Circulating Fetuin-A and Risk of Type 2 Diabetes: A Mendelian Randomization Analysis

J. Kroger; K. Meidtner; N. Stefan; M. Guevara; N. D. Kerrison; E. Ardanaz; D. Aune; H. Boeing; M. Dorronsoro; C. Dow; G. Fagherazzi; P. W. Franks; H. Freisling; M. J. Gunter; J. M. Huerta; R. Kaaks; T. J. Key; K. T. Khaw; V. Krogh; T. Kuhn; F. R. Mancini; A. Mattiello; P. M. Nilsson; A. Olsen; K. Overvad; D. Palli; J. R. Quiros; O. Rolandsson; C. Sacerdote; N. Sala; E. Salamanca-Fernandez; I. Sluijs; A. M. W. Spijkerman; A. Tjonneland; K. K. Tsilidis; R. Tumino; Y. T. van der Schouw; N. G. Forouhi; S. J. Sharp; C. Langenberg; E. Riboli; M. B. Schulze; N. J. Wareham

doi:10.2337/db17-1268

Circulating Fetuin-A and Risk of Type 2 Diabetes: A Mendelian Randomization Analysis

J. Kroger, K. Meidtner, N. Stefan, M. Guevara, N. D. Kerrison, E. Ardanaz, D. Aune, H. Boeing, M. Dorronsoro, C. Dow, G. Fagherazzi, P. W. Franks, H. Freisling, M. J. Gunter, J. M. Huerta, R. Kaaks, T. J. Key, K. T. Khaw, V. Krogh, T. KuhnF. R. Mancini, A. Mattiello, P. M. Nilsson, A. Olsen, K. Overvad, D. Palli, J. R. Quiros, O. Rolandsson, C. Sacerdote, N. Sala, E. Salamanca-Fernandez, I. Sluijs, A. M. W. Spijkerman, A. Tjonneland, K. K. Tsilidis, R. Tumino, Y. T. van der Schouw, N. G. Forouhi, S. J. Sharp, C. Langenberg, E. Riboli, M. B. Schulze, N. J. Wareham

School of Biological Sciences

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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 µg/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
Journal	Diabetes
Volume	67
Issue number	6
DOIs	https://doi.org/10.2337/db17-1268
Publication status	Published - 01 Jun 2018

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Kroger, 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{afccaf8971e841ccbdd1af86b2cb7f7a,

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 µg/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 = "J. Kroger and K. Meidtner and N. Stefan and M. Guevara and Kerrison, {N. D.} and E. Ardanaz and D. Aune and H. Boeing and M. Dorronsoro and C. Dow and G. Fagherazzi and Franks, {P. W.} and H. Freisling and Gunter, {M. J.} and Huerta, {J. M.} and R. Kaaks and Key, {T. J.} and Khaw, {K. T.} and V. Krogh and T. Kuhn and Mancini, {F. R.} and A. Mattiello and Nilsson, {P. M.} and A. Olsen and K. Overvad and D. Palli and Quiros, {J. R.} and O. Rolandsson and C. Sacerdote and N. Sala and E. Salamanca-Fernandez and I. Sluijs and Spijkerman, {A. M. W.} and A. Tjonneland and Tsilidis, {K. K.} and R. Tumino and {van der Schouw}, {Y. T.} and Forouhi, {N. G.} and Sharp, {S. J.} and C. Langenberg and E. Riboli and Schulze, {M. B.} and Wareham, {N. J.}",

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",

}

Kroger, 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, Kuhn, T, Mancini, FR, Mattiello, A, Nilsson, PM, Olsen, A, Overvad, K, Palli, D, Quiros, JR, Rolandsson, O, Sacerdote, C, Sala, N, Salamanca-Fernandez, 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: A Mendelian Randomization Analysis

AU - Kroger, J.

AU - Meidtner, K.

AU - Stefan, N.

AU - Guevara, M.

AU - Kerrison, N. D.

AU - Ardanaz, E.

AU - Aune, D.

AU - Boeing, H.

AU - Dorronsoro, M.

AU - Dow, C.

AU - Fagherazzi, G.

AU - Franks, P. W.

AU - Freisling, H.

AU - Gunter, M. J.

AU - Huerta, J. M.

AU - Kaaks, R.

AU - Key, T. J.

AU - Khaw, K. T.

AU - Krogh, V.

AU - Kuhn, T.

AU - Mancini, F. R.

AU - Mattiello, A.

AU - Nilsson, P. M.

AU - Olsen, A.

AU - Overvad, K.

AU - Palli, D.

AU - Quiros, J. R.

AU - Rolandsson, O.

AU - Sacerdote, C.

AU - Sala, N.

AU - Salamanca-Fernandez, E.

AU - Sluijs, I.

AU - Spijkerman, A. M. W.

AU - Tjonneland, A.

AU - Tsilidis, K. K.

AU - Tumino, R.

AU - van der Schouw, Y. T.

AU - Forouhi, N. G.

AU - Sharp, S. J.

AU - Langenberg, C.

AU - Riboli, E.

AU - Schulze, M. B.

AU - Wareham, N. 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 µg/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 µg/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.

U2 - 10.2337/db17-1268

DO - 10.2337/db17-1268

M3 - Article

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

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