An Expanded Genome-Wide Association Study of Fructosamine Levels Identifies RCN3 as a Replicating Locus and Implicates FCGRT as the Effector Transcript

Fernando Riveros-McKay, David Roberts, Emanuele Di Angelantonio, Bing Yu, Nicole Soranzo, John Danesh, Elizabeth Selvin, Adam S. Butterworth, Ines Barroso*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Fructosamine is a measure of short-term glycemic control, which has been suggested as a useful complement to glycated hemoglobin (HbA1c) for the diagnosis and monitoring of diabetes. To date, a single genome-wide association study (GWAS) including 8,951 U.S. White and 2,712 U.S. Black individuals without a diabetes diagnosis has been published. Results in Whites and Blacks yielded different association loci, near RCN3 and CNTN5, respectively. In this study, we performed a GWAS on 20,731 European-ancestry blood donors and meta-analyzed our results with previous data from U.S. White participants from the Atherosclerosis Risk in Communities (ARIC) study (Nmeta = 29,685). We identified a novel association near GCK (rs3757840, βmeta = 0.0062; minor allele frequency [MAF] = 0.49; Pmeta = 3.66 × 10−8) and confirmed the association near RCN3 (rs113886122, βmeta = 0.0134; MAF = 0.17; Pmeta = 5.71 × 10−18). Colocalization analysis with whole-blood expression quantitative trait loci data suggested FCGRT as the effector transcript at the RCN3 locus. We further showed that fructosamine has low heritability (h2 = 7.7%), has no significant genetic correlation with HbA1c and other glycemic traits in individuals without a diabetes diagnosis (P > 0.05), but has evidence of shared genetic etiology with some anthropometric traits (Bonferroni-corrected P < 0.0012). Our results broaden knowledge of the genetic architecture of fructosamine and prioritize FCGRT for downstream functional studies at the established RCN3 locus.

Original languageEnglish
Pages (from-to)359-364
Number of pages6
JournalDiabetes
Volume71
Issue number2
DOIs
Publication statusPublished - Feb 2022
Externally publishedYes

Bibliographical note

Funding Information:
Acknowledgments. The authors thank the staff and participants of the ARIC study for their important contributions. The academic coordinating center thanks the blood donor center staff and blood donors for participating in the INTERVAL trial. Funding. Participants in the INTERVAL randomized controlled trial were recruited with the active collaboration of NHS Blood and Transplant (U.K.; www.nhsbt.nhs.uk), which has supported field work and other elements of the trial. DNA extraction and genotyping was cofunded by the National Institute for Health Research (NIHR), the NIHR BioResource (https://biore-source.nihr.ac.uk), and the NIHR (Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust). The sequencing work was supported by Wellcome Trust grant 206194. The academic coordinating center for INTERVAL was supported by core funding from NIHR Blood and Transplant Research Unit in Donor Health and Genomics (NIHR BTRU-2014-10024), UK Medical Research Council (MR/L003120/1), British Heart Foundation (SP/09/002, RG/13/13/30194, and RG/18/13/33946), and the NIHR (Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust). A complete list of the investigators and contributors to the INTERVAL trial is provided in Di Angelantonio E, Thompson SG, Kaptoge SK, et al.; INTERVAL Trial Group. Efficiency and safety of varying the frequency of whole blood donation (INTERVAL): a randomised trial of 45,000 donors. Lancet 2017;390: 2360–2371. This work was supported by Health Data Research UK, which is funded by the U.K. Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation, and Wellcome. 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), and Department of Health and Human Services (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN2682017000 03I, HHSN2682017 00005I, and HHSN268201700004I), grants R01HL087641, R01HL059367, and R01HL086694; National Human Genome Research Institute contract U01H G004402; and NIH contract HHSN268200625226C. Infrastructure was partly supported by the NIH and NIH Roadmap for Medical Research grant UL1RR025005. This work was funded in part by an “Expanding excellence in England” award from Research England (to I.B.). I.B. further acknowledges funding from Wellcome (WT206194). F.R.-M. received funding from Consejo Nacional de Ciencia y Tecnología México (489672). J.D. is funded by the NIHR and holds a British Heart Foundation Professorship and an NIHR Senior Investigator Award. E.S. was supported by NIH/NHLBI grant K24 HL152440 and NIH/National Institute of Diabetes and Digestive and Kidney Diseases grant R01DK089174. The GTEx Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health and by the National Cancer Institute, National Human Genome Research Institute, NHLBI, National Institute on Drug Abuse, National Institute of Mental Health, and National Institute of Neurological Disorders and Stroke. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 9 October 2020.

Publisher Copyright:
© 2022 by the American Diabetes Association.

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