Janine Kroeger, 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, Jose Maria Huerta, Rudolf Kaaks, Timothy J. Key, Kay Tee Khaw, Vittorio Krogh, Tilman Kuehn, Francesca Romana Mancini, Amalia Mattiello, Peter M. Nilsson, Anja Olsen, Kim Overvad, Domenico Palli, J. Ramon Quiros, Olov Rolandsson, Carlotta Sacerdote, Nuria Sala, Elena Salamanca-Fernandez, 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

• 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. Weaimed 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 mu g/mL higher fetuin-A concentration with diabetes risk (hazard ratio 1.02 [95% CI 0.97, 1.07]). Combining our results with thoseFetuin-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. Weaimed 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 mu g/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.…