Circulating fetuin - A and risk of type 2 diabetes: A mendelian randomization analysis

Janine Kröger; Karina Meidtner; Norbert Stefan; Marcela Guevara; Nicola D. Kerrison; Eva Ardanaz; Dagfinn Aune; Heiner Boeing; Miren Dorronsoro; Courtney Dow; Guy Fagherazzi; Paul W. Franks; Heinz Freisling; Marc J. Gunter; José María Huerta; Rudolf Kaaks; Timothy J. Key; Kay Tee Khaw; Vittorio Krogh; Tilman Kühn; Francesca Romana Mancini; Amalia Mattiello; Peter M. Nilsson; Anja Olsen; Kim Overvad; Domenico Palli; J. Ramón Quirós; Olov Rolandsson; Carlotta Sacerdote; Núria Sala; Elena Salamanca-Fernández; Ivonne Sluijs; Annemieke M.W. Spijkerman; Anne Tjonneland; Konstantinos K. Tsilidis; Rosario Tumino; Yvonne T. Van Der Schouw; Nita G. Forouhi; Stephen J. Sharp; Claudia Langenberg; Elio Riboli; Matthias B. Schulze; Nicholas J. Wareham

doi:10.2337/db17-1268

Circulating fetuin - A and risk of type 2 diabetes: A mendelian randomization analysis

Janine Kröger, Karina Meidtner, Norbert Stefan, Marcela Guevara, Nicola D. Kerrison, Eva Ardanaz, Dagfinn Aune, Heiner Boeing, Miren Dorronsoro, Courtney Dow, Guy Fagherazzi, Paul W. Franks, Heinz Freisling, Marc J. Gunter, José María Huerta, Rudolf Kaaks, Timothy J. Key, Kay Tee Khaw, Vittorio Krogh, Tilman KühnFrancesca Romana Mancini, Amalia Mattiello, Peter M. Nilsson, Anja Olsen, Kim Overvad, Domenico Palli, J. Ramón Quirós, Olov Rolandsson, Carlotta Sacerdote, Núria Sala, Elena Salamanca-Fernández, Ivonne Sluijs, Annemieke M.W. Spijkerman, Anne Tjonneland, Konstantinos K. Tsilidis, Rosario Tumino, Yvonne T. Van Der Schouw, Nita G. Forouhi, Stephen J. Sharp, Claudia Langenberg, Elio Riboli, Matthias B. Schulze^*, Nicholas J. Wareham

^*Corresponding author for this work

Research output: Contribution to journal › Article › Research › peer-review

16 Citations (Scopus)

Abstract

Fetuin-A, a hepatic-origin protein, is strongly positively associated with risk of type 2 diabetes in human observational studies, but it is unknown whether this association is causal. We aimed to study the potential causal relation of circulating fetuin-A to risk of type 2 diabetes in a Mendelian randomization study with single nucleotide polymorphisms located in the fetuin-A–encoding AHSG gene. We used data from eight European countries of the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study including 10,020 incident cases. Plasma fetuin-A concentration was measured in a subset of 965 subcohort participants and 654 case subjects. A genetic score of the AHSG single nucleotide polymorphisms was strongly associated with fetuin-A (28% explained variation). Using the genetic score as instrumental variable of fetuin-A, we observed no significant association of a 50 mg/mL higher fetuin-A concentration with diabetes risk (hazard ratio 1.02 [95% CI 0.97, 1.07]). Combining our results with those from the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium (12,171 case subjects) also did not suggest a clear significant relation of fetuin-A with diabetes risk. In conclusion, although there is mechanistic evidence for an effect of fetuin-A on insulin sensitivity and secretion, this study does not support a strong, relevant relationship between circulating fetuin-A and diabetes risk in the general population.

Original language	English
Pages (from-to)	1200-1205
Number of pages	6
Journal	Diabetes
Volume	67
Issue number	6
DOIs	https://doi.org/10.2337/db17-1268
Publication status	Published - 1 Jun 2018
Externally published	Yes

Access to Document

10.2337/db17-1268

Cite this

Kröger, J., Meidtner, K., Stefan, N., Guevara, M., Kerrison, N. D., Ardanaz, E., Aune, D., Boeing, H., Dorronsoro, M., Dow, C., Fagherazzi, G., Franks, P. W., Freisling, H., Gunter, M. J., Huerta, J. M., Kaaks, R., Key, T. J., Khaw, K. T., Krogh, V., ... Wareham, N. J. (2018). Circulating fetuin - A and risk of type 2 diabetes: A mendelian randomization analysis. Diabetes, 67(6), 1200-1205. https://doi.org/10.2337/db17-1268

