Fructosamine and glycated albumin are potentially useful alternatives to hemoglobin A1c (HbA1c) as diabetes biomarkers. The genetic determinants of fructosamine and glycated albumin, however, are unknown. We performed genome-wide association studies of fructosamine and glycated albumin among 2,104 black and 7,647 white participants without diabetes in the Atherosclerosis Risk in Communities (ARIC) Study and replicated findings in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Among whites, rs34459162, a novel missense single nucleotide polymorphism (SNP) in RCN3, was associated with fructosamine (P = 5.3 3 1029) and rs1260236, a known diabetes-related missense mutation in GCKR, was associated with percent glycated albumin (P = 5.9 3 1029) and replicated in CARDIA. We also found two novel associations among blacks: an intergenic SNP, rs2438321, associated with fructosamine (P = 6.2 3 1029), and an intronic variant in PRKCA, rs59443763, associated with percent glycated albumin (P = 4.1 3 1029), but these results did not replicate. Few established fasting glucose or HbA1c SNPs were also associated with fructosamine or glycated albumin. Overall, we found genetic variants associated with the glycemic information captured by fructosamine and glycated albumin as well as with their nonglycemic component. This highlights the importance of examining the genetics of hyperglycemia biomarkers to understand the information they capture, including potential glucose-independent factors.
Bibliographical noteFunding Information:
Acknowledgments. This article is dedicated to our dear friend and colleague, Dr. W.H. Linda Kao (1972–2014). We would like to acknowledge Linda’s contributions to the design of the study and early discussions of this work. The authors thank the staff and participants of the ARIC Study for their important contributions. Funding. The ARIC Study has been funded in whole or in part with federal funds from the National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Department of Health and Human Services (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I, and HHSN268201700005I and grant numbers R01HL087641 and R01HL086694), NHGRI contract U01HG004402, and NIH contract HHSN268200625226C. Infrastructure was partly supported by grant number UL1RR025005, a component of the NIH and NIH Roadmap for Medical Research. Reagents for the glycated albumin assays were donated by the Asahi Kasei Corporation. Reagents for the fructosamine assays were donated by Roche Diagnostics Corporation. S.J.L. was supported by an institutional training grant from the NIH/NHLBI (T32 HL007024). E.S. was supported by NIH National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK) grants K24DK106414 and R01DK089174. A.K. was supported German Research Foundation, Deutsche For-schungsgemeinschaft (KO 3598/3-1). The CARDIA study is conducted and supported by the NHLBI in collaboration with the University of Alabama at Birmingham (HHSN268201300025C and HHSN268201300026C), Northwestern University (HHSN268201300027C), University of Minnesota (HHSN268201300028C), Kaiser Foundation Research Institute (HHSN268201300029C), and The Johns Hopkins University School of Medicine (HHSN268200900041C). CARDIA is also partially supported by the Intramural Research Program of the National Institute on Aging (NIA) and an intra-agency agreement between NIA and NHLBI (AG0005). Genotyping was funded as part of the NHLBI Candidate Gene Association Resource (N01-HC-65226) and the NHGRI Gene Environment Association Studies (GENEVA) (U01-HG004729, U01-HG04424, and U01-HG004446). J.C. was supported by NIH NIDDK grants K01DK095928 and P30DK079626 and NIH National Center for Advancing Translational Sciences grant UL1TR000165. Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. S.J.L. and N.M.M. wrote the manuscript. M.L. and A.S.B. performed data analysis and reviewed and edited the manuscript. K.E.N., H.M., A.M., A.P.C., J.S.P., E.B., R.S., L.J.R.-T., and J.C. reviewed and edited the manuscript. P.D., A.K., and E.S. contributed to discussion, provided guidance, and reviewed and edited the manuscript. S.J.L. and M.L. are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
© 2018 by the American Diabetes Association.