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

• Published in: Diabetes (New York, N.Y.) Vol. 67; no. 6; pp. 1200 - 1205
• Main Authors: 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 M.W., 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.
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.06.2018
• Subjects: Adult; Aged; alpha-2-HS-Glycoprotein - analysis; alpha-2-HS-Glycoprotein - genetics; Biomarkers - blood; Cancer; Case-Control Studies; Clinical Medicine; Cohort Studies; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - epidemiology; Endocrinology and Diabetes; Endokrinologi och diabetes; Enzyme-Linked Immunosorbent Assay; Europe - epidemiology; Female; Genetic Association Studies; Genetic diversity; Genomes; Germany - epidemiology; Humans; Immunoturbidimetry; Incidence; Insulin; Kidney diseases; Kidneys; Klinisk medicin; Male; Medical and Health Sciences; Medicin och hälsovetenskap; Mendelian Randomization Analysis; Middle Aged; Nephrology; Peritoneal dialysis; Polymorphism, Single Nucleotide; Prospective Studies; Reproducibility of Results; Risk; Secretion; Single-nucleotide polymorphism; Europe; Germany
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db17-1268

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.