@article{8a1ad12cdbcc4053a0a7e6f7e078747f,

title = "Circulating fetuin - A and risk of type 2 diabetes: A mendelian randomization analysis",

abstract = "Fetuin-A, a hepatic-origin protein, is strongly positively associated with risk of type 2 diabetes in human observational studies, but it is unknown whether this association is causal. We aimed to study the potential causal relation of circulating fetuin-A to risk of type 2 diabetes in a Mendelian randomization study with single nucleotide polymorphisms located in the fetuin-A–encoding AHSG gene. We used data from eight European countries of the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study including 10,020 incident cases. Plasma fetuin-A concentration was measured in a subset of 965 subcohort participants and 654 case subjects. A genetic score of the AHSG single nucleotide polymorphisms was strongly associated with fetuin-A (28% explained variation). Using the genetic score as instrumental variable of fetuin-A, we observed no significant association of a 50 mg/mL higher fetuin-A concentration with diabetes risk (hazard ratio 1.02 [95% CI 0.97, 1.07]). Combining our results with those from the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium (12,171 case subjects) also did not suggest a clear significant relation of fetuin-A with diabetes risk. In conclusion, although there is mechanistic evidence for an effect of fetuin-A on insulin sensitivity and secretion, this study does not support a strong, relevant relationship between circulating fetuin-A and diabetes risk in the general population.",

author = "Janine Kr{\"o}ger and Karina Meidtner and Norbert Stefan and Marcela Guevara and Kerrison, {Nicola D.} and Eva Ardanaz and Dagfinn Aune and Heiner Boeing and Miren Dorronsoro and Courtney Dow and Guy Fagherazzi and Franks, {Paul W.} and Heinz Freisling and Gunter, {Marc J.} and Huerta, {Jos{\'e} Mar{\'i}a} and Rudolf Kaaks and Key, {Timothy J.} and Khaw, {Kay Tee} and Vittorio Krogh and Tilman K{\"u}hn and Mancini, {Francesca Romana} and Amalia Mattiello and Nilsson, {Peter M.} and Anja Olsen and Kim Overvad and Domenico Palli and Quir{\'o}s, {J. Ram{\'o}n} and Olov Rolandsson and Carlotta Sacerdote and N{\'u}ria Sala and Elena Salamanca-Fern{\'a}ndez and Ivonne Sluijs and Spijkerman, {Annemieke M.W.} and Anne Tjonneland and Tsilidis, {Konstantinos K.} and Rosario Tumino and {Van Der Schouw}, {Yvonne T.} and Forouhi, {Nita G.} and Sharp, {Stephen J.} and Claudia Langenberg and Elio Riboli and Schulze, {Matthias B.} and Wareham, {Nicholas J.}",

