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 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 journalArticleResearchpeer-review

11 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 languageEnglish
Pages (from-to)1200-1205
Number of pages6
JournalDiabetes
Volume67
Issue number6
DOIs
Publication statusPublished - 1 Jun 2018
Externally publishedYes

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