Kröger, JanineMeidtner, KarinaStefan, NorbertGuevara, MarcelaKerrison, Nicola DArdanaz, EvaAune, DagfinnBoeing, HeinerDorronsoro, MirenDow, CourtneyFagherazzi, GuyFranks, Paul WFreisling, HeinzGunter, Marc JHuerta, José MaríaKaaks, RudolfKey, Timothy JKhaw, Kay TeeKrogh, VittorioKühn, TilmanMancini, Francesca RomanaMattiello, AmaliaNilsson, Peter MOlsen, AnjaOvervad, KimPalli, DomenicoQuirós, J RamónRolandsson, OlovSacerdote, CarlottaSala, NúriaSalamanca-Fernández, ElenaSluijs, IvonneSpijkerman, Annemieke M WTjonneland, AnneTsilidis, Konstantinos KTumino, Rosariovan der Schouw, Yvonne TForouhi, Nita GSharp, Stephen JLangenberg, ClaudiaRiboli, ElioSchulze, Matthias BWareham, Nicholas J2023-01-252023-01-252018-03-09http://hdl.handle.net/10668/12223Fetuin-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.enAdultAgedBiomarkersCase-Control StudiesCohort StudiesDiabetes Mellitus, Type 2Enzyme-Linked Immunosorbent AssayEuropeFemaleGenetic Association StudiesGermanyHumansImmunoturbidimetryIncidenceMaleMendelian Randomization AnalysisMiddle AgedPolymorphism, Single NucleotideProspective StudiesReproducibility of ResultsRiskalpha-2-HS-Glycoproteinresearch article29523632open access10.2337/db17-12681939-327XPMC6278908https://europepmc.org/articles/pmc6278908?pdf=renderhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278908/pdf