note = "Funding Information: EPIC-InterAct project was provided by the European Union Sixth Framework Programme (grant number LSHM_CT_2006_037197). In addition, InterAct investigators acknowledge funding from the following agencies: K.M. and M.B.S. are supported by a grant from the German Federal Ministry of Education and Research (BMBF) to the German Center for Diabetes Research (DZD) and the State of Brandenburg. M.G. is supported by the Regional Government of Navarre. M.G., E.A., and E.S.-F. are supported by Instituto de Salud Carlos III (PIE14/00045). E.A. is supported by Health Research Fund (FIS) of the Spanish Ministry of Health and Navarre Regional Government. P.W.F. is supported by the Swedish Research Council, Novo Nordisk, Swedish Diabetes Association, and Swedish Heart-Lung Foundation. J.M.H. is supported by the Health Research Fund of the Spanish Ministry of Health, Murcia Regional Government (N? 6236). R.K. is supported by German Cancer Aid and BMBF. T.J.K. is supported by Cancer Research UK (C8221/A19170) and the Medical Research Council (MR/M012190/1). K.T.K. is supported by the Medical Research Council and Cancer Research UK. T.K. is supported by German Cancer Aid, German Cancer Research Center (DKFZ), and BMBF. P.M.N. is supported by the Swedish Research Council, K.O. by the Danish Cancer Society, J.R.Q. by the Regional Government of Asturias, and O.R. by the V?sterboten County Council. N.Sa. is supported by the Spanish Ministry of Health network RTICCC (ISCIII RD12/0036/0018), cofunded by FEDER funds/European Regional Development Fund (ERDF), ?a way to build Europe,? and Generalitat de Catalunya (AGAUR 2014SGR726). I.S. is supported by the Dutch Ministry of Health, Welfare and Sport (VWS); Netherlands Cancer Registry (NKR); LK Research Funds; Dutch Prevention Funds; Dutch ZON (Zorg Onderzoek Nederland); World Cancer Research Fund (WCRF); and Statistics Netherlands. Verification of diabetes cases in EPIC-Netherlands (NL) was additionally funded by NL Agency grant IGE05012 and an Incentive Grant from the Board of the University Medical Center Utrecht. A.M.W.S. and Y.T.v.d.S.: EPIC Bilthoven and Utrecht acknowledge the VWS, NKR, LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), WCRF, and Statistics Netherlands. A.T. is supported by the Danish Cancer Society. R.T.: EPIC-Ragusa acknowledges funding from the Sicilian Regional Government and L?Associazione Iblea per la Ricerca Epidemiologica?Un?organizzazione Non Lucrativa di Utilit? Sociale. E.R. is supported by Imperial College Biomedical Research Centre. Funding Information: EPIC-InterAct project was provided by the European Union Sixth Framework Programme (grant number LSHM_CT_2006_037197). In addition, InterAct investigators acknowledge funding from the following agencies: K.M. and M.B.S. are supported by a grant from the German Federal Ministry of Education and Research (BMBF) to the German Center for Diabetes Research (DZD) and the State of Brandenburg. M.G. is supported by the Regional Government of Navarre. M.G., E.A., and E.S.-F. are supported by Instituto de Salud Carlos III (PIE14/00045). E.A. is supported by Health Research Fund (FIS) of the Spanish Ministry of Health and Navarre Regional Government. P.W.F. is supported by the Swedish Research Council, Novo Nordisk, Swedish Diabetes Association, and Swedish Heart-Lung Foundation. J.M.H. is supported by the Health Research Fund of the Spanish Ministry of Health, Murcia Regional Government (N° 6236). R.K. is supported by German Cancer Aid and BMBF. T.J.K. is supported by Cancer Research UK (C8221/A19170) and the Medical Research Council (MR/M012190/1). K.T.K. is supported by the Medical Research Council and Cancer Research UK. T.K. is supported by German Cancer Aid, German Cancer Research Center (DKFZ), and BMBF. P.M.N. is supported by the Swedish Research Council, K.O. by the Danish Cancer Society, J.R.Q. by the Regional Government of Asturias, and O.R. by the V{\"a}sterboten County Council. N.Sa. is supported by the Spanish Ministry of Health network RTICCC (ISCIII RD12/0036/0018), cofunded by FEDER funds/European Regional Development Fund (ERDF), “a way to build Europe,” and Generalitat de Catalunya (AGAUR 2014SGR726). I.S. is supported by the Dutch Ministry of Health, Welfare and Sport (VWS); Netherlands Cancer Registry (NKR); LK Research Funds; Dutch Prevention Funds; Dutch ZON (Zorg Onderzoek Nederland); World Cancer Research Fund (WCRF); and Statistics Netherlands. Verification of diabetes cases in EPIC-Netherlands (NL) was additionally funded by NL Agency grant IGE05012 and an Incentive Grant from the Board of the University Medical Center Utrecht. A.M.W.S. and Y.T.v.d.S.: EPIC Bilthoven and Utrecht acknowledge the VWS, NKR, LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), WCRF, and Statistics Netherlands. A.T. is supported by the Danish Cancer Society. R.T.: EPIC-Ragusa acknowledges funding from the Sicilian Regional Government and L{\textquoteright}Associazione Iblea per la Ricerca Epidemiologica–Un{\textquoteright}organizzazione Non Lucrativa di Utilit{\`a} Sociale. E.R. is supported by Imperial College Biomedical Research Centre. Funding Information: Acknowledgments. The authors thank all EPIC participants and staff for their contribution to the study. Funding. Funding for the EPIC-InterAct project was provided by the European Union Sixth Framework Programme (grant number LSHM_CT_2006_037197). In addition, InterAct investigators acknowledge funding from the following agencies: K.M. and M.B.S. are supported by a grant from the German Federal Ministry of Education and Research (BMBF) to the German Center for Diabetes Research (DZD) and the State of Brandenburg. M.G. is supported by the Regional Government of Navarre. M.G., E.A., and E.S.-F. are supported by Instituto de Salud Carlos III (PIE14/00045). E.A. is supported by Health Research Fund (FIS) of the Spanish Ministry of Health and Navarre Regional Government. P.W.F. is supported by the Swedish Research Council, Novo Nordisk, Swedish Diabetes Association, and Swedish Heart-Lung Foundation. J.M.H. is supported by the Health Research Fund of the Spanish Ministry of Health, Murcia Regional Government (N° 6236). R.K. is supported by German Cancer Aid and BMBF. T.J.K. is supported by Cancer Research UK (C8221/A19170) and the Medical Research Council (MR/M012190/1). K.T.K. is supported by the Medical Research Council and Cancer Research UK. T.K. is supported by German Cancer Aid, German Cancer Research Center (DKFZ), and BMBF. P.M.N. is supported by the Swedish Research Council, K.O. by the Danish Cancer Society, J.R.Q. by the Regional Government of Asturias, and O.R. by the V{\"a}sterboten County Council. N.Sa. is supported by the Spanish Ministry of Health network RTICCC (ISCIII RD12/0036/0018), cofunded by FEDER funds/European Regional Development Fund (ERDF), “a way to build Europe,” and Generalitat de Catalunya (AGAUR 2014SGR726). I.S. is supported by the Dutch Ministry of Health, Welfare and Sport (VWS); Netherlands Cancer Registry (NKR); LK Research Funds; Dutch Prevention Funds; Dutch ZON (Zorg Onderzoek Nederland); World Cancer Research Fund (WCRF); and Statistics Netherlands. Verification of diabetes cases in EPIC-Netherlands (NL) was additionally funded by NL Agency grant IGE05012 and an Incentive Grant from the Board of the University Medical Center Utrecht. A.M.W.S. and Y.T.v.d.S.: EPIC Bilthoven and Utrecht acknowledge the VWS, NKR, LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), WCRF, and Statistics Netherlands. A.T. is supported by the Danish Cancer Society. R.T.: EPIC-Ragusa acknowledges funding from the Sicilian Regional Government and L{\textquoteright}Associazione Iblea per la Ricerca Epidemiologica–Un{\textquoteright}organizzazione Non Lucrativa di Utilit{\`a} Sociale. E.R. is supported by Imperial College Biomedical Research Centre. Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. J.K. analyzed the data and drafted the manuscript. J.K. and M.B.S. conceptualized the project. K.M. provided support with the statistical analysis. N.St. was responsible for the measurement of fetuin-A. All authors contributed to conception and design, interpretation of data, revising the article critically for important intellectual content, and final approval of the version to be published. J.K. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Prior Presentation. Parts of this study were presented in German at the 12th Annual Meeting of the German Society for Epidemiology, L{\"u}beck, Germany, 5–8 September 2017. Publisher Copyright: {\textcopyright} 2018 by the American Diabetes Association.",

