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

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

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Title

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

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Diabetes 2018; 67(6):1200-5

Publiekssamenvatting

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 SNPs located in the fetuin-A-encodingAHSGgene. We used data from eight European countries of the prospective 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 cases. A genetic score of theAHSGSNPs 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 (HR 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 cases) also did not suggest a clear significant relation of fetuin-A with diabetes risk. In conclusion, although there is mechanistical evidence for an effect of fetuin-A on insulin sensitivity and secretion, this study doesn't support a strong, relevant relationship between circulating fetuin-A and diabetes risk in the general population.