Circulating fetuin - A and risk of type 2 diabetes: A mendelian randomization analysis

Research output: Contribution to journalArticle


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.


  • Janine Kröger
  • Karina Meidtner
  • Norbert Stefan
  • Marcela Guevara
  • Nicola D. Kerrison
  • Eva Ardanaz
  • Dagfinn Aune
  • Heiner Boeing
  • Miren Dorronsoro
  • Courtney Dow
  • Guy Fagherazzi
  • Heinz Freisling
  • Marc J. Gunter
  • José María Huerta
  • Rudolf Kaaks
  • Timothy J. Key
  • Kay Tee Khaw
  • Vittorio Krogh
  • Tilman Kühn
  • Francesca Romana Mancini
  • Amalia Mattiello
  • 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
External organisations
  • German Institute of Human Nutrition
  • University Hospital of Tubingen
  • University of Tübingen
  • Health Research Institute of Navarra (IDISNA)
  • University of Cambridge
  • Imperial College London
  • Bjørknes University College
  • Public Health Division of Gipuzkoa
  • Centre for Research in Epidemiology and Population Health (CESP)
  • Institut Gustave Roussy
  • Umeå University
  • International Agency for Research on Cancer, World Health Organization
  • Murcia Regional Health Council
  • German Cancer Research Centre
  • University of Oxford
  • Istituto Nazionale dei Tumori
  • University of Naples Federico II
  • Danish Cancer Society Research Center
  • Aarhus University
  • Cancer Research and Prevention Institute (ISPO)
  • University of Turin
  • Catalan Institute of Oncology
  • Instituto de Investigación Biosanitaria de Granada (Granada.ibs)
  • University Medical Center Utrecht
  • National Institute for Public Health and the Environment (RIVM)
  • University of Ioannina
  • Azienda Sanitaria Provinciale di Ragusa
  • University of Potsdam
  • German Center for Diabetes Research
  • CIBER Epidemiology and Public Health (CIBERESP)
  • Biodonostia Health Research Institute
  • University of Paris-Saclay
  • Aalborg University Hospital
  • Public Health Directorate
  • Human Genetics Foundation (HuGeF)
  • Andalusian School of Public Health
  • Associazione Iblea per la Ricerca Epidemiologica
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Endocrinology and Diabetes
Original languageEnglish
Pages (from-to)1200-1205
Number of pages6
Issue number6
Publication statusPublished - 2018 Jun 1
Publication categoryResearch