year = "2018",

month = jun,

day = "1",

doi = "10.2337/db17-1268",

language = "English",

volume = "67",

pages = "1200--1205",

journal = "Diabetes",

issn = "0012-1797",

publisher = "American Diabetes Association Inc.",

number = "6",

}

Kröger, J, Meidtner, K, Stefan, N, Guevara, M, Kerrison, ND, Ardanaz, E, Aune, D, Boeing, H, Dorronsoro, M, Dow, C, Fagherazzi, G, Franks, PW, Freisling, H, Gunter, MJ, Huerta, JM, Kaaks, R, Key, TJ, Khaw, KT, Krogh, V, Kühn, T, Mancini, FR, Mattiello, A, Nilsson, PM, Olsen, A, Overvad, K, Palli, D, Quirós, JR, Rolandsson, O, Sacerdote, C, Sala, N, Salamanca-Fernández, E, Sluijs, I, Spijkerman, AMW, Tjonneland, A, Tsilidis, KK, Tumino, R, Van Der Schouw, YT, Forouhi, NG, Sharp, SJ, Langenberg, C, Riboli, E, Schulze, MB & Wareham, NJ 2018, 'Circulating fetuin - A and risk of type 2 diabetes: A mendelian randomization analysis', Diabetes, vol. 67, no. 6, pp. 1200-1205. https://doi.org/10.2337/db17-1268

TY - JOUR

T1 - Circulating fetuin - A and risk of type 2 diabetes

T2 - A mendelian randomization analysis

AU - Kröger, Janine

AU - Meidtner, Karina

AU - Stefan, Norbert

AU - Guevara, Marcela

AU - Kerrison, Nicola D.

