEST; GLYCEMIC TRAITS; ADIPOSE-TISSUE; POLYMORPHISMS; OBESITY;

D O I：

10.2337/db13-0128

中图分类号：

R5 [内科学];

学科分类号：

100201 [内科学];

摘要：

Adiponectin is strongly inversely associated with insulin resistance and type 2 diabetes, but its causal role remains controversial. We used a Mendelian randomization approach to test the hypothesis that adiponectin causally influences insulin resistance and type 2 diabetes. We used genetic variants at the ADIPOQ gene as instruments to calculate a regression slope between adiponectin levels and metabolic traits (up to 31,000 individuals) and a combination of instrumental variables and summary statistics-based genetic risk scores to test the associations with gold-standard measures of insulin sensitivity (2,969 individuals) and type 2 diabetes (15,960 case subjects and 64,731 control subjects). In conventional regression analyses, a 1-SD decrease in adiponectin levels was correlated with a 0.31-SD (95% CI 0.26-0.35) increase in fasting insulin, a 0.34-SD (0.30-0.38) decrease in insulin sensitivity, and a type 2 diabetes odds ratio (OR) of 1.75 (1.47-2.13). The instrumental variable analysis revealed no evidence of a causal association between genetically lower circulating adiponectin and higher fasting insulin (0.02 SD; 95% CI -0.07 to 0.11; N = 29,771), nominal evidence of a causal relationship with lower insulin sensitivity (-0.20 SD; 95% CI -0.38 to -0.02; N = 1,860), and no evidence of a relationship with type 2 diabetes (OR 0.94; 95% CI 0.75-1.19; N = 2,777 case subjects and 13,011 control subjects). Using the ADIPOQ summary statistics genetic risk scores, we found no evidence of an association between adiponectin-lowering alleles and insulin sensitivity (effect per weighted adiponectin-lowering allele: -0.03 SD; 95% CI -0.07 to 0.01; N = 2,969) or type 2 diabetes (OR per weighted adiponectin-lowering allele: 0.99; 95% CI 0.95-1.04; 15,960 case subjects vs. 64,731 control subjects). These results do not provide any consistent evidence that interventions aimed at increasing adiponectin levels will improve insulin sensitivity or risk of type 2 diabetes.

引用

页码：3589 / 3598

页数：10

共 58 条

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Genetic association of adiponectin with type 2 diabetes in Jordanian Arab population [J].