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 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

^*Corresponding author for this work

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

23 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

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10.2337/db17-1268

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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 = "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.

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 - https://www.scopus.com/pages/publications/85047763125

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

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