AU - Ardanaz, Eva

AU - Aune, Dagfinn

AU - Boeing, Heiner

AU - Dorronsoro, Miren

AU - Dow, Courtney

AU - Fagherazzi, Guy

AU - Franks, Paul W.

AU - Freisling, Heinz

AU - Gunter, Marc J.

AU - Huerta, José María

AU - Kaaks, Rudolf

AU - Key, Timothy J.

AU - Khaw, Kay Tee

AU - Krogh, Vittorio

AU - Kühn, Tilman

AU - Mancini, Francesca Romana

AU - Mattiello, Amalia

AU - Nilsson, Peter M.

AU - Olsen, Anja

AU - Overvad, Kim

AU - Palli, Domenico

AU - Quirós, J. Ramón

AU - Rolandsson, Olov

AU - Sacerdote, Carlotta

AU - Sala, Núria

AU - Salamanca-Fernández, Elena

AU - Sluijs, Ivonne

AU - Spijkerman, Annemieke M.W.

AU - Tjonneland, Anne

AU - Tsilidis, Konstantinos K.

AU - Tumino, Rosario

AU - Van Der Schouw, Yvonne T.

AU - Forouhi, Nita G.

AU - Sharp, Stephen J.

AU - Langenberg, Claudia

AU - Riboli, Elio

AU - Schulze, Matthias B.

AU - Wareham, Nicholas J.

