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

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 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 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.

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References

Mathews S, Rakhade S, Zhou X, Parker G, Coscina D, Grunberger G . Fetuin-null mice are protected against obesity and insulin resistance associated with aging. Biochem Biophys Res Commun. 2006; 350(2):437-43. DOI: 10.1016/j.bbrc.2006.09.071. View

Stefan N, Fritsche A, Weikert C, Boeing H, Joost H, Haring H . Plasma fetuin-A levels and the risk of type 2 diabetes. Diabetes. 2008; 57(10):2762-7. PMC: 2551687. DOI: 10.2337/db08-0538. View

Denecke B, Graber S, Schafer C, Heiss A, Woltje M, Jahnen-Dechent W . Tissue distribution and activity testing suggest a similar but not identical function of fetuin-B and fetuin-A. Biochem J. 2003; 376(Pt 1):135-45. PMC: 1223762. DOI: 10.1042/BJ20030676. View

Riboli E, Hunt K, Slimani N, Ferrari P, Norat T, Fahey M . European Prospective Investigation into Cancer and Nutrition (EPIC): study populations and data collection. Public Health Nutr. 2003; 5(6B):1113-24. DOI: 10.1079/PHN2002394. View

Fisher E, Stefan N, Saar K, Drogan D, Schulze M, Fritsche A . Association of AHSG gene polymorphisms with fetuin-A plasma levels and cardiovascular diseases in the EPIC-Potsdam study. Circ Cardiovasc Genet. 2009; 2(6):607-13. DOI: 10.1161/CIRCGENETICS.109.870410. View

Pal D, Dasgupta S, Kundu R, Maitra S, Das G, Mukhopadhyay S . Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance. Nat Med. 2012; 18(8):1279-85. DOI: 10.1038/nm.2851. View

Haftenberger M, Schuit A, Tormo M, Boeing H, Wareham N, Bueno-de-Mesquita H . Physical activity of subjects aged 50-64 years involved in the European Prospective Investigation into Cancer and Nutrition (EPIC). Public Health Nutr. 2003; 5(6B):1163-76. DOI: 10.1079/PHN2002397. View

Roshanzamir F, Miraghajani M, Rouhani M, Mansourian M, Ghiasvand R, Safavi S . The association between circulating fetuin-A levels and type 2 diabetes mellitus risk: systematic review and meta-analysis of observational studies. J Endocrinol Invest. 2017; 41(1):33-47. DOI: 10.1007/s40618-017-0697-8. View

Jensen M, Jensen R, Mukamal K, Guo X, Yao J, Sun Q . Detection of genetic loci associated with plasma fetuin-A: a meta-analysis of genome-wide association studies from the CHARGE Consortium. Hum Mol Genet. 2017; 26(11):2156-2163. PMC: 6075215. DOI: 10.1093/hmg/ddx091. View

10.

Laughlin G, Barrett-Connor E, Cummins K, Daniels L, Wassel C, Ix J . Sex-specific association of fetuin-A with type 2 diabetes in older community-dwelling adults: the Rancho Bernardo study. Diabetes Care. 2013; 36(7):1994-2000. PMC: 3687317. DOI: 10.2337/dc12-1870. View

11.

Stefan N, Haring H . Circulating fetuin-A and free fatty acids interact to predict insulin resistance in humans. Nat Med. 2013; 19(4):394-5. DOI: 10.1038/nm.3116. View

12.

Barlow W, Ichikawa L, ROSNER D, Izumi S . Analysis of case-cohort designs. J Clin Epidemiol. 1999; 52(12):1165-72. DOI: 10.1016/s0895-4356(99)00102-x. View

13.

Stefan N, Hennige A, Staiger H, Machann J, Schick F, Krober S . Alpha2-Heremans-Schmid glycoprotein/fetuin-A is associated with insulin resistance and fat accumulation in the liver in humans. Diabetes Care. 2006; 29(4):853-7. DOI: 10.2337/diacare.29.04.06.dc05-1938. View

14.

Ix J, Biggs M, Mukamal K, Kizer J, Zieman S, Siscovick D . Association of fetuin-a with incident diabetes mellitus in community-living older adults: the cardiovascular health study. Circulation. 2012; 125(19):2316-22. PMC: 3390925. DOI: 10.1161/CIRCULATIONAHA.111.072751. View

15.

Auberger P, Falquerho L, Contreres J, Pages G, Le Cam G, Rossi B . Characterization of a natural inhibitor of the insulin receptor tyrosine kinase: cDNA cloning, purification, and anti-mitogenic activity. Cell. 1989; 58(4):631-40. DOI: 10.1016/0092-8674(89)90098-6. View

16.

Brion M, Shakhbazov K, Visscher P . Calculating statistical power in Mendelian randomization studies. Int J Epidemiol. 2013; 42(5):1497-501. PMC: 3807619. DOI: 10.1093/ije/dyt179. View

17.

Aroner S, Mukamal K, St-Jules D, Budoff M, Katz R, Criqui M . Fetuin-A and Risk of Diabetes Independent of Liver Fat Content: The Multi-Ethnic Study of Atherosclerosis. Am J Epidemiol. 2016; 185(1):54-64. PMC: 5209585. DOI: 10.1093/aje/kww095. View

18.

Langenberg C, Sharp S, Forouhi N, Franks P, Schulze M, Kerrison N . Design and cohort description of the InterAct Project: an examination of the interaction of genetic and lifestyle factors on the incidence of type 2 diabetes in the EPIC Study. Diabetologia. 2011; 54(9):2272-82. PMC: 4222062. DOI: 10.1007/s00125-011-2182-9. View

19.

Jensen M, Bartz T, Djousse L, Kizer J, Zieman S, Rimm E . Genetically elevated fetuin-A levels, fasting glucose levels, and risk of type 2 diabetes: the cardiovascular health study. Diabetes Care. 2013; 36(10):3121-7. PMC: 3781539. DOI: 10.2337/dc12-2323. View

20.

Mathews S, Singh G, Ranalletta M, Cintron V, Qiang X, Goustin A . Improved insulin sensitivity and resistance to weight gain in mice null for the Ahsg gene. Diabetes. 2002; 51(8):2450-8. DOI: 10.2337/diabetes.51.8.2450. View