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 Mw 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 Mw 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

Research output: Contribution to journal › Journal article › Research › peer-review

18 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
Journal	Diabetes
Volume	67
Issue number	6
Pages (from-to)	1200-1205
Number of pages	6
ISSN	0012-1797
DOIs	https://doi.org/10.2337/db17-1268
Publication status	Published - 1 Jun 2018

Keywords

Adult
Aged
Biomarkers/blood
Case-Control Studies
Cohort Studies
Diabetes Mellitus, Type 2/blood
Enzyme-Linked Immunosorbent Assay
Europe/epidemiology
Female
Genetic Association Studies
Germany/epidemiology
Humans
Immunoturbidimetry
Incidence
Male
Mendelian Randomization Analysis
Middle Aged
Polymorphism, Single Nucleotide
Prospective Studies
Reproducibility of Results
Risk
alpha-2-HS-Glycoprotein/analysis

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10.2337/db17-1268

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278908/pdf/emss-80720.pdf

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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{9de7054356b64663a09e0ad9e2d2fbff,

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.",

keywords = "Adult, Aged, Biomarkers/blood, Case-Control Studies, Cohort Studies, Diabetes Mellitus, Type 2/blood, Enzyme-Linked Immunosorbent Assay, Europe/epidemiology, Female, Genetic Association Studies, Germany/epidemiology, Humans, Immunoturbidimetry, Incidence, Male, Mendelian Randomization Analysis, Middle Aged, Polymorphism, Single Nucleotide, Prospective Studies, Reproducibility of Results, Risk, alpha-2-HS-Glycoprotein/analysis",

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 Mw} 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}",

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doi = "10.2337/db17-1268",

language = "English",

volume = "67",

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journal = "Diabetes",

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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, AM, 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 Mw

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.

KW - Adult

KW - Aged

KW - Biomarkers/blood

KW - Case-Control Studies

KW - Cohort Studies

KW - Diabetes Mellitus, Type 2/blood

KW - Enzyme-Linked Immunosorbent Assay

KW - Europe/epidemiology

KW - Female

KW - Genetic Association Studies

KW - Germany/epidemiology

KW - Humans

KW - Immunoturbidimetry

KW - Incidence

KW - Male

KW - Mendelian Randomization Analysis

KW - Middle Aged

KW - Polymorphism, Single Nucleotide

KW - Prospective Studies

KW - Reproducibility of Results

KW - Risk

KW - alpha-2-HS-Glycoprotein/analysis

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

U2 - 10.2337/db17-1268

DO - 10.2337/db17-1268

M3 - Journal article

C2 - 29523632

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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