N1 - Funding Information: EPIC-InterAct project was provided by the European Union Sixth Framework Programme (grant number LSHM_CT_2006_037197). In addition, InterAct investigators acknowledge funding from the following agencies: K.M. and M.B.S. are supported by a grant from the German Federal Ministry of Education and Research (BMBF) to the German Center for Diabetes Research (DZD) and the State of Brandenburg. M.G. is supported by the Regional Government of Navarre. M.G., E.A., and E.S.-F. are supported by Instituto de Salud Carlos III (PIE14/00045). E.A. is supported by Health Research Fund (FIS) of the Spanish Ministry of Health and Navarre Regional Government. P.W.F. is supported by the Swedish Research Council, Novo Nordisk, Swedish Diabetes Association, and Swedish Heart-Lung Foundation. J.M.H. is supported by the Health Research Fund of the Spanish Ministry of Health, Murcia Regional Government (N? 6236). R.K. is supported by German Cancer Aid and BMBF. T.J.K. is supported by Cancer Research UK (C8221/A19170) and the Medical Research Council (MR/M012190/1). K.T.K. is supported by the Medical Research Council and Cancer Research UK. T.K. is supported by German Cancer Aid, German Cancer Research Center (DKFZ), and BMBF. P.M.N. is supported by the Swedish Research Council, K.O. by the Danish Cancer Society, J.R.Q. by the Regional Government of Asturias, and O.R. by the V?sterboten County Council. N.Sa. is supported by the Spanish Ministry of Health network RTICCC (ISCIII RD12/0036/0018), cofunded by FEDER funds/European Regional Development Fund (ERDF), ?a way to build Europe,? and Generalitat de Catalunya (AGAUR 2014SGR726). I.S. is supported by the Dutch Ministry of Health, Welfare and Sport (VWS); Netherlands Cancer Registry (NKR); LK Research Funds; Dutch Prevention Funds; Dutch ZON (Zorg Onderzoek Nederland); World Cancer Research Fund (WCRF); and Statistics Netherlands. Verification of diabetes cases in EPIC-Netherlands (NL) was additionally funded by NL Agency grant IGE05012 and an Incentive Grant from the Board of the University Medical Center Utrecht. A.M.W.S. and Y.T.v.d.S.: EPIC Bilthoven and Utrecht acknowledge the VWS, NKR, LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), WCRF, and Statistics Netherlands. A.T. is supported by the Danish Cancer Society. R.T.: EPIC-Ragusa acknowledges funding from the Sicilian Regional Government and L?Associazione Iblea per la Ricerca Epidemiologica?Un?organizzazione Non Lucrativa di Utilit? Sociale. E.R. is supported by Imperial College Biomedical Research Centre. Funding Information: EPIC-InterAct project was provided by the European Union Sixth Framework Programme (grant number LSHM_CT_2006_037197). In addition, InterAct investigators acknowledge funding from the following agencies: K.M. and M.B.S. are supported by a grant from the German Federal Ministry of Education and Research (BMBF) to the German Center for Diabetes Research (DZD) and the State of Brandenburg. M.G. is supported by the Regional Government of Navarre. M.G., E.A., and E.S.-F. are supported by Instituto de Salud Carlos III (PIE14/00045). E.A. is supported by Health Research Fund (FIS) of the Spanish Ministry of Health and Navarre Regional Government. P.W.F. is supported by the Swedish Research Council, Novo Nordisk, Swedish Diabetes Association, and Swedish Heart-Lung Foundation. J.M.H. is supported by the Health Research Fund of the Spanish Ministry of Health, Murcia Regional Government (N° 6236). R.K. is supported by German Cancer Aid and BMBF. T.J.K. is supported by Cancer Research UK (C8221/A19170) and the Medical Research Council (MR/M012190/1). K.T.K. is supported by the Medical Research Council and Cancer Research UK. T.K. is supported by German Cancer Aid, German Cancer Research Center (DKFZ), and BMBF. P.M.N. is supported by the Swedish Research Council, K.O. by the Danish Cancer Society, J.R.Q. by the Regional Government of Asturias, and O.R. by the Västerboten County Council. N.Sa. is supported by the Spanish Ministry of Health network RTICCC (ISCIII RD12/0036/0018), cofunded by FEDER funds/European Regional Development Fund (ERDF), “a way to build Europe,” and Generalitat de Catalunya (AGAUR 2014SGR726). I.S. is supported by the Dutch Ministry of Health, Welfare and Sport (VWS); Netherlands Cancer Registry (NKR); LK Research Funds; Dutch Prevention Funds; Dutch ZON (Zorg Onderzoek Nederland); World Cancer Research Fund (WCRF); and Statistics Netherlands. Verification of diabetes cases in EPIC-Netherlands (NL) was additionally funded by NL Agency grant IGE05012 and an Incentive Grant from the Board of the University Medical Center Utrecht. A.M.W.S. and Y.T.v.d.S.: EPIC Bilthoven and Utrecht acknowledge the VWS, NKR, LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), WCRF, and Statistics Netherlands. A.T. is supported by the Danish Cancer Society. R.T.: EPIC-Ragusa acknowledges funding from the Sicilian Regional Government and L’Associazione Iblea per la Ricerca Epidemiologica–Un’organizzazione Non Lucrativa di Utilità Sociale. E.R. is supported by Imperial College Biomedical Research Centre. Funding Information: Acknowledgments. The authors thank all EPIC participants and staff for their contribution to the study. Funding. Funding for the EPIC-InterAct project was provided by the European Union Sixth Framework Programme (grant number LSHM_CT_2006_037197). In addition, InterAct investigators acknowledge funding from the following agencies: K.M. and M.B.S. are supported by a grant from the German Federal Ministry of Education and Research (BMBF) to the German Center for Diabetes Research (DZD) and the State of Brandenburg. M.G. is supported by the Regional Government of Navarre. M.G., E.A., and E.S.-F. are supported by Instituto de Salud Carlos III (PIE14/00045). E.A. is supported by Health Research Fund (FIS) of the Spanish Ministry of Health and Navarre Regional Government. P.W.F. is supported by the Swedish Research Council, Novo Nordisk, Swedish Diabetes Association, and Swedish Heart-Lung Foundation. J.M.H. is supported by the Health Research Fund of the Spanish Ministry of Health, Murcia Regional Government (N° 6236). R.K. is supported by German Cancer Aid and BMBF. T.J.K. is supported by Cancer Research UK (C8221/A19170) and the Medical Research Council (MR/M012190/1). K.T.K. is supported by the Medical Research Council and Cancer Research UK. T.K. is supported by German Cancer Aid, German Cancer Research Center (DKFZ), and BMBF. P.M.N. is supported by the Swedish Research Council, K.O. by the Danish Cancer Society, J.R.Q. by the Regional Government of Asturias, and O.R. by the Västerboten County Council. N.Sa. is supported by the Spanish Ministry of Health network RTICCC (ISCIII RD12/0036/0018), cofunded by FEDER funds/European Regional Development Fund (ERDF), “a way to build Europe,” and Generalitat de Catalunya (AGAUR 2014SGR726). I.S. is supported by the Dutch Ministry of Health, Welfare and Sport (VWS); Netherlands Cancer Registry (NKR); LK Research Funds; Dutch Prevention Funds; Dutch ZON (Zorg Onderzoek Nederland); World Cancer Research Fund (WCRF); and Statistics Netherlands. Verification of diabetes cases in EPIC-Netherlands (NL) was additionally funded by NL Agency grant IGE05012 and an Incentive Grant from the Board of the University Medical Center Utrecht. A.M.W.S. and Y.T.v.d.S.: EPIC Bilthoven and Utrecht acknowledge the VWS, NKR, LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), WCRF, and Statistics Netherlands. A.T. is supported by the Danish Cancer Society. R.T.: EPIC-Ragusa acknowledges funding from the Sicilian Regional Government and L’Associazione Iblea per la Ricerca Epidemiologica–Un’organizzazione Non Lucrativa di Utilità Sociale. E.R. is supported by Imperial College Biomedical Research Centre. Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. J.K. analyzed the data and drafted the manuscript. J.K. and M.B.S. conceptualized the project. K.M. provided support with the statistical analysis. N.St. was responsible for the measurement of fetuin-A. All authors contributed to conception and design, interpretation of data, revising the article critically for important intellectual content, and final approval of the version to be published. J.K. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Prior Presentation. Parts of this study were presented in German at the 12th Annual Meeting of the German Society for Epidemiology, Lübeck, Germany, 5–8 September 2017. Publisher Copyright: © 2018 by the American Diabetes Association.

PY - 2018/6/1

Y1 - 2018/6/1

N2 - Fetuin-A, a hepatic-origin protein, is strongly positively associated with risk of type 2 diabetes in human observational studies, but it is unknown whether this association is causal. We aimed to study the potential causal relation of circulating fetuin-A to risk of type 2 diabetes in a Mendelian randomization study with single nucleotide polymorphisms located in the fetuin-A–encoding AHSG gene. We used data from eight European countries of the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study including 10,020 incident cases. Plasma fetuin-A concentration was measured in a subset of 965 subcohort participants and 654 case subjects. A genetic score of the AHSG single nucleotide polymorphisms was strongly associated with fetuin-A (28% explained variation). Using the genetic score as instrumental variable of fetuin-A, we observed no significant association of a 50 mg/mL higher fetuin-A concentration with diabetes risk (hazard ratio 1.02 [95% CI 0.97, 1.07]). Combining our results with those from the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium (12,171 case subjects) also did not suggest a clear significant relation of fetuin-A with diabetes risk. In conclusion, although there is mechanistic evidence for an effect of fetuin-A on insulin sensitivity and secretion, this study does not support a strong, relevant relationship between circulating fetuin-A and diabetes risk in the general population.

AB - Fetuin-A, a hepatic-origin protein, is strongly positively associated with risk of type 2 diabetes in human observational studies, but it is unknown whether this association is causal. We aimed to study the potential causal relation of circulating fetuin-A to risk of type 2 diabetes in a Mendelian randomization study with single nucleotide polymorphisms located in the fetuin-A–encoding AHSG gene. We used data from eight European countries of the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study including 10,020 incident cases. Plasma fetuin-A concentration was measured in a subset of 965 subcohort participants and 654 case subjects. A genetic score of the AHSG single nucleotide polymorphisms was strongly associated with fetuin-A (28% explained variation). Using the genetic score as instrumental variable of fetuin-A, we observed no significant association of a 50 mg/mL higher fetuin-A concentration with diabetes risk (hazard ratio 1.02 [95% CI 0.97, 1.07]). Combining our results with those from the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium (12,171 case subjects) also did not suggest a clear significant relation of fetuin-A with diabetes risk. In conclusion, although there is mechanistic evidence for an effect of fetuin-A on insulin sensitivity and secretion, this study does not support a strong, relevant relationship between circulating fetuin-A and diabetes risk in the general population.

UR - http://www.scopus.com/inward/record.url?scp=85047763125&partnerID=8YFLogxK

U2 - 10.2337/db17-1268

DO - 10.2337/db17-1268

M3 - Article

C2 - 29523632

AN - SCOPUS:85047763125

SN - 0012-1797

VL - 67

SP - 1200

EP - 1205

JO - Diabetes

JF - Diabetes

IS - 6

ER -

Circulating fetuin - A and risk of type 2 diabetes: A mendelian randomization analysis

Abstract

Access to Document

Other files and links

Fingerprint